Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Cardiovascular, Respiratory, and Gastrointestinal Disorders [Hardcover ed.] 0128125322, 9780128125328

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EMERY AND RIMOIN’S PRINCIPLES AND PRACTICE OF MEDICAL GENETICS AND GENOMICS

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EMERY AND RIMOIN’S PRINCIPLES AND PRACTICE OF MEDICAL GENETICS AND GENOMICS Cardiovascular, Respiratory, and Gastrointestinal Disorders Seventh Edition

Edited by Reed E. Pyeritz

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Bruce R. Korf

University of Alabama at Birmingham, Birmingham, AL, United States

Wayne W. Grody

UCLA School of Medicine, Los Angeles, CA, United States

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2020 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and e­ xperience broaden our understanding, changes in research methods, professional ­practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or e­ ditors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-812532-8 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Andre Gerhard Wolff Senior Acquisition Editor: Peter B. Linsley Editorial Project Manager: Pat Gonzalez Production Project Manager: Punithavathy Govindaradjane Designer: Matthew Limbert Typeset by TNQ Technologies

CONTENTS List of Contributors  ix Preface to the Seventh Edition of Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics xiii Preface to Cardiovascular, Respiratory, and Gastrointestinal Disorders  xv

3 Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)  115 Beth L. Roman, Douglas A. Marchuk, Scott O. Trerotola and Reed E. Pyeritz



SECTION 1  Cardiovascular Disorders 1  Congenital Heart Defects  3



Rocio Moran and Nathaniel H. Robin



1.1 Introduction  3 1.2 The Evaluation of the Patient With Congenital Heart Defect  4 1.3 Embryology  5 1.4 Specific Syndromes With Congenital Heart Defect  14 1.5 Genes Responsible for Congenital Heart Malformations as Monogenic Traits  21 1.6 Environmental Causes and the Teratogen Syndromes 21 1.7 Maternal Diabetes  22 1.8 Maternal Cigarette Smoking  22 1.9 Maternal Drug Ingestion  22 1.10 Folic Acid Supplementation  23 1.11 The Adult With Congenital Heart Defect 23 1.12 Empirical Risks for Offspring  24 1.13 Future Developments  24 References 72 Further Reading  75

2 Genetic Cardiomyopathies 

77

Ronald M. Paranal, Polakit Teekakirikul, Carolyn Y. Ho, Diane Fatkin and Christine E. Seidman



2.1 Introduction  77 2.2 Hypertrophic Cardiomyopathy  78 2.3 Dilated Cardiomyopathy  91 2.4 Arrhythmogenic Right Ventricular Cardiomyopathy 98 2.5 Ventricular Noncompaction  100 2.6 Conclusion  102 References 102



3.1 Introduction  115 3.2 Phenotype and Natural History  116 3.3 Genetics  120 3.4 Genotype–Phenotype Correlations in HHT 122 3.5 ALK1 Signaling and HHT Pathogenesis 123 3.6 Animal Models of HHT  124 3.7 Mechanistic Basis of AVM Pathogenesis 125 3.8 Diagnosis  127 3.9 Management  128 Acknowledgments 133 References 133

4 Genetics of Electrophysiologic Disorders  141 Katie A. Walsh and Rajat Deo



4.1 Long QT Syndrome  141 4.2 Brugada Syndrome  151 4.3 Catecholaminergic Polymorphic Ventricular Tachycardia  155 4.4 Arrhythmogenic Right Ventricular Cardiomyopathy 158 4.5 Medical Workup after Sudden Unexplained Death  161 References 163 Further Reading  173

5 Heritable Thoracic Aortic Disease: Single Gene Disorders Predisposing to Thoracic Aortic Aneurysms and Acute Aortic Dissections  175 Shaine A. Morris and Dianna M. Milewicz





5.1 Mechanisms of Heritable Thoracic Aortic Disease Due to Highly Penetrant, Pathogenic Variants in Single Genes 176 5.2 Gene-­Based Clinical Management for Heritable Thoracic Aortic Disease  185 References 191

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vi

CONTENTS

6  The Genetics of Blood Pressure Regulation  197



Henry J. Lin, Xiuqing Guo and Jerome I. Rotter



6.1 Introduction  197 6.2 History  197 6.3 Complexity of Blood Pressure Regulation 199 6.4 Single Gene Conditions with Hypertension or Hypotension  200 6.5 The GWAS Era  201 6.6 Conclusions  205 References 205

10 Capillary Malformation/Arteriovenous Malformation 261 Nicole Revencu, Laurence M. Boon and Miikka Vikkula



7 Genetics and Genomics of Atherosclerotic Cardiovascular Disease  209





Gwenola Boulday and Elisabeth Tournier-­Lasserve

7.1 Introduction  209 7.2 Mouse Models of Atherosclerosis  210 7.3 Candidate Gene Studies in Humans  211 7.4 Family-­Based Studies in Humans  211 7.5 Association Studies in Humans  211 7.6 GWAS Findings for Atherosclerotic Traits 213 7.7 Mendelian Randomization  218 7.8 Genetic Risk Scores and Prediction Algorithms for Personalized Medicine 219 7.9 Summary and Future Directions  220 References 221





12 Cystic Fibrosis 





8.1 Introduction  231 8.2 Development of the Lymphatic System 231 8.3 Disorders of the Lymphatic System  232 8.4 Autosomal Dominant Inheritance  233 8.5 Autosomal Recessive Inheritance  240 8.6 Mosaic Disorders with Lymphatic Phenotype 243 8.7 Genetic Counseling  244 References 244



Christopher J. Cardinale, Michael E. March, Patrick M.A. Sleiman and Hakon Hakonarson

Pascal Brouillard, Nisha Limaye, Laurence M. Boon and Miikka Vikkula



9.1 Introduction  251 9.2 The Venous System  251 9.3 Disorders of the Venous System  252

Summary 285 12.1 Incidence of Cystic Fibrosis  286 12.2 Clinical Features  287 12.3 Genetics  291 12.4 Diagnosis and Differential Diagnosis 304 12.5 Management  306 Acknowledgments 310 References 310

13 Genetic Underpinnings of Asthma and Related Traits 341

9 Disorders of the Venous System  251



285

Joseph M. Collaco and Garry R. Cutting

Sahar Mansour, Silvia Martin-­Almedina and Pia Ostergaard



11.1 Introduction  267 11.2 Clinical Genetics  267 11.3 CCM Molecular Genetics  270 11.4 CCM Protein Partners and Signaling Pathways 272 11.5 Modeling Human CCM Disease in Mouse Models for the Development of ­ Pre-­clinical Trials  275 References 278

SECTION 2  Respiratory Disorders

8 Genetic Disorders of the Lymphatic System  231

10.1 Introduction  261 10.2 Capillary Malformation  261 10.3 Sturge–Weber Syndrome  262 10.4 Capillary Malformation—Arteriovenous Malformation 263 Acknowledgments 265 References 265

11 Cerebral Cavernous Malformations, Molecular Biology, and Genetics  267

Kiran Musunuru, Atif N. Qasim and Muredach P. Reilly



Acknowledgments 257 References 257



Glossary 341 Nomenclature 342 13.1 Introduction  342 13.2 The Genetics of Asthma and Allergic Diseases 343

CONTENTS



13.4 Conclusion  References 354

354



14 Hereditary Pulmonary Emphysema  361 Nestor A. Molfino





Abbreviations 361 14.1 Introduction  361 14.2 Diseases With Airflow Limitation: Definitions 362 14.3 Phenotypic Evaluation in COPD  363 14.4 Cigarette Smoking and COPD  367 14.5 Severe AAT Deficiency  368 14.6 Risk of COPD in Z Allele Heterozygotes 381 14.7 COPD and COPD-­Related Phenotypes in Other Genetic Syndromes  382 14.8 Risk to Relatives for Non-­AAT COPD* 383 14.9 Linkage Analysis  385 14.10 Genetic Association Studies  387 14.11 Animal Models of COPD  389 14.12 Conclusions  391 Acknowledgments 391 References 391 Further Reading  403



17 Gastrointestinal Tract and Hepatobiliary Duct System 465 Eberhard Passarge





Reed E. Pyeritz

15.1 Introduction  405 15.2 Idiopathic Interstitial Pneumonias 406 15.3 Genetic Basis of IIP  409 15.4 Systemic Diseases that can Cause ILD 418 15.5 Other Genetic Diseases that Can Cause ILD 421 15.6 Other Restrictive Lung Diseases  422 15.7 Conclusion  424 References 424



16 Heritable and Idiopathic Forms of Pulmonary Arterial Hypertension  439 Eric D. Austin, John H. Newman, James E. Loyd and John A. Phillips





16.1 Historical Perspectives and Introduction 439 16.2 Nomenclature  440

17.1 Introduction  465 17.2 Embryological Background  465 17.3 Classification of Gastrointestinal Disorders 467 17.4 The GI Microbiome  479 References 480

18 Inflammatory Bowel Disease  485

Susan K. Mathai, David A. Schwartz and Raphael Borie



16.3 Incidence and Prevalence of HPAH and IPAH 440 16.4 Phenotype and Natural History of HPAH and IPAH  441 16.5 Inheritance and Genetics of PAH in Families 442 16.6 Connecting BMPR2 to PAH  445 16.7 Molecular and Cellular Pathogenesis 448 16.8 Diagnosis  450 16.9 Management  452 16.10 Counseling  455 Acknowledgments 456 References 457 Further Reading  462

SECTION 3  Gastrointestinal Disorders

15 Genetic Determinants of Interstitial Lung Diseases 405

vii



18.1 Introduction and Disease Definition 485 18.2 Phenotypic Heterogeneity  487 18.3 Racial and Ethnic Differences  488 18.4 Familial Aggregation  490 18.5 Twin and Spouse Studies  491 18.6 Inferences Regarding Mode of Inheritance 492 18.7 Association of Inflammatory Bowel Disease with Rare Genetic Syndromes 494 18.8 Associations With Other Diseases  496 18.9 Gene and Environmental Interactions 496 18.10 Gene Identification  499 18.11 Meta-­Analysis Across all Genome Scans 501 18.12 Candidate Gene Studies   501

viii

CONTENTS

18.13 Clinical Application of Genetic Information 502 References 502 Further Reading  505

19 Bile Pigment Metabolism and Its Disorders  507 Namita Roy-Chowdhury, Xia Wang and Jayanta Roy-Chowdhury



19.1 Introduction  507 19.2 Formation of Bilirubin  507 19.3 Structure of Bilirubin  509 19.4 Possible Physiologic Benefits of Biliverdin and Bilirubin  510



19.5 Bilirubin-­Induced Neurological Dysfunctions 511 19.6 Disposition of Bilirubin  513 19.7 Bilirubin in Body Fluids  519 19.8 Disorders of Bilirubin Metabolism  519 Acknowledgments 537 References 537 Further Reading  551

Index  555

LIST OF CONTRIBUTORS Eric D. Austin

Vanderbilt University Medical Center, Department of Pediatrics, Division of Allergy, Pulmonary and Immunology Medicine, Nashville, TN, United States

Laurence M. Boon

Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium; Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires St-­Luc, Université catholique de Louvain, Brussels, Belgium

Raphael Borie

Service de Pneumologie A Hopital Bichat, APHP, Paris, France; INSERM U1152, Paris, France

Gwenola Boulday

Université de Paris, NeuroDiderot, INSERM, F-­75019 Paris, France

Xiuqing Guo

David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Division of Genomic Outcomes, Department of Pediatrics, Harbor-­UCLA Medical Center, Torrance, CA, United States

Hakon Hakonarson

Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, United States; Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Abramson Research Center, Philadelphia, PA, United States

Carolyn Y. Ho

Pascal Brouillard

Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium

Cardiovascular Genetics Center and Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States

Christopher J. Cardinale

Nisha Limaye

Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, United States

Joseph M. Collaco

Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Garry R. Cutting

McKusick-­Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Rajat Deo

Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Diane Fatkin

Cardiology Department, St Vincent’s Hospital, Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, Australia

Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium

Henry J. Lin

The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Divisions of Medical Genetics and Genomic Outcomes, Department of Pediatrics, Harbor-­UCLA Medical Center, Torrance, CA, United States; David Geffen School of Medicine at UCLA, Los Angeles, CA, United States

James E. Loyd

Vanderbilt University Medical Center, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Nashville, TN, United States

Sahar Mansour

Professor in Clinical Genetics, SW Thames Regional Genetics Service and St George’s, University of London, London, United Kingdom ix

x

LIST OF CONTRIBUTORS

Michael E. March

Pia Ostergaard

Susan K. Mathai

Ronald M. Paranal

Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, United States Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States; Center for Advanced Heart & Lung Diseases, Baylor University Medical Center at Dallas, Dallas, TX, United States

Associate Professor in Human Genetics, Molecular and Clinical Sciences, St George’s, University of London, London, United Kingdom Department of Genetics, Harvard Medical School, Boston, MA, United States

Eberhard Passarge

Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany

Douglas A. Marchuk

John A. Phillips

Silvia Martin-­Almedina

Reed E. Pyeritz

Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, United States

Vanderbilt University Medical Center, Department of Pediatrics, Division of Medical Genetics and Genomic Medicine, Nashville, TN, United States

Research Fellow, Molecular and Clinical Sciences, St George’s, University of London, London, United Kingdom

Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Dianna M. Milewicz

University of California, San Francisco, San Francisco, CA, United States

Division of Medical Genetics, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States

Nestor A. Molfino

US Medical Expert, Respiratory Medical Affairs, GlaxoSmithKline, Bethesda, MA, United States

Rocio Moran

Department of Pediatrics, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH, United States

Shaine A. Morris

Division of Cardiology, Department of Pediatrics, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, United States

Kiran Musunuru

Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

John H. Newman

Vanderbilt University Medical Center, Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Nashville, TN, United States

Atif N. Qasim

Muredach P. Reilly

Columbia University Medical Center, New York, NY, United States

Nicole Revencu

Center for Human Genetics, Cliniques universitaires St-Luc and Université catholique de Louvain, Brussels, Belgium

Nathaniel H. Robin

Department of Genetics, Pediatrics, and Surgery, University of Alabama at Birmingham, Birmingham, AL, United States

Beth L. Roman

Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, United States

Jerome I. Rotter

David Geffen School of Medicine at UCLA, Los Angeles, CA, United States; The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, Division of Genomic Outcomes, Departments of Pediatrics, Medicine, and Human Genetics, Harbor-­UCLA Medical Center, Torrance, CA, United States

LIST OF CONTRIBUTORS

Jayanta Roy-Chowdhury

Departments of Medicine and Genetics, and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, NY, United States

Namita Roy-Chowdhury

Departments of Medicine and Genetics, and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, NY, United States

David A. Schwartz

Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado School of Medicine, Aurora, CO, United States

Christine E. Seidman

Department of Genetics, Harvard Medical School, Cardiovascular Genetics Center and Cardiovascular Division, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Boston, MA, United States; Howard Hughes Medical Institute, Chevy Chase, MD, United States

Patrick M.A. Sleiman

Center for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, United States

Polakit Teekakirikul

Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital and Chinese University of Hong Kong, Hong Kong

xi

Elisabeth Tournier-­Lasserve

Université de Paris, NeuroDiderot, INSERM, F-­75019 Paris, France; Service de Génétique, Assistance Publique Hôpitaux de Paris, Hopital Lariboisière, Paris, France

Scott O. Trerotola

Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Miikka Vikkula

Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium; Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Université catholique de Louvain, Brussels, Belgium

Katie A. Walsh

Section of Electrophysiology, Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Xia Wang

Departments of Medicine and Genetics, and Marion Bessin Liver Research Center, Albert Einstein College of Medicine, New York, NY, United States

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P R E FAC E TO T H E S E V E N T H EDITION OF EMERY AND RIMOIN’S PRINCIPLES AND PRACTICE OF MEDICAL GENETICS AND GENOMICS The first edition of Emery and Rimoin’s Principles and Practice of Medical Genetics appeared in 1983. This was several years prior to the start of the Human Genome Project in the early days of molecular genetic testing, a time when linkage analysis was often performed for diagnostic purposes. Medical genetics was not yet a recognized medical specialty in the United States, or anywhere else in the world. Therapy was mostly limited to a number of biochemical genetic conditions, and the underlying pathophysiology of most genetic disorders was unknown. The first edition was nevertheless published in two volumes, reflecting the fact that genetics was relevant to all areas of medical practice. Thirty-five years later we are publishing the seventh edition of Principles and Practice of Medical Genetics and Genomics. Adding “genomics” to the title recognizes the pivotal role of genomic approaches in medicine, with the human genome sequence now in hand and exome/ genome-level diagnostic sequencing becoming increasingly commonplace. Thousands of genetic disorders have been matched with the underlying genes, often illuminating pathophysiological mechanisms and in some cases enabling targeted therapies. Genetic testing is becoming increasingly incorporated into specialty medical care, though applications of adequate family history, genetic risk assessment, and pharmacogenetic testing are only gradually being integrated into routine medical practice. Sadly, this is the first edition of the book to be produced without the guidance of one of the founding coeditors, Dr David Rimoin, who passed away just as the previous edition went to press. The seventh edition incorporates two major changes from previous editions. The first is publication of the text in 11 separate volumes. Over the years the book had grown from two to three massive volumes, until the electronic version was introduced in the previous

edition. The decision to split the book into multiple smaller volumes represents an attempt to divide the content into smaller, more accessible units. Most of these are organized around a unifying theme, for the most part based on specific body systems. This may make the book more useful to specialists who are interested in the application of medical genetics to their area but do not wish to invest in a larger volume that covers all areas of medicine. It also reflects our recognition that genetic concepts and determinants now underpin all medical specialties and subspecialties. The second change might seem on the surface to be a regressive one in today’s high-tech world—the publication of the 11 volumes in print rather than strictly electronic form. However, feedback from our readers, as well as the experience of the editors, indicated that access to the web version via a password-protected site was cumbersome, and printing a smaller volume with two-page summaries was not useful. We have therefore returned to a full print version, although an eBook is available for those who prefer an electronic version. One might ask whether there is a need for a comprehensive text in an era of instantaneous internet searches for virtually any information, including authoritative open sources such as Online Mendelian Inheritance in Man and GeneReviews. We recognize the value of these and other online resources, but believe that there is still a place for the long-form prose approach of a textbook. Here the authors have the opportunity to tell the story of their area of medical genetics and genomics, including in-depth background about pathophysiology, as well as giving practical advice for medical practice. The willingness of our authors to embrace this approach indicates that there is still enthusiasm for a textbook on medical genetics; we will appreciate feedback from our readers as well. xiii

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PREFACE TO THE SEVENTH EDITION OF EMERY AND RIMOIN’S PRINCIPLES

The realities of editing an 11-volume set have become obvious to the three of us as editors. We are grateful to our authors, many of whom have contributed to multiple past volumes, including some who have updated their contributions from the first or second editions. We are also indebted to staff from Elsevier, particularly Peter Linsley and Pat Gonzalez, who have worked patiently with us in the conception and production of

this large project. Finally, we thank our families, who have indulged our occasional disappearances into writing and editing. As always, we look forward to feedback from our readers, as this has played a critical role in shaping the evolution of Principles and Practice of Medical Genetics and Genomics in the face of the exponential changes that have occurred in the landscape of our discipline.

P R E FAC E TO C A R D I O V A S C U L A R , RESPIRATORY, AND GASTROINTESTINAL DISORDERS This volume of Principles and Practice of Medical Genetics and Genomics presents topics focused on the genetics and genomics of the cardiovascular, gastrointestinal, and pulmonary systems. Three of the authors (Eberhard Passarge and Namita and Jayanta Roy Chowdhury) have composed and updated their chapters since the first edition of this treatise. Due to the recognition of the evolution of genomic, not just genetic, applications, a number

of new chapters required addition since the sixth edition, including thoracic aortic disease and cerebral cavernous malformations. The knowledge and perspectives gained from the chapters in this volume inform the diagnosis, management, and prognosis of the disorders in these three organ systems. Reed E. Pyeritz, MD, PhD

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SECTION

Cardiovascular Disorders

1

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1 Congenital Heart Defects Rocio Moran,1 Nathaniel H. Robin2 1Department

of Pediatrics, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH, United States, 2Department of Genetics, Pediatrics, and Surgery, University of Alabama at Birmingham, Birmingham, AL, United States

1.1 INTRODUCTION Congenital heart defects are both common and serious. With an estimated prevalence of approximately 8 in 1000 they are the most common birth defect worldwide, and they are the most common cause of birth defect–related death [1]. As a result of advances in echocardiography, fetal echocardiography, cardiac catheterization, electrophysiology, and improving surgical techniques and approaches, many individuals with even the most severe heart lesions now survive to adulthood and lead productive lives [2]. This has raised awareness for the need to identify genes involved in all forms of congenital heart disease, isolated as well as syndromic, as patients and their families are asking for information regarding their risks of having a child with a congenital heart defect [3]. While the majority of heart defects are isolated, about one-third occurs as one component of a genetic syndrome [4]. Often, it is the congenital heart lesion that is the presenting finding that alerts the health-care team to the possibility of a genetic syndrome. As with any patient with a birth defect, a primary role of the medical geneticist is to assess whether the finding is an isolated finding or represents one manifestation of an underlying syndrome. A syndrome is typically suspected when the heart lesion is associated with findings identified on the medical, prenatal or family history, or specific dysmorphic findings (major and minor anomalies) on physical examination. In these cases, confirmatory testing may be ordered, be it chromosome microarray or single/multi gene analysis. For other cases with additional findings

that are not in a recognizable pattern, a chromosome microarray should be considered as a comprehensive first-line genetic “screening test” (with prenatal specific and postnatal specific arrays available) [5]. Making an accurate genetic diagnosis for a patient with a congenital heart defect has several clear benefits including the ability to provide medical management recommendations, accurate counseling on prognosis, precise causality, and recurrence risk for both the parents and the child [6,7]. While the same benefits exist when it is determined that the heart lesion is isolated, there is unfortunately simply less information. Recurrence risk counseling, for example, remains based on empiric data [3]. Despite advances in basic science and technology, our understanding of the genetic basis of congenital heart defects is emerging. That is because congenital heart defects are not variable manifestations of a single developmental aberration. Rather, they are an etiologically heterogeneous collection of malformations, with overlapping genetic and environmental factors. Further hindering genetic discovery is the fact that it is rare for isolated heart defects to present with ­Mendelian inheritance, so most of the progress in this area has been made using animal models [8]. However, as our understanding of the underlying genetic etiology advances, it highlights the importance of follow-up of undiagnosed patients. This chapter will provide an overview of congenital heart defects from a perspective most relevant to the clinical geneticist. Cardiac embryology will be reviewed

Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics. https://doi.org/10.1016/B978-0-12-812532-8.00001-X Copyright © 2020 Elsevier Inc. All rights reserved.

3

4

SECTION 1 

Cardiovascular Disorders

and correlated with specific cardiac lesions. We will review the common genetic syndromes that have a cardiac defect as a major manifestation, categorized by etiology: chromosomal/aneuploidy syndromes, segmental chromosomal deletion/duplication syndromes, single gene mutations, and teratogenic. Lastly, recurrence risk counseling will be reviewed. 

1.2 THE EVALUATION OF THE PATIENT WITH CONGENITAL HEART DEFECT For the physician caring for the patient with a congenital heart defect, an important first step is to determine whether there is an underlying syndrome or if the congenital heart defect occurred as an isolated birth defect. Appropriate identification of a syndrome if present can direct the team to investigate for other organ system involvement, provide the team with important prognostic information, particularly with regards to natural history, as well as provide reproductive risk counseling for the patient or family [9]. This first step can be challenging as patients can present anytime from prenatal referrals based on abnormal imaging to the adult patient seeking recurrence risk information. While some genetic syndromes can be readily recognized through history and physical examination, other syndromes often have variable manifestations and phenotypes that can be less apparent at birth or become less obvious with age. Therefore, the diagnostic evaluation must be approached with this continuum in mind. The patient’s medical history can be rich with diagnostic clues and it is from this foundation that the differential diagnosis can be established to guide testing strategies. Regardless of age, a careful review of the patient’s medical history, prenatal history, family history, previous evaluations if obtained can often provide the first clues in determining whether the heart defect is syndromic or isolated. The physical examination of the patient should seek out patterns of major and minor anomalies. It is important to note that the best clues to an underlying diagnosis are not always the most obvious anomalies nor those with the most significant impact on a patient’s health, but the rarest or most atypical [10]. Minor anomalies can be helpful diagnostic clues to an underlying genetic disorder and can be instrumental in directing genetic testing options. After review of the history, and performing a physical examination, additional investigations are often

necessary to determine if the heart defect is isolated or associated with extracardiac manifestations. Additional evaluations can include, but are not limited to, head ultrasound or brain MRI, renal ultrasound, hearing evaluation, dilated eye examination, or skeletal imaging. Identification of additional anomalies can be applied to the differential diagnosis and further refine the genetic testing strategy. In those with obvious patterns of malformations suggestive of aneuploidy, such as Trisomy 21 or Turner syndrome, a standard chromosome analysis should be obtained. Those individuals with recognized microdeletion syndromes should undergo chromosome microarray. It is important to note that some microdeletion syndromes can be identified by fluorescence in situ hybridization (FISH) of the region of interest. However, FISH probes may be larger than some microdeletions and could be missed via this technology. Therefore, it is recommended that individuals presenting with microdeletion syndromes that have not been FISH confirmed in other family members or have not had testing, a full chromosome microarray should be considered. For those patients with extracardiac anomalies suspected of single gene disorders, single gene sequencing, usually accompanied by deletion duplication studies of the gene in question are appropriate. Disorder specific panels can also be considered as a cost-effective strategy in interrogating genes with common presentations. In these patients, genetic counseling is an important component of the evaluation to discuss outcomes of testing and address variant of undetermined clinical significance. For example, a patient suspected of a Noonan spectrum disorder would benefit from a RASopathy panel after genetic counseling. For some patients, depending on the clinical scenario, exome sequencing is proving to have clinical utility as well (al, 2016). As our understanding of the genetic etiology of congenital heart defects improves, more comprehensive cardiac panels are an additional consideration with the potential for a high diagnostic rate [11].While these panels do not yet differentiate isolated from those with extracardiac anomalies, the reported diagnostic yield has been high. For those cases with multiple anomalies but without a recognizable syndrome, chromosome microarray should be considered as a first-line screening test. For additional information, previous volumes address chromosome microarray testing in more detail.

CHAPTER 1 

In the event a specific genetic diagnosis is not made, follow-up of the patient should be arranged. Our knowledge and understanding of the genetics underlying birth defects is advancing at a rapid pace with new and affordable molecular technologies to accurately identify underlying genetic abnormalities. Reevaluation of undiagnosed patients is an important part of the evaluation strategy. This is particularly important for the adult patient who may not have had access to new testing technologies. 

1.3 EMBRYOLOGY A discussion of embryology is important to the understanding of isolated and syndromic congenital heart defects. The cardiovascular system is the first major system to function in the embryo as a result of the nutritional and oxygen demands made by the growing embryo that cannot be sustained by diffusion alone. Two distinct heart fields that share a common origin appear to contribute to the developing heart identified as the first and second heart fields [12]. By week three in humans, cells from the first heart field coalesce along the ventral midline to form the primitive heart tube. As the heart tube develops, cells from the second heart field migrate in and with rightward looping of the heart tube populate much of the outflow tract, future right ventricle, and atria [13]. Precursors of the left ventricle are largely derived from the first heart field. Both first and second heart fields are regulated by bone morphogenic proteins (BMPs), fibroblast growth factors, Wnt and Notch proteins, from signals that arise from the adjacent endoderm [8]. Once formed, the primitive heart tube must break the preexisting L-R symmetry and undergo a series of septation events that culminate in the formation of a four-chambered heart. L-R symmetry is first broken at 3 weeks with the rightward looping of the heart tube that occurs due to the rapid growth of the bulbus cordis and the outer curvature of the right ventricle. The mechanisms of this looping are largely unknown in humans (Fig. 1.1A–E). More than 40 genes have been associated with L-R patterning in mammals and there are approximately 10 genes currently implicated in humans [14]. (See Table 1.1.) During the fourth week, endocardial cushions begin to form the partitioning of the atrioventricular canal. The endocardial cushions form from the cardiac jelly, fuse with the developing atrial septum and muscular

Congenital Heart Defects

5

interventricular septum, remodel and form the atrioventricular valves and septa. Transforming growth factor B, bone morphogenetic proteins (BMP2A and BMP4) and ChALK2 have been implicated in the process [15]. PitX2, GATA4, and FOG-2 through its interaction with GATA4 are also involved in the formation of the atrioventricular septum [16]. Atrial septation occurs through the growth of two septa: the septum primum that grows from the ventral and posterior walls of the atrium, and the septum secundum. As the atria enlarge, the septum primum grows toward the developing atrioventricular canal, later divided by the superior and inferior endocardial cushions. Eventually, the septum primum fuses with the atrioventricular cushions narrowing the opening between the two atria, which is then defined as the ostium primum. The septum secundum grows adjacent to the septum primum as a thick muscular fold. The septum secundum partly overlaps the septum primum and the flap-like opening is the foramen ovale [17] (Fig. 1.2E1–H1). Nkx2.5 in mouse models is required for normal chamber formation and in humans, mutations in NKX2.5 are associated with septal and conduction defects [18]. TBX5, the gene implicated in Holt–Oram syndrome is also essential for normal atrial formation and may modulate NKX2.5 transcriptional activity [19]. Additional genes implicated in abnormal atrial septal formation are listed in Table 1.2. The atria develop on the left and right sides of the heart and are thus truly lateralized structures. The two ventricles, on the other hand, develop from the single ventricle and bulbus cordis. Ventricular septation begins at the floor of the primitive ventricle through the proliferation of the interventricular septum. A foramen exists until the end of week seven with the formation of the membranous part of the interventricular septum with tissue contributed from the right and left bulbar ridges, and the endocardial cushion [20] (Fig. 1.3A–E). This septum eventually fuses with the aortopulmonary septum resulting with alignment and communication of the right ventricle with the pulmonary trunk and the aorta with the left ventricle. Failure of this process results in the common and relatively minor membranous ventricular septal defect (VSD). Although VSDs are the most common congenital heart lesion, familial clustering has been described only in rare instances and single gene disorders have yet to be identified. Additional genes implicated in septal defects are listed in Table 1.2.

6

SECTION 1 

Cardiovascular Disorders

(A)

(B) Foregut

(C)

1st pharyngeal arch artery

Neural groove

Future forebrain 1st pharyngeal arch artery

Neural fold

1st pharyngeal arch artery

Primordial pharynx

Epicardium

Amnion

Amnion

Myocardium

Bulbus cordis

Sites of fusion of endocardial heart tubes

Ventricle

Pericardial cavity

Endocardium Heart tube Pericardial cavity

Myocardium Primordial atrium

Endocardial heart tubes

Cardiac jelly

Wall of umbilical vesicle Left vitelline vein

(D) Neural fold

Bulbus cordis

Cavity of umbilical vesicIe

(E)

Neural groove

2nd pharyngeal arch artery

1st pharyngeal arch artery

Truncus arteriosus

Ventricle Primordial atrium

Future left ventricle

Truncus arteriosus

Future right ventricle

Primordial atrium Common cardinal vein

Sinus venosus

Umbilical vein

Umbilical vein

Vitelline vein

Figure 1.1  Ventral views of the developing hear and pericardial region.

Most of the wall between the ventricles comprises the myocardium, which becomes part of the pump chamber. Much of the surface is trabeculated, giving it a weblike appearance. The right ventricle is distinguished from the left by the coarser structure of the trabeculae. The programmed cell death involved in this process is a likely factor in the appearance of holes through the

wall, allowing blood to cross from left to right after birth. These muscular VSDs often close spontaneously as hypertrophy of the surrounding muscle obstructs the flow. Membranous VSDs are sometimes closed secondarily by valve tissue from the tricuspid valve. In genetic counseling terms, these resolving heart murmurs are significant. Failure of equal and appropriate growth of

CHAPTER 1 

Congenital Heart Defects

7

TABLE 1.1  Laterality defects and congenital heart defects

Other Reported Anomalies

Gene

Gene Function

Cardiac Anomalies

ACVR2B

Member of transforming growth factor-beta (TGFbeta) superfamily of structurally related signaling proteins Found to be differentially expressed by the ciliated cells of frog epidermis and in skin fibroblasts from humans  Member of the epidermal growth factor (EGF)-Cripto, Frl-1, and Cryptic (CFC) family. Plays key role in intercellular signaling pathways during vertebrate embryogenesis including left-right asymmetry in the heart Member of a subfamily of EGF-related protein Member of the TGF-beta family of proteins. Plays a role in left-right asymmetry determination of organ systems during development The MMP21 gene encodes a member of the matrix metalloproteinase superfamily that is known to hydrolyze extracellular matrix components

Transposition of the great Polysplenia, asplearteries (TGA), double nia, midline liver, outlet right ventricle malrotation (DORV), ventricular inversion, aberrant systemic venous return Dextrocardia, complex Situs inversus viscecongenital heart malrum, midline liver, formation (in 1 patient), inverted spleen, TGA, anomalous pulmonormal ciliary strucnary drainage  ture and function 

CFAP53

CFC1

CRELD1

LEFTY2

MMP21

Dextrocardia, right atrial isomerism, left atrial isomerism, TGA, DORV, aberrant systemic venous return

OMIM

Autosomal dominant (AD)

613751

Autosomal recessive (AR)

614779

Holoprosencephaly, AD, reduced agenesis of the penetrance corpus callosum, microcephaly, malrotation, polysplenia, asplenia, neural tube defects, pulmonary isomerism

Atrioventricular septal None defect (AVSD), dextrocardia, DORV Hypoplastic left heart, Malrotation, midline AVSD, dextrocardia, liver, polysplenia aberrant systemic venous return

Dextrocardia, TGA, pulmonary atresia, bilateral superior vena cava, aortic arch abnormalities, septal defects, atrioventricular canal defect, total anomalous pulmonary venous return (TAPVR), pulmonary trunk defects, valvular stenosis 

Inheritance

AD

Situs inversus, situs AR ambiguous, midline liver 

605194 605376

607170 606217 601877

616749

Continued

8

SECTION 1 

Cardiovascular Disorders

TABLE 1.1  Laterality defects and congenital heart defects—cont’d

Other Reported Anomalies

Gene

Gene Function

Cardiac Anomalies

NODAL

Member of TGF-b superfamily. Plays a key role in specification and patterning in mammalian embryogenesis PKD1L1 represses PKD2 in the node and that nodal flow relieves this repression on the left side only, activating PKD2 and initiating a signaling cascade that results in left-sided NODAL activity Putative member of the TRAP family involved in early embryonic patterning expressed in brain, heart, skeletal muscle, kidney, placenta, and peripheral blood leukocytes Member of the ZIC family of C2H2-type zinc finger proteins. Functions as a transcription factor in early stages of left-right asymmetry

DORV, TGA, TAPVR, Holoprosencephaly, AR partial anomalous pulmalrotation, asplemonary venous return, nia, hydronephrosis ASD, VSD, aortic coarctation, persistent ductus arteriosus (PDA) Complex congenital Situs inversus visAR heart disease, atrial cerum  situs solitus, atrial situs ambiguus, unbalanced AVSD, ventricular septal defect, left ventricular hypoplasia, DORV, malposition of the great arteries, pulmonary atresia 

270100 601265

TGA, VSD, aortic coarctation

Mental retardation, microcephaly

AD, reduced penetrance

608771 608808

TGA, DORV, right atrial isomerism, TAPVR, PDA, aberrant systemic venous return

Asplenia, biliary atresia, vertebral anomalies, anal anomalies, malrotation

X-linked

300265 306955

PKD1L1

THRAP2

ZIC3

the two ventricles may result from abnormal heart looping, abnormal inlet orifices, or obstruction of the outlet vessels. The most serious is failure of growth of the left ventricle, known as hypoplastic left heart (HLHS). Mutations in HAND1 and GJA1 have both been implicated in the development of HLHS [21]. A more specific defect of development of the right ventricular muscular wall results in a distended saclike right ventricle with various names, including right ventricular dysplasia and Uhl anomaly.

Inheritance

OMIM

617205

Partitioning of the outflow tract begins during the fifth week. There are two pairs of ridges (bulbar and truncal) that fuse to form a spiral septum that separates the aortic and pulmonary outflow tracts. These ridges are derived from cardiac neural crest cells. Abnormal contributions of cells from the cardiac neural crest have been implicated in the 22q11 phenotype and ablation of the cardiac neural crest cells in chick embryos results in outflow tract and right ventricular hypoplasia [22]. Complete failure of septation results in a common

CHAPTER 1  Septum secundum (upper limb) Foramen secundum Oval foramen (foramen ovale) Valve of oval foramen (derived from septum primum)

Septum secundum (lower limb)

E1 Septum secundum (upper limb)

Oval foramen

Septum secundum (lower limb)

F1

Degenerating part of septum primum

Oval foramen closed by valve of oval foramen

G1 Superior vena cava

Oval foramen open Valve of oval foramen Inferior vena cava (carrying welloxygenated blood)

H1

Figure 1.2  Illustrations of the progressive stages of the partitioning of the primordial atrium.

arterial trunk or, as it is more commonly known, persistent truncus arteriosus This spiraling separation ultimately results in placing the aorta on the left and the pulmonary artery on the right (Fig. 1.4A–H). If this

Congenital Heart Defects

9

process is incomplete or distorted, the aorta overrides the upper margin of the ventricular septum, the membranous septum remains incomplete, and the outlet of the right ventricle is narrowed. These malformations combine to cause hypertrophy of the right ventricle. The combination of an aorta overriding a VSD with right ventricular outflow tract obstruction and right ventricular hypertrophy constitutes the Tetralogy of Fallot. If the process is further distorted, the aorta lies predominantly over the right ventricle and the term double-outlet right ventricle (DORV) is applied. This anomaly may also form part of the spectrum that results in an abnormal plane of the outflow septum such that the anterior vessel becomes connected to the left ventricle and the morphologic aorta to the right ventricle. Transposition of the great arteries (TGA) is thus distinct from most outflow defects in that it results from a malformation of the septum rather than a neural crest migration anomaly. This distinction is reflected in the syndrome associations and recurrence risks. Malformations involving the major vessels connected to the heart are generally included with heart defects in discussions of cause and recurrence risk. Systemic venous drainage is rarely of major genetic importance, although absence of the last segment of the inferior vena cava and its replacement by an azygous connection to the superior vena cava is a valuable diagnostic sign of lack of a morphologic right atrium in a left isomerism sequence. Abnormality of pulmonary venous drainage is of much greater significance. Four pulmonary veins rendezvous with an outgrowth from the back of the left atrium. The coalescence incorporates into the posterior wall, producing four separate orifices. If one or more orifices are displaced, the term anomalous pulmonary venous drainage is applied, which may be partial, involving up to three vessels, or complete, when it is known as total anomalous pulmonary venous return (TAPVR). The ductus arteriosus (arterial duct) connects the right ventricular outflow to the descending aorta. It is usually called the sixth aortic arch, but it is morphologically distinct and has evolved to have an oxygen-sensitive lining, which allows it to constrict and occlude after birth, allowing the pulmonary circulation to open. It often stays open after birth, particularly in preterm infants, in whom the duct is not mature. The persistent ductus arteriosus (PDA) is, therefore, one of the most common anomalies of the cardiovascular system in postnatal life, but an essential physiologic structure in utero.

10

SECTION 1 

Cardiovascular Disorders

TABLE 1.2  Nonsyndromic Congenital Heart Disease Heart Defect

Gene

Atrioventricular CRELD1 septal defect GDF1

GJA1

Hypoplastic left GJA1 heart HAND1

Septal defects

NKX2.5 CITED2 GATA4 HAND1

HAND2

TBX20 ACTC1 MYH6 THRAP2

Double outlet CFC1 right ventricle GDF1

NKX2.5

Gene Function

OMIM

Member of a subfamily of epidermal growth factor (EGF)-related protein. Member of the bone morphogenetic protein (BMP) family and the TGFbeta superfamily. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies suggest that this protein is involved in the establishment of left-right asymmetry in early embryogenesis. Member of the connexin gene family. Major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. Member of the connexin gene family. Major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. Part of a family of basic helix-loop-helix transcription factors. One of two HAND proteins asymmetrically expressed in the developing ventricular chambers. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries. Functions in early determination of the heart field and may play a role in formation of the cardiac conduction system Inhibits transactivation of HIF1A-induced genes by competing with binding of HIF1a to p300-CH1 Family of zinc-finger transcription factors. Regulates genes involved in embryogenesis and in myocardial differentiation and function. Part of a family of basic helix-loop-helix transcription factors. One of two HAND proteins asymmetrically expressed in the developing ventricular chambers. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries. Part of a family of basic helix-loop-helix transcription factors. One of two HAND proteins asymmetrically expressed in the developing ventricular chambers. Working in a complementary fashion, they function in the formation of the right ventricle and aortic arch arteries. Interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5. Actins are highly conserved proteins that are involved in various types of cell motility and are major constituents of the contractile apparatus of the heart. Encodes the alpha heavy chain subunit of cardiac myosin. Putative member of the TRAP family involved in early embryonic patterning expressed in brain, heart, skeletal muscle, kidney, placenta, and peripheral blood leukocytes. Member of the EGF-Cripto, Frl-1, and Cryptic (CFC) family. Plays a key role in intercellular signaling pathways during vertebrate embryogenesis including left-right patterning in the heart. Member of the BMP family and the TGF-beta superfamily. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies suggest that this protein is involved in the establishment of left-right asymmetry in early embryogenesis. Functions in early determination of the heart field and may play a role in formation of the cardiac conduction system.

606217 600309

121014

121014 241550 241550 602406

108900 600584 602937 607941 241550 602406

602407

611363 612794 160710

605194

217095

600584

CHAPTER 1 

Congenital Heart Defects

11

TABLE 1.2  Nonsyndromic Congenital Heart Disease—cont’d Heart Defect

Gene

Gene Function

Tetralogy of Fallot

GATA4

Member of the GATA family of zinc-finger transcription factors. Thought 187500 to regulate genes involved in embryogenesis and in myocardial differen- 600576 tiation and function. Ligand for the receptor notch 1. 187500 601920 Functions in early determination of the heart field and may play a role in 600584 formation of the cardiac conduction system. Member of the FOG family of transcription factors. Modulates the activity 187500 of GATA family proteins. 603693 Member of the BMP family and the TGF-beta superfamily. The mem600309 bers of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies suggest that this protein is involved in the establishment of left-right asymmetry in early embryogenesis. Binds to hepatocyte nuclear factor-1alpha (HNF-1alpha) for cooperative 617912 activation of the intestinal lactase-phlorizin hydrolase promoter.  Member of the Notch family of proteins which function as a receptor for 109730 membrane bound ligands and may play multiple roles during development. SMAD proteins are signal transducers and transcriptional modulators 614823 that mediate multiple signaling pathways. This protein functions in the negative regulation of BMP and TGF-beta/activin-signalling. Activator of MAP3K7/TAK1, required for the IL-1 induced activation of 614980 nuclear factor kappaB and MAPK8/JNK. Forms a kinase complex with TRAF6, MAP3K7, and TAB1 and serves as an adaptor that links MAP3K7 and TRAF6. Protein product is one of the two components of elastic fibers 130160 185500

JAG1 NKX2.5 ZFPM2/ FOG2 GDF1

Bicuspid aortic valve

GATA5 NOTCH1

SMAD6

TAB2

Supravalvular aortic stenosis Transposition of the great arteries

Elastin

CFC1

GDF1

THRAP2

Aortic coarctation

THRAP2

Member of the EGF-Cripto, Frl-1, and Cryptic (CFC) family. Plays a key role in intercellular signaling pathways during vertebrate embryogenesis including left-right patterning in the heart. Member of the BMP family and the TGF-beta superfamily. The members of this family are regulators of cell growth and differentiation in both embryonic and adult tissues. Studies suggest that this protein is involved in the establishment of left-right asymmetry in early embryogenesis. Putative member of the TRAP family involved in early embryonic patterning expressed in brain, heart, skeletal muscle, kidney, placenta, and peripheral blood leukocytes. Putative member of the TRAP family involved in early embryonic patterning expressed in brain, heart, skeletal muscle, kidney, placenta, and peripheral blood leukocytes.

OMIM

217095 605194 600309

608771 608808 608771 608808

12

SECTION 1 

Cardiovascular Disorders

(A)

(B) Pharyngeal arch arteries (aortic arches)

Atrium

Sinus venosus

Truncus arteriosus

Pulmonary trunk

Conus arteriosus

Bulbus cordis

Bulbar ridge

Atrioventricular canal Aortic vestibule Interventricular foramen

Left ventricle Right ventricle

Interventricular septum

Primordial interventricular septum Interventricular groove

(C)

(D)

Pulmonary trunk

Arch of aorta

Right bulbar ridge

Left bulbar ridge

Interventricular foramen

Left atrioventricular canal

Fused endocardial cushions

Free edge of muscular part of interventricular septum

(E)

Left bulbar ridge

Right atrioventricular canal

Aorticopulmonary septum

Right bulbar ridge Endocardial cushion Right ventricle Membranous part of interventricular septum

Muscular part of interventricular septum

Figure 1.3  Illustrations of the incorporation of the bulbus cordis into the ventricles and the partitioning into the aorta and pulmonary trunk.

This brief overview has focused on anomalies relevant to a group of major defects that are serious after birth but compatible with intrauterine survival. The dependence of the embryo and fetus on a

functional circulation means that any systemic defect that would compromise more generalized intrauterine development and/or function is lost at an early stage. 

CHAPTER 1 

(A)

(B)

Pharyngeal arch 3rd 4th arteries

Congenital Heart Defects

(C)

6th Truncal ridge

1

Truncus arteriosus

1

2

Bulbus cordis

3 2

Bulbar ridges

Ventricle 3 Left atrioventricular canal

(D)

(E)

Aorta (A)

Pulmonary trunk (PT)

(F)

Aorticopulmonary septum

1 2

PT A

1

3

A

PT

2 A

3

(G)

Pulmonary trunk Aorta

Right atrioventricular canal

PT

Interventricular septum

(H)

Aorticopulmonary septum

Ascending aorta Left pulmonary artery Pulmonary trunk Aorta Aorticopulmonary septum Figure 1.4  Partitioning of the bulbus cordis and truncus arteriosus.

13

14

SECTION 1 

Cardiovascular Disorders

1.4 SPECIFIC SYNDROMES WITH CONGENITAL HEART DEFECT It is not surprising given the complexity of cardiovascular embryology and the large number of genes involved in normal heart development that the list of syndromes associated with congenital heart defects is not short. [NaN–14] contains a list of well-researched syndromes as grouped by their cardiac malformation. This appendix draws heavily on the work published by the chapter’s previous authors and is recommended as a reference source for the evaluation of syndromic causes of congenital heart defects. Common syndromes are discussed in more detail in the following sections.

1.4.1 Chromosomal Disorders While the application of array-based comparative genomic hybridization (aCGH) has quickly become the diagnostic screening test of choice, chromosome analysis continues to be clinically useful particularly as a prenatal screening test and in the patient with findings suggestive of an aneuploidy syndrome. We have highlighted in the next section those aneuploidy syndromes commonly encountered by the medical ­ geneticist.

1.4.1.1 Trisomy 21 (Down Syndrome) Down syndrome is one of the most common genetic syndromes, with an estimated birth prevalence of 1 per 700 live births [23]. Clinical features can include midface hypoplasia, epicanthal folds, upslanting palpebral fissures, Brushfield spots on the irides, single palmar crease, brachydactyly, and increased sandal gap. Approximately 40% of patients with Down syndrome will have a congenital heart defect and of these, almost half will have the otherwise rare atrioventricular septal defect (AVSD) [24]. Tetralogy of Fallot may be found in 10%–15%. To date no single gene or set of genes on chromosome 21 has been shown to contribute to the risk of heart defects in Down syndrome. Recently, mutations in CRELD1 have been identified in patients with Down syndrome and AVSD, implicating CRELD1 mutations, together with Trisomy 21 and possible environmental factors as a risk susceptibility gene for AVSD in Down syndrome [25]. For additional information, previous volumes address Trisomy 21 in more detail. 

1.4.1.2 Trisomy 18 (Edwards Syndrome) Trisomy 18 is the second most common autosomal aneuploidy after Down syndrome. This is an important bedside diagnosis to confirm due to the very poor prognosis and markedly diminished life expectancy that may influence medical management. Interestingly, recent studies have suggested that more aggressive management is becoming more common, despite this well-recognized poor prognosis. The craniofacial manifestations of an infant with Trisomy 18 may be subtle, but typically include prominent occiput, low-set ears, micrognathia, small palpebral fissures, short sternum, and typical finger clenching (Fig. 1.5). Heart defects are a recognized association and a cause of early demise. There is evidence that suggests heart defects are often more complex in boys than in girls with Trisomy 18 and associated with increased mortality [26]. For additional information, previous volumes address Trisomy 18 in more detail.  1.4.1.3 Trisomy 13 (Patau Syndrome) The birth incidence of Trisomy 13 is about 1 in 7000. Survival beyond the first year of life is rare [27]. The characteristic clinical features are postaxial polydactyly, cleft lip and palate (often bilateral and severe), and hypotelorism associated with holoprosencephaly. There is a high incidence of cardiac defects, in particular atrial septal defects (ASDs) and ventricular septal defects. Disturbance of cardiac position, including dextrocardia, is common, suggesting a role for a gene or genes on chromosome 13 in laterality development [28]. Appropriate identification of Trisomy 13 is important for recurrence risk counseling as well as directing clinical management, as aggressive medical interventions are not recommended given the high mortality rate and poor prognosis in long-term survivors. For additional information, previous volumes address Trisomy 13 in more detail.  1.4.1.4 Turner Syndrome (Ulrich–Turner Syndrome) Turner syndrome has a high birth prevalence of ∼1 in 1850 live female births. In addition, a large proportion of affected fetuses are lost as early miscarriages, many of which can be attributed to the presence of a severe congenital heart defects, particularly hypoplastic left heart [15]. For live births, ∼ 10% of Turner syndrome females have a clinically evident heart defect, with an additional 10% having an anomaly on echocardiogram,

CHAPTER 1 

Congenital Heart Defects

15

Figure 1.5  Facial dysmorphology and characteristic fist clenching and polydactyly seen in Trisomy 18.

such as a bicuspid aortic valve. The most common abnormality is bicuspid aortic valve (16%) and coarctation of the aorta (11%); however, structural defects such as partial anomalous pulmonary venous return and atrial and ventricular septal defects are also seen [29]. And while the congenital heart defect may be detected and repaired in childhood, young adults with Turner syndrome require lifelong cardiac follow-up as studies show an increased incidence of aortic dissection in adulthood [30]. Additional findings are variable and include short stature, gonadal dysgenesis, and a variable dysmorphic appearance with neck webbing (pterygium colli), downslanting palpebral fissures, and lowset ears (Fig. 1.6). Patients with ring X chromosomes are at risk for intellectual disability although classic Turner patients can struggle with learning disabilities. For additional information, previous volumes address Turner syndrome in more detail. 

1.4.2 Microdeletions/Microduplication Syndromes

Advances in molecular cytogenetic technology have significantly increased the ability to detect smaller and smaller chromosomal imbalances. This includes both FISH and, more recently, aCGH. aCGH has quickly become the most important diagnostic screening tool in patients with congenital heart disease who do not have a genetic syndrome readily identified by clinical

examination [31]. While the identification of copy number variants of unknown clinical significance has been a significant limitation of aCGH, array technology has been instrumental in defining the loss or gain of chromosomal material with such detail as to permit knowing which gene/s are involved. This has led to further identification of genes that may have critical roles in both syndromic and nonsyndromic congenital heart defects.

1.4.2.1 22q11 Deletion Syndrome 22q11 deletion syndrome is the most common human chromosomal deletion syndrome occurring in approximately 1 per 4000–6000 live births [32]. Clinical features include learning disabilities/impairments, palate anomalies (including velopharangeal insufficiency (VPI)), characteristic facial appearance (Fig. 1.7A–C), neonatal hypocalcemia, thymic hypoplasia, and immune deficiencies. Approximately 15% of cases are familial segregating as an autosomal dominant (AD) trait with marked variability. While the deletion is visible by routine G-banded cytogenetic testing in some, about two-thirds of cases require FISH testing to confirm the diagnosis. Therefore, a clinical suspicion is required. The most commonly reported heart defects include Tetralogy of Fallot, Tetralogy of Fallot with pulmonary atresia, ventricular septal defect, interrupted aortic arch (type B), and truncus arteriosus [33]. Individuals with a cardiac defect and an anomaly of the aortic arch are more

16

SECTION 1 

Cardiovascular Disorders

Figure 1.6 Wide, short neck and facial dysmorphology ­commonly seen in Turner syndrome.

likely to harbor a 22q11 deletion than those with other heart defects such as DORV or TGA. 22q11 deletions are rarely identified in such nonconotruncal defects [9]. Most individuals with 22q11 deletion syndrome harbor either a 3 or 1.5 Mb deletion in 22q11.22. This region includes TBX1, which has emerged as a major genetic determinant of the 22q11 deletion phenotype [34]. Point mutations in TBX1 have been identified in patients with findings suggestive of the 22q11 deletion syndrome phenotype but with normal chromosome microarray. Appropriate identification of the cardiac patient with a 22q11 deletion is important to facilitate identification of associated anomalies, renal defects, and possible calcium abnormalities. In addition, a higher operative mortality may exist in those individuals with a 22q11 deletion [35]. 

1.4.2.2 Williams Syndrome Williams syndrome, or Williams–Beuren syndrome, is characterized by learning disability with a unique

personality profile: a “cocktail party” personality which demonstrates a readiness to converse in a friendly outgoing fashion but with little content. The dysmorphic features are easily recognized and include malar flattening, periorbital fullness, heavy sagging cheeks, short nose, poorly developed Cupid’s bow on the upper lip, and everted lower lip (Fig. 1.8). The cardinal cardiovascular malformation in this syndrome is supravalvular aortic stenosis (SVAS), which affects about one-third of cases and tends to be progressive with age. Less well recognized and more difficult to detect are peripheral pulmonary artery stenoses (PPSs), which produce murmurs over the lung fields. The striking association with SVAS, which had been described as an isolated AD trait in many families, prompted the speculation that Williams syndrome would turn out to be a deletion involving the gene responsible for AD SVAS [36]. The identification of a balanced translocation associated with SVAS provided an additional clue. Curran and associates showed first that dominant SVAS mapped to chromosome 7 at a translocation breakpoint and subsequently that most Williams syndrome cases could be shown to have a deletion of this region of chromosome 7 [37]. Elastin (ELN) was shown to be the causative gene in isolated SVAS by the demonstration of loss-of-function mutations [38,39]. 

1.4.2.3 Alagille Syndrome Alagille syndrome is characterized by hypoplasia of the intrahepatic bile ducts, leading to a variable degree of cholestasis, which may present with neonatal jaundice or become apparent later in life [40]. Up to 90% of affected probands have single or multiple areas of peripheral PPS. In about one-third, a variety of other intra- and extracardiac malformations are seen. The face is mildly dysmorphic, with a prominent forehead, deep-set eyes, and thin nose (Fig. 1.9). Other typical clinical features include skeletal defects (particularly butterfly vertebrae) and anterior chamber eye defects, confusingly called posterior embryotoxon. Externally, the striking feature is a pale ring around the iris known as arcus juvenilis (Fig. 1.10) [41]. A microdeletion of 20p12, which includes JAG1, is demonstrable in 7% of cases. JAG1 is part of the Notch signaling pathway and point mutations are responsible for the phenotype in approximately 89% of cases; NOTCH2 accounts for approximately 1% of cases [42]. 

CHAPTER 1 

(A)

Congenital Heart Defects

17

(C)

(B)

Figure 1.7  Variable facial dysmorphology seen in 22q11 deletion syndrome. Facial characteristics include a long face, malar fl ­ attening, hypertelorism, short palpebral fissures, hooded/swollen eyelids, tubular form of the nose with a bulbous nasal tip, low-set.

18

SECTION 1 

Cardiovascular Disorders

Figure 1.8 Characteristic facial dysmorphology in Williams syndrome: epicanthal folds, full cheeks, and full lips and small, widely spaced teeth.

1.4.3 Single-Gene Disorders Chromosome analysis, FISH, and chromosome microarray analysis are useful diagnostic tools in the evaluation of syndromic causes of congenital heart defects. However, these technologies are not able to detect abnormalities at the single gene level. So, if they are used without recognition of the single gene causes of many syndromic congenital heart defects, important diagnoses will be missed. A few of these syndromes are highlighted in the next section.

1.4.3.1 Noonan Syndrome One of the best recognized syndromes in the pediatric cardiology clinic is Noonan syndrome (NS). Earliest descriptions have been traced back over a century, but the syndrome derives its name from the report by Noonan and Ehmke in 1963 of nine children with valvar pulmonary stenosis, short stature, mild learning difficulties, and dysmorphic appearance. Fig. 1.11A and B illustrate the variable phenotype. Collectively

Figure 1.9  Characteristic facial dysmorphology in Alagille syndrome: broad forehead, deep-set eyes, and pointed chin.

they have the full picture, yet none has the complete pattern. In infancy, the striking features are the widely set, downslanting eyes with low-set, posteriorly rotated ears and low posterior hairline. Later the face becomes more triangular and rather coarse in appearance. In adulthood, the eyes are less prominent and the nose has a thinner bridge and pinched root with wide base; the neck becomes longer, accentuating the prominent trapezius and/or neck webbing, which caused original confusion with Turner syndrome in the literature. Other important features are the feeding difficulties of infancy, pectus excavatum/carinatum with wide-spaced nipples, cryptorchidism, a predisposition to lymphatic dysplasia and bleeding diathesis, and a high frequency of nevi and café au lait macules. Two-thirds of children with NS have a heart defect, with valvar pulmonary stenosis in 50%. Often the valve is dysplastic, making balloon dilation more difficult. Among a variety of other defects reported, the most frequent are ASD, asymmetrical

CHAPTER 1 

septal hypertrophy, and PDA; VSD occurs in about 5% [43,44]. The electrocardiogram typically shows left axis deviation with a wide QRS complex, giant Q waves, and a negative pattern in the left precordial leads [45]. There is a phenotypic overlap with a number of syndromes, particularly LEOPARD syndrome (an allelic disorder with mutations in PTPN11), neurofibromatosis type 1, Costello syndrome, and cardiofaciocutaneous syndrome. NS is a genetically heterogeneous disorder that results in dysregulation

Figure 1.10  Arcus juvenilis in Alagille syndrome.

(A)

Congenital Heart Defects

19

of the Ras/MAPK mitogen-activated protein kinase signal transduction pathway. The Ras/MAPK pathway is implicated in growth factor–mediated cell proliferation, differentiation, and cell death. Over nine genes have been identified in association with altered Ras/MAPK signaling with resulting overlapping phenotypes. Mutations identified in PTPN11, SOS1, RAF1, and KRAS are responsible for the NS phenotype. While some genotype/phenotype correlations exist, for example hypertrophic cardiomyopathy is a complication in ∼20% of NS patients, and more frequent in RAF1 mutation patients, there is insufficient evidence to correlate genotype with occurrence of a specific type of congenital heart defect [46]. Lifelong cardiac follow-up is important for adults with NS as left-sided obstructive lesions may develop in adulthood. Pulmonary valve insufficiency and right ventricular dysfunction are also potential problems after early pulmonary valve surgery [47]. 

1.4.3.2 Holt–Oram Syndrome Holt–Oram syndrome is the best recognized of the heart-hand syndromes and is caused by mutations in the T-box transcription factor TBX5. The characteristic

(B)

Figure 1.11  Mother and two affected daughters with Noonan syndrome.

20

SECTION 1 

Cardiovascular Disorders

anomalies are underdevelopment of the shoulder girdle with triphalangeal thumb and ASD [48] (Fig. 1.12). The limb defects can vary from phocomelia to minor anomalies of joint movement at the thumb, elbow, or shoulder. About half of gene carriers have a secundum ASD, with occasional reports including VSD, AVSD, and truncus arteriosus. Patients may also present with mild to severe cardiac arrhythmias, commonly atrioventricular block [49]. 

1.4.3.3 CHARGE Syndrome CHARGE is a mnemonic that stands for coloboma, heart defects, choanal atresia, retarded growth and development, genital abnormalities, and ear anomalies. Formerly an association, the specific developmental anomalies of the optic vesicle, otic capsule, midline central nervous system (CNS) structures, and upper pharynx has been attributed, in the majority of cases, to mutations in the CHD7 gene. Updated diagnostic criteria for CHARGE have been proposed and emphasize the importance of additional findings, for example anomalies of the semicircular canals, not included in the mnemonic [50]. Congenital heart defects are seen in approximately 75% of children diagnosed with CHARGE syndrome, with Tetralogy of Fallot or Fallot spectrum being the most common [51,52]. 

1.4.4 Heart Malformation and Metabolic Disorders

The inborn errors of metabolism, such as the mucopolysaccharidoses (for additional information, previous volumes address the mucopolysaccharidoses in more detail), develop cardiac involvement as a postnatal event, particularly involving valve dysfunction due to deposition of storage material and, most dramatically in type 2 glycogenosis or Pompe disease, with accumulation of material in the cardiac muscle. More recently, it has become apparent that some metabolic defects are not corrected by the maternal influence and can produce congenital malformations that may include the heart. Two are worthy of mention, since simple diagnostic biochemical tests exist making prenatal diagnosis available.

1.4.4.1 Zellweger Syndrome Zellweger or cerebrohepatorenal syndrome was originally described as a lethal multiple malformation syndrome of infancy characterized by profound hypotonia,

Figure 1.12  Characteristic thumb anomalies in Holt–Oram syndrome. Upper limb malformations may be variable and can be unilateral, bilateral ranging from triphalangeal or absent thumbs to phocomelia.

a marked paucity of facial movement, open anterior fontanelle, hypoplastic supraorbital ridges, and a broad nasal bridge. Hepatomegaly, renal cortical cysts, deafness, cataracts, and calcific stippling of the patellae complete the typical phenotype. Following the discovery of a peroxisomal defect in a child with this syndrome, it has become apparent that this pattern represents one end of a clinical spectrum that may result from at least 10 genetic defects in peroxisomal assembly or the function of the single matrix enzymes, including PEX1, on chromosome 7q [53]. Peroxisomes are single membrane– bound organelles present in virtually all eukaryotic cells. They are involved in numerous metabolic processes, both anabolic and catabolic, including b-oxidation of very-long-chain fatty acids, the basis of the standard diagnostic test [54]. Severe cerebral dysfunction results from premature arrest of migrating neuroblasts. Thymic hypoplasia and outflow tract cardiac malformations occur [55]. 

1.4.4.2 Smith–Lemli–Opitz Syndrome Smith–Lemli–Opitz (SLO) syndrome is characterized by severe learning disability, failure to thrive, cleft palate, hypospadias in males, and 2/3 syndactyly. The facies are dysmorphic, with bitemporal narrowing and  anteverted nares. In one series, 16% of patients with SLO were found to have an AVSD, 7% with TAPVR [56].

CHAPTER 1 

Congenital Heart Defects

21

The discovery that affected individuals have hypocholesterolemia and markedly elevated levels of 7-dehydrocholesterol due to a defect in the 7-dehydrocholesterol reductase gene showed that another multiple malformation syndrome had a metabolic basis [57]. By 2003, 91 different pathologic mutations had been reported in the gene [58]. How and why a defect in the cholesterol biosynthesis pathway should have such an adverse effect on, for example, the septation of the ventricular inlet remains to be established, but from the practical perspective, the possibility of SLO syndrome must be considered in a dysmorphic infant with a heart defect in view of the recessive mode of inheritance and the availability of pre- and postnatal diagnostic tests. 

have been identified in patients with isolated AVSD [60,61]. Coarctation of the aorta, interrupted aortic arch, and hypoplastic left heart have been identified in multigenerations with clinical variability and reduced penetrance [62,63]. Through advances in molecular diagnostics, the overall number of single-gene causes of isolated heart defects continues to grow; however, for many congenital heart malformations, multiple pathologic factors, both genetics and environmental, are likely required to result in pathology. This suggests that congenital heart defects in general are heterogeneous and genetically complex (Table 1.2). 

1.5 GENES RESPONSIBLE FOR CONGENITAL HEART MALFORMATIONS AS MONOGENIC TRAITS

The search for specific environmental associations of congenital heart defects has scored notable successes. This began with congenital rubella, which was once a major cause of congenital heart defects, but has now receded in most developed countries, where inoculation is widespread. Table 1.3 lists several teratogens that are well recognized as causes of congenital heart disease. In general terms, the evidence for a major contribution from specific environmental exposures is not strong [64]. In practical terms, maternal diabetes and alcohol abuse remain the most important external threats to normal heart development, but it is ­important to take a history of drug ingestion before offering recurrence risks. This is important when the

The investigation of deletion syndromes and traditional mapping have identified the location, and in some cases the identity, of genes that, when defective, can produce isolated heart defects. The classic examples are ELN as a cause of supravalvar aortic stenosis and JAG1 leading to peripheral PPS. In addition, mapping studies and candidate gene analysis led to the discovery of ZIC3 as a cause of X-linked laterality syndrome (Table 1.1), and the same approach yielded TFAP2B as the cause of AD PDA [59]. Mutations in GATA4 and CRELD 1

1.6 ENVIRONMENTAL CAUSES AND THE TERATOGEN SYNDROMES

TABLE 1.3  Some Common Teratogen Teratogenic Influence

Risk of Heart Defect (%)

Maternal rubella Maternal diabetes Maternal phenylketonuria Systemic lupus erythematosus Maternal alcohol abuse Hydantoin Trimethadione Thalidomide Lithium Retinoic acid Cocaine

35 3–5 25–50 20–40 25–30 2–3 15–30 45–50 mm); valve sparing technique option Progressive dilatation, rupture Prophylactic grafting of any portion of the aorta when the risks of surgery are less than the risks of medical management, or in the case of end-organ ischemia, persistent pain Mitral regurgitation, heart failure Mitral valve repair or replacement Aortic dissection, rupture Prophylactic aortic root repair to prevention dissection, but using aortic diameter criteria less than what is used for Marfan syndrome (>40 mm instead of 50 mm in the adult) Arterial dissection, rupture Prophylactic repair

Aneurysm of other major arteries Pulmonary arteriove- Cyanosis; paradoxic embolizanous malformations tion leading to stroke or brain abscess Hepatic arteriovenous Cirrhosis; hepatic encephalopmalformations athy Pulmonic stenosis Can present in adulthood for the first time; those with previous surgery or balloon angioplasty in childhood can have residual PS and/or pulmonary insufficiency ASD, secundum type Residual shunt after repair in childhood; some adults have undetected large defect and fatigue symptoms; in combination with pulmonary stenosis may have risk for stroke Hypertrophic cardioRight ventricular outflow myopathy obstruction; can coexist with a CHD such as pulmonary stenosis; risk of arrhythmias

Therapeutic or prophylactic embolization of the AVM with coils when the diameter of the feeding artery is 1 mm or greater Medical management of liver dysfunction Options for severe pulmonary stenosis include balloon valvuloplasty or valve replacement; severe pulmonary insufficiency often requires valve replacement

Depending on size of shunt may require surgical closure or closure by a septal occluder device

Treatment considerations include surgical myomectomy and beta blockers; careful monitoring for arrhythmias may also include treatment such as amiodarone, pacemaker defibrillator

ASD, atrial septal defect; AVC, atrioventricular canal defect; CAVC, complete atrioventricular canal; CHD, congenital heart defect; CTA, CT angiography; ECG, electrocardiographic; VSD, ventricular septal defect. aGuidelines provide general information for primary care providers, but individuals require specific management by cardiologists. In the interest of brevity, each cardiac abnormality for each disorder was not listed. bASD, VSD, and tetralogy of Fallot were not discussed. Antibiotic prophylaxis for subacute bacterial endocarditis should be offered in appropriate doses per standard practice. (reference). Modified from Lin AE, Basson CT, et al. Adults with genetic syndromes and cardiovascular abnormalities: clinical history and management. Genet Med 2008;10(7):469–94.

28

SECTION 1 

Cardiovascular Disorders

TABLE 1.5  The British Offspring Study: Affected and Total Offspring According to Proband

Sex and Malformations

OFFSPRING Of Males TAPVD TGA Abnormal situs and other abnormal connections AVSD Tetralogy of Fallot Totals Heart defects All major malformations

Of Females

Proband No. 38 97 90

Affected/Total 0/14 0/10 1/14

% — — 7.1

Affected/Total 1/20 0/3 2/13

% 5.0 — 15.4

85 384

1/12 2/129 Males 4/179 4/179

8.3 1.6 % 2.2 2.2

4/38 6/127 Females 13/201 16/201

10.5 4.7 % 6.5a

Etiology

Inheritance

OMIM

Autosomal dominant (AD)

214800

AD

617364

Nondisjunction, unbalanced robertsonian translocations

190685

Section IV Approaches to Specific Disorders aM:F contrast: P = 0.01

APPENDIX 1 Cardiac Defect

Syndrome Name

Atrioventric- CHARGE ular septal defect (AVSD)

Congenital heart defects and ectodermal dysplasia (CHDED)

Down

Cardinal Features

Colobomata (iris and/or retina, CHD7 heart defects, atresia choanae, retardation of growth and development and/or central nervous system anomalies, genital hypoplasia in males, ears cup shaped and hearing loss (pulmonary valve stenosis) Developmental delay, ectoderPRKD1 mal dysplasia, microcephaly, prominent forehead, prominent nasal bridge, depressed nasal bridge, broad thumbs, short digits, nystagmus, scoliosis, feeding difficulties, hypotonia Hypotonia, mental retardation, Trisomy 21 up-slanting palpebral fissures, epicanthal folds, brachycephaly, single palmar crease

CHAPTER 1 

Cardiac Defect

Congenital Heart Defects

Syndrome Name

Cardinal Features

Etiology

Inheritance

OMIM

Growth retardation, developmental delay, facial dysmorphism Short-rib thoracic dysplasia-15 with polydactyly (SRTD15) Ellis–van Creveld

Severe psychomotor retardation, poor overall growth, and dysmorphic facial features Short stature, postaxial polydactyly, miso/acromelic shortening of limbs, short ribs Short stature, postaxial polydactyly, miso/acromelic shortening of limbs, short ribs Macrocephaly (absolute and relative), congenital hypotonia, small ears, agenesis of the corpus callosum, constipation, mental retardation Postaxial polydactyly, hydrometrocolpos Short stature, pectus excavatum/carinatum, hypertelorism, low-set ears, mild mental retardation Constricted thoracic cage, short ribs, shortened tubular bones

FTO

Autosomal recessive (AR)

612938

DYNC2LI1

AR

617088

EVC1, EVC2

AR

225500

MED12

X-linked

305450

MKKS

AR

236700

PTPN11, SOS1, KRAS, RAF1 INTU

AD

163950

AR

617925

AR

270400

X-linked

314390

FG

McKusick–Kaufman Noonan

Short-rib thoracic dysplasia 20 with polydactyly Smith–Lemli–Opitz

Mental retardation, failure to DHCR7 thrive, feeding, difficulties, premature death, microcephaly, micrognathia, ptosis, anteverted nostrils, 2/3 syndactyly of toes, broad alveolar ridges, short stature, genital anomalies; occasional, polydactyly, cleft palate, various other visceral malformations, cataract VACTERL syndrome with Tracheoesophageal fistula, atrial ZIC3 or without hydrocephaisomerism, imperforate anus, lus (VACTERLX) anal atresia, hydronephrosis, enlarged kidneys, urethral atresia, vertebral anomalies, humeral hypoplasia, radial aplasia, hexadactyly, hydrocephalus 

 

29

30

SECTION 1 

Cardiovascular Disorders

APPENDIX 2 Cardiac Defecta

Syndrome Name

Cardinal Features

Bicuspid aortic valve

1q21.1 microdeletion

Microcephaly, mild facial dysmor1q21.1 deletion phism, autism, various heart defects

Etiology

Inheritance

OMIM

Autosomal 612474 dominant (AD), reduced penetrance AD, sporadic 610253

9q subteloModerate to severe mental retarmeric deletion dation, hypotonia, facial dys(Kleefstra) morphisms, urogenital defects, seizures, behavior problems 17q21.31 Mental retardation, hypotonia, and deletion characteristic face Baraitser– Pre- and postnatal growth retardation, Winter microcephaly, dysmorphic facies, hypoplastic genitalia, renal abnormalities, mental retardation Beals Arachnodactyly, large joint contractures, camptodactyly, “crumpled” ears, kyphoscoliosis Cantu Large for gestational age, macrocephaly, coarse facies, facial dysmorphism, narrow thorax, osteoporosis, skeletal anomalies, lymphedema, mild mental retardation 

9q34.3 deletion resulting in haploinsufficiency of EHMT1 Deletion 17q21.31 AD

Cranioectoder- Sagittal craniosynostosis facial dysmal dysplamorphism, ectodermal and skeletal sia-1 anomalies Diamond-Black- Normochromic macrocytic anemia, fan anemia 11 reticulocytopenia, growth retardation, variable craniofacial, upper limb, and urinary system congenital malformations Familial thoAortic aneurysms and dissections, racic aortic PDA aneurysm and dissection Fontaine proPrenatal and postnatal growth retargeroid dation, decreased subcutaneous fat tissue, sparse hair, triangular face, widely open anterior fontanel, convex and broad nasal ridge, micrognathia, craniosynostosis Frontometaphy- Progressive sclerosing skeletal dysseal dysplasia plasia, small and large joint contrac2 tures, cardiorespiratory system and genitourinary tract anomalies

610443

ACTB inv2(p12q14)

AD

243310

FBN2

AD

121050

ABCC9

AD

239850

IFT122

Autosomal recessive (AR) AD

218330

MYH11 ACTA2 LOX

AD

132900 611788 617168

SLC25A24

AD

612289

MAP3K7

AD

617137

RPL26

614900

CHAPTER 1 

Cardiac Defecta

Syndrome Name

Cardinal Features

Inheritance

OMIM

YY1AP1

AR

602531

Deletion 17q21.31 KANSL1 B3GAT3

AD

610443

AR

245600

SMAD TGFB2 TGFBR1 TGFBR2 PTPN11, SOS1, KRAS, RAF1

AD

614816 609192 610168

Short stature, pectus excavatum/carinatum, hypertelorism, low-set ears, mild mental retardation Majority female with in utero male FLNA lethality, PDA, aortic dilation, periventricular heterotopic nodules, seizures, mild mental retardation, coagulopathy, strokes Nystagmus, dysmorphic, subglottic SNIP1 stenosis, poor feeding, short hands, short tapered fingers, hypotonia, severe developmental delay, abnormal MRI, multifocal intractable seizures

AD

163950

X-linked

300049

AR

614501

Mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features Short stature, intrauterine growth restriction, facial dysmorphology, telecanthus, anogenital malformations, renal anomalies Short stature, gonadal dysgenesis, short webbed neck, wide-spaced nipples, renal anomalies Distinctive facial characteristics, mental retardation unique personality, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism) Mental retardation, microcephaly, short stature, hypotonia, hearing loss Homogentisic acid in the urine, ochronosis (blue-black pigmentation in connective tissue), and arthritis of the spine and large joints.

CREBBP EP300

AD, de novo

180849

FAM58A

X-linked

300707

Monosomy X

Sporadic

Deletion chromosome 7q11.23

AD

194050

Deletion 18q

AD, sporadic

601808

HGD

AR

203500

Multiple arterial stenoses, arterial aneurysms, mental retardation, bone fragility Koolen-de Vries Mental retardation, hypotonia, and characteristic face Larsen Multiple joint dislocations, short stature, craniofacial dysmorphism Loeys–Dietz Arterial tortuosity and aneurysms, hypertelorism, bifid uvula or cleft palate, craniosynostosis

Periventricular nodular heterotopia

Psychomotor retardation, epilepsy, and craniofacial dysmorphism Rubinstein– Taybi

STAR

Turner

Williams

Aortic valve stenosis

18q deletion

Alkaptonuria

31

Etiology

Grange

Noonan

Congenital Heart Defects

Continued

32

SECTION 1 

Cardiac Defecta

Cardiovascular Disorders

Syndrome Name

Inheritance

OMIM

AD

243310

Multiple congenital anomalies, craniofacial dysmorphism, mental retardation Meckel–Gruber Renal cysts, CNS anomalies (typically MKS1 encephalocele), hepatic ductal dysplasia and cysts, and polydactyly MicrophthalMicrophthalmia, microcephaly, short BCOR mia-2 stature, congenital cataract, dysmorphic facial features Morquio B Skeletal dysplasia, corneal clouding GLB1 (mucopolysaccharidosis type IVB)

609029

Emanuel

AR

249000

X-linked

300166

AR

253010

Pallister–Killian

Sporadic

601803

AR

208540 615415

WSHC5

AR

220210

IDUA

AR

607016

FBN1 ADAMTS10

AD AR

608328

Baraitser–Winter

Cardinal Features

Pre- and postnatal growth retardation, ACTB microcephaly, dysmorphic facies, inv2(p12q14) hypoplastic genitalia, renal abnormalities, mental retardation Malsegregation of the t(11;22) (q23;q11.2) translocation

Severe mental retardation, seizures, Mosaic 12p tetrashort stature, coarse face, frontal somy bossing, temporal balding, upturned nose, full cheeks, droopy mouth, patchy hypopigmented skin, diaphragmatic hernia, supernumerary nipples Potter facies, oligohydramnios, cystic NPHP3 malformations of the kidneys, liver, NEK8 and pancreas

Renal-hepatic-pancreatic dysplasia (RHPD) Ritscher– Craniofacial abnormalities, congenital Schinzel heart defects, and cerebellar brain syndrome malformations Scheie (muco- Coarse facial features, cloudy cornea, polysacchastiff joints ridosis type V) Weill–Marches- Microspherophakia, ectopia lentis, ani short stature, brachydactyly, joint stiffness aSpace

Etiology

does not permit the inclusion of every case report or occasional observation. 

CHAPTER 1 

Congenital Heart Defects

33

APPENDIX 3 Cardiac Defecta

Syndrome Name

Cardinal Features

Coarctation of 1q21.1 Microcephaly, mild facial dysmorthe aorta microdeletion phism, autism, various heart defects 22q11 deletion Immune deficiency, palate abnormalities, hypocalcemia, psychiatric illness 9q deletion Moderate to severe mental retar(Kleefstra) dation, hypotonia, facial dysmorphisms, urogenital defects, seizures, behavior problems Adams–Oliver Alagille

Etiology

Inheritance

1q21.1 deletion

Autosomal 612474 dominant (AD), reduced penetrance AD 188400 192430

22q11 deletion

9q34.3 deletion resulting in haploinsufficiency of EHMT1 Unknown

AD, sporadic

610253

AD, autosomal recessive (AR) AD

100300

FOX transcription factor gene cluster on chromosome 16q24.1q24.2

AD

265380

FGFR2

AD

101200

WDPCP

AR

217085

Scalp defects, terminal transverse defects Intrahepatic cholestasis (95%); JAG1 defects of the arterior chamNOTCH1 ber of the eye (80%), mainly posterior embryotoxon; abnormal facies (90%); vertebral anomalies (70%)

Alveolar Failure of formation and in-growth capillary dysof alveolar with medial muscular plasia with thickening of small pulmonary misalignment arterioles presenting as perof pulmonary sistent pulmonary hypertension veins (ACD/ of the newborn, multiple congenMPVs) ital anomalies: gastrointestinal, genitourinary, musculoskeletal, and/or disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs Apert Severe craniosynostosis, flat face, hypertelorism syndactyly (mitten hands), occasional cleft palate, deafness, mental retardation, renal and genitourinary anomalies CongeniHamartomas of the tongue, polytal heart dactyly defects, hamartomas of tongue, and polysyndactyly

OMIM

118450 610205

Continued

34 Cardiac Defecta

SECTION 1 

Cardiovascular Disorders

Syndrome Name Cornelia de Lange

Cutis laxa

DiamondBlackfan anemia

Goldenhar

Cardinal Features

Etiology

Inheritance

OMIM

Mental retardation, growth failure, microbrachycephaly, hirsutism, synophrys, variable upper limb reduction defects Lax skin, prematurely aged appearance, beaked nose, hoarse voice, joint dislocations, hernias Growth retardation, normochromic, macrocytic, anemia, craniofacial, upper-limb, or genitourinary malformations

NIPBL SMC1A

AD X-linked

122470 300590

ELN FBLN5

AD

123700 604580

Hemifacial microsomia, epibulbar dermoid, preauricular ear tags, deafness, microtia, eyelid coloboma, cleft palate, vertebral anomalies

Kabuki

Mental retardation, short stature, characteristic face with tented eyebrows and everted lower palpebral fissures, prominent ears, occasional skeletal and visceral malformations MicrophthalBilateral microphthalmia, intramia-9 uterine growth restriction, short stature, bilateral pulmonary hypoplasia/agenesis, diaphragmatic hernia, mental retardation, hypotonia, early death Mowat–Wilson Distinctive facial appearance, Hirschsprung disease or chronic constipation, fleshy upturned ear lobules Myhre Short stature, joint limitations, thick skin, muscular hypertrophy, autism spectrum disorder Neurofibroma- Cafe au lait macules, Lisch nodules tosis type I in the eye, fibromatous tumors of the skin Noonan Short stature, pectus excavatum/ carinatum, hypertelorism, low-set ears, mild mental retardation Opitz G/BBB

Hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay

RPS19, RPL5, AD 105650 RPL11, RPL35A, RPS24, RPS17, RPS7, RPS10, RPS26 Unknown Sporadic, AD, AR 164210

MLL2

AD

147920

STRA6

AR

601186

ZEB2

AD, de novo

235730

SMAD4

AD

139210

NF1

AD

162200

PTPN11, SOS1, KRAS, RAF1, SOS2, LZTR1, RIT1 MID1 gene

AD

163950

X-linked

300000

CHAPTER 1 

Cardiac Defecta

Syndrome Name

Cardinal Features

Pallister–Killian Severe mental retardation, seizures, short stature, coarse face, frontal bossing, temporal balding, upturned nose, full cheeks, droopy mouth, patchy hypopigmented skin, diaphragmatic hernia, supernumerary nipples Rubinstein– Mental retardation, postnatal Taybi growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features Short-rib Short-rib thoracic dysplasia and thoracic dyspolydactyly plasia 15 Sifrim–Hitz– Mental retardation, variable conWeiss  genital defects—cardiac, skeletal, and urogenital  Smith–Lemli– Mental retardation, failure to thrive, Opitz feeding, difficulties, premature death, microcephaly, micrognathia, ptosis, anteverted nostrils, 2/3 syndactyly of toes, broad alveolar ridges, short stature, genital anomalies; occasional, polydactyly, cleft palate, various other, visceral malformations, cataract ThrombocyBilateral absent radius, (thumbs topenia– are present) ulnar hypoplasia, absent radius thumbs present, occasionally mentally retarded, squint Transaldolase Variable cardiac defects, wrinkly deficiency skin, and dysmorphic facial features  Turner Short stature, gonadal dysgenesis, short webbed neck, wide-spaced nipples, renal anomalies Williams Distinctive facial characteristics, mental retardation unique personality, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism) aSpace

Congenital Heart Defects

35

Etiology

Inheritance

OMIM

Mosaic 12p tetrasomy

Sporadic

601803

CREBBP EP300

AD, de novo

180849

DYNC2LI1

AR

617088

CHD4

AD

617159

DHCR7

AR

270400

RBM8A

AR

274000

TALDO1

AR

606003

Monosomy X

Sporadic

Deletion chromosome 7q11.23

AD

does not permit the inclusion of every case report or occasional observation. 

194050

36

SECTION 1 

Cardiovascular Disorders

APPENDIX 4 Cardiac Defecta

Syndrome Name

Double CHARGE outlet right ventricle

Congenital disorders of glycosylation Ia Edwards

Frank-ter Haar

Goldenhar

Opitz G/BBB

Pancreatic agenesis and congenital heart defects Pentalogy of Cantrell

aSpace

Cardinal Features

Etiology

Inheritance

OMIM

Colobomata (iris and/or retina, heart defects, atresia choanae, retardation of growth and development and/or central nervous system anomalies, genital hypoplasia in males, ears cup shaped and hearing loss (pulmonary valve stenosis) Developmental delay, hypotonia, failure to thrive, hepatic dysfunction, coagulopathy, abnormal subcutaneous fat, seizures, cerebellar hypoplasia/atrophy, and small brain stem Growth failure, hypertonia, small palpebral fissures, clenched hands with overlapping digits, omphalocele, neural tube defect Brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea, glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers Hemifacial microsomia, epibulbar dermoid, preauricular ear tags, deafness, microtia, eyelid coloboma, cleft palate, vertebral anomalies Hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay Pancreatic hypoplasia

CHD7

Autosomal dominant (AD)

214800

PMM2

Autosomal recessive (AR)

212065

Trisomy 18

Sporadic

TKS4

AR

249420

Unknown

Sporadic, AD, AR

164210

MID1

X-linked

300000

GATA6

AD

600001

Anterior body wall defect, short or bifid sternum, diaphragmatic pericardium defect

Unknown Sporadic with some cases linked to Xq26.1 Duplication of 8q22.1qter and deletion of 8pter-p23.1  WSHC5 AR

313850

PEX1, 2, 3, 5, 6, 10, 12, 13, 14, 16, 19, 26

214100

Recombinant chromosome 8

Postnatal growth retardation, microcephaly, dysmorphic facial features, hearing loss, skeletal anomalies, genitourinary anomalies, mental retardation

Ritscher– Schinzel syndrome Zellweger

Craniofacial abnormalities, congenital heart defects, and cerebellar brain malformations Failure to thrive, facial dysmorphism, hearing loss, cataracts, glaucoma, liver dysfunction

does not permit the inclusion of every case report or occasional observation. 

AR

179613

220210

CHAPTER 1 

Congenital Heart Defects

37

APPENDIX 5 Cardiac Defecta

Syndrome Name

Hypoplastic 16p12.1 deleleft heart tion

Cardinal Features

Developmental delay, craniofacial dysmorphology, bipolar disorder, seizures, growth abnormalities Alveolar Failure of formation and capillary in-growth of alveolar with dysplasia with medial muscular thickening misalignment of small pulmonary arterioles of pulmonary presenting as persistent pulveins (ACD/ monary hypertension of the MPVs) newborn, multiple congenital anomalies: gastrointestinal, genitourinary, musculoskeletal, and/or disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs CHARGE Colobomata (iris and/or retina, heart defects, atresia choanae, retardation of growth and development and/or central nervous system anomalies, genital hypoplasia in males, ears cup shaped and hearing loss (pulmonary valve stenosis) Ellis–van CreShort stature, postaxial veld polydactyly, miso/acromelic shortening of limbs, short ribs Holt–Oram Triphalangeal or hypoplastic to absent thumb bifid thumb, variable hypoplasia of first metacarpal, radius or whole limy, narrow shoulders Jacobsen Growth retardation, mental retardation, dysmorphic features, strabismus, thrombocytopenia Ritscher– Craniofacial abnormalities, Schinzel congenital heart defects, and syndrome cerebellar brain malformations Short-rib thoracic Short-rib thoracic dysplasia dysplasia 15 and polydactyly

Etiology

Inheritance

OMIM

Deletion 16p12.1

Autosomal dominant (AD), variable expressivity

136570

FOX transcription factor gene cluster on chromosome 16q24.1q24.2

AD

265380

CHD7 gene

AD variable expressivity

214800

EVC1 and EVC2

Autosomal recessive 225500 (AR)

TBX5

AD

142900

Terminal deletion 11q

AD

147791

WSHC5

AR

220210

DYNC2LI1

AR

617088 Continued

38

SECTION 1 

Cardiac Defecta

Cardiovascular Disorders

Syndrome Name Smith–Lemli– Opitz

aSpace

Cardinal Features

Etiology

Mental retardation, failure to DHCR7 thrive, feeding, difficulties, premature death, microcephaly, micrognathia, ptosis, anteverted nostrils, 2/3 syndactyly of toes, broad alveolar ridges, short stature, genital anomalies; occasional, polydactyly, cleft palate, various other, visceral malformations, cataract

Inheritance

OMIM

AR

270400

does not permit the inclusion of every case report or occasional observation. 

APPENDIX 6 Cardiac Defecta

Syndrome Name

Patent ductus arteriosus (PDA)

1q21.1 deletion

Cardinal Features

Etiology

Microcephaly, mild facial dysmor1q21.1 delephism, autism, various heart defects tion

1p36 deletion

Inheritance

OMIM

Autosomal dominant (AD)

612474

Intrauterine growth restriction (IUGR), failure to thrive, microcephaly, dysmorphic facial features, hearing loss, CL/P, seizures 3MC Facial dysmorphism, cleft lip and palate, postnatal growth deficiency, mental retardation, hearing loss, craniosynostosis, radioulnar synostosis, genital and vesicorenal anomalies  Recombinant chro- Postnatal growth retardation, micromosome 8 cephaly, dysmorphic facial features, hearing loss, skeletal anomalies, genitourinary anomalies, mental retardation 9p deletion Mental retardation, trigonocephaly, dysmorphic facial features, myopia, scoliosis, hypotonia 

1p36 deletion

AD, sporadic

607872

MASP1

Autosomal recessive (AR)

257920

17q21.31 deletion

Deletion 17q21.31 Deletion 18q

18q deletion

Mental retardation, hypotonia, and characteristic face Mental retardation, microcephaly, short stature, hypotonia, hearing loss

Duplication of 8q22.1qter and deletion of 8pter-p23.1  9p deletion

179613

De novo, 158170 inherited from parental translocation AD 610443 AD, sporadic

601808

CHAPTER 1 

Cardiac Defecta

Syndrome Name 22q11 deletion Acrofacial dysostosis, Cincinnati type Adams–Oliver

Congenital Heart Defects

Cardinal Features

Etiology

Immune deficiency, palate abnormalities, hypocalcemia, psychiatric illness Spectrum of mandibulofacial dysostosis phenotypes, with or without extrafacial skeletal defects Scalp defects, terminal transverse defects, CL/P Agenesis of the corpus callosum, mental retardation, coloboma, micrognathia

22q11 deletion AD

Agenesis of the corpus callosum with mental retardation, ocular coloboma, and micrognathia Axenfeld-Rieger Axenfeld-Rieger anomaly, sensorineusyndrome type 3 ral hearing loss Baraitser–Winter Pre- and postnatal growth retardation, microcephaly, dysmorphic facies, hypoplastic genitalia, renal abnormalities, mental retardation Beals Arachnodactyly, large joint contractures, camptodactyly, “crumpled” ears, kyphoscoliosis C (opitz trigonoFacial dysmorphism, mental retardacephaly) tion, redundant skin, omphalocele, hepatomegaly Cantu Large for gestational age, macrocephaly, coarse facies, facial dysmorphism, narrow thorax, osteoporosis, skeletal anomalies, lymphedema, mild mental retardation  Carpenter Craniosynostosis, preaxial polydactyly, brachysyndactyly, ptosis, obesity Cerebrocostoman- Severe micrognathia, rib defects, and dibular mental retardation CHAR Facial dysmorphism, abnormal fifth digit CHARGE Colobomata (iris and/or retina, heart defects, atresia choanae, retardation of growth and development and/or central nervous system anomalies, genital hypoplasia in males, ears cup shaped and hearing loss (pulmonary valve stenosis) CHOPS Cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia

Inheritance

39

OMIM

POLR1A

AD

188400 192430 616462

Unknown

AD, AR

100300

IGBP1

X-linked

300472

FOXC1

AD

602482

ACTB AD inv2(p12q14)

243310

FBN2

AD

121050

CD96

AR

211750

ABCC9

AD

239850

RAB23 MEGF8 SNRPB

AR AD

201000 614976 117650

TFAP2B

AD

169100

CHD7 gene

AD

214800

AFF4

AD

616368

Continued

40 Cardiac Defecta

SECTION 1 

Cardiovascular Disorders

Syndrome Name Chronic idiopathic intestinal pseudoobstruction Coffin–Siris

Cardinal Features

Etiology

Gastrointestinal dysmotility, mild FLNA duplicafacial dysmorphism, thrombocytope- tion nia, large platelets Growth deficiency, mental retardaUnknown tion, microcephaly Combined oxidaCardiomyopathy, respiratory failure, TSFM tive phosphorylaneonatal hypotonia, seizures, lactic tion deficiency-3 acidosis, facial dysmorphism (COXPD3) Combined oxidaAgenesis of the corpus callosum, MRPS16 tive phosphoryladysmorphism, fatal neonatal lactic tion deficiency-2 acidosis (COXPD2) Congenital disorAcquired microcephaly, failure to DPM1 der of glycosylathrive, hepatomegaly, splenomegtion type Ie aly, hypotonia, seizures, mental retardation Congenital alveRespiratory distress at birth due to FOXF1 olar capillary congenital alveolar dysplasia dysplasia with misalignment of pulmonary veins Cranioectodermal Craniosynostosis facial dysmorphism, WDR35 dysplasia-2 ectodermal and skeletal anomalies Desmosterolosis Microcephaly, facial dysmorphic feaDHCR24 tures, osteosclerosis Diamond-Blackfan Growth retardation, normochromic, RPS19, RPL5, anemia macrocytic, anemia, craniofacial, RPL11, upper-limb, or genitourinary malforRPL35A, mations RPS24, RPS17, RPS7, RPS10, RPS26 Emanuel Multiple congenital anomalies, Malsegregacraniofacial dysmorphism, mental tion of the retardation t(11;22) (q23;q11.2) translocation Familial thoracic Aortic aneurysms and dissections, MYH11 aortic aneurysm bicuspid aortic valve (BAV) ACTA2 and dissection Feingold Abnormalities of the hands and feet, MYCN short palpebral fissures, microcephaly, learning disability, esophageal/ duodenal atresia

Inheritance

OMIM

X-linked

300048

?AR

135900

AR

610505

AR

610498

AR

608799

AR

265380

AR

613610

AR

602398

AD

105650

609029

AD

132900 611788

AD

164280

CHAPTER 1 

Cardiac Defecta

Syndrome Name

Congenital Heart Defects

Cardinal Features

Fontaine progeroid Prenatal and postnatal growth retardation, decreased subcutaneous fat tissue, sparse hair, triangular face, widely open anterior fontanel, convex and broad nasal ridge, micrognathia, craniosynostosis FrontometaphyProgressive sclerosing skeletal dysseal dysplasia 2 plasia, small and large joint contractures, cardiorespiratory system and genitourinary tract anomalies Fryns Diaphragmatic defects, cloudy cornea, hypoplastic distal digits Goldenhar Hemifacial microsomia, epibulbar dermoid, preauricular ear tags, deafness, microtia, eyelid coloboma, cleft palate, vertebral anomalies Goltz (Focal dermal Focal dermal hypoplasia, oligodactyly, hypoplasia) hypoplastic teeth, microphthalmos, coloboma, alopecia, mental retardation Growth retardaSevere psychomotor retardation, poor tion, developoverall growth, and dysmorphic mental delay, facial features facial dysmorphism Hajdu–Cheney Short stature, coarse and dysmorphic facies, bowing of the long bones, and vertebral anomalies Hay–Wells Congenital ectodermal dysplasia, ankyloblepharon filiforme adnatum, maxillary hypoplasia; and cleft lip/palate Holt–Oram Triphalangeal or hypoplastic to absent thumb bifid thumb, variable hypoplasia of first metacarpal, radius or whole limy, narrow shoulders Intestinal pseuAbnormal gastrointestinal motility doobstruction  with onset in infancy Kabuki Mental retardation, short stature, characteristic face with tented eyebrows and everted lower palpebral fissures, prominent ears, occasional skeletal and visceral malformations Lateral meningoLateral meningocele, dysmorphic cele facial features, vertebral anomalies Loeys–Dietz Arterial tortuosity and aneurysms, hypertelorism, bifid uvula or cleft palate

41

Etiology

Inheritance

OMIM

SLC25A24

AD

612289

MAP3K7

AD

617137

Unknown

Presumed AR

229850

Unknown

Sporadic, AD, AR

164210

PORCN gene

X-linked

305600

FTO

AR

612938

NOTCH2

AD

102500

TP63

AD

106260

TBX5

AD

142900

FLNA

X-linked

300048

MLL2 gene

AD

147920

NOTCH3

AD

130720

TGFBR1 TGFBR2

AD

609192 610168 Continued

42 Cardiac Defecta

SECTION 1 

Cardiovascular Disorders

Syndrome Name

Cardinal Features

Etiology

Inheritance

OMIM

Lymphedema-disti- Extra row of eyelashes, late-onset chiasis lymphedema; occasional cleft palate, micrognathia, pterygium colli, ptosis, Arnold–Chiari malformation, urinary tract malformations, spinal extradural cysts, vertebral anomalies, double uterus Marshall–Smith Accelerated linear growth, failure to thrive, mental retardation, and characteristic facial appearance (prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia) Meckel–Gruber Renal cysts, CNS anomalies (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly Mental retardation, Intellectual disability, microcephaly, AD 32 poor growth, absent speech Mental retardaIntellectual disability, poor speech, tion, X-linked, dysmorphic facial features, and syndromic 34 mild structural brain abnormalities, including thickening of the corpus callosum Mental retardaMild to moderate intellectual disabiltion, X-linked ity, scoliosis, postaxial polydactyly, 99, syndromic, mild cardiac or urogenital anomalies, female-restricted dysmorphic facial features, and mild structural brain abnormalities  Microphthalmia-2 Microphthalmia, microcephaly, short stature, congenital cataract, dysmorphic facial features Microphthalmia-3  Anophthalmia/microphthalmia, brain anomalies, seizures, mental retardation, sensorineural hearing loss, esophageal atresia, growth hormone deficiency, gonadotropin deficiency Microphthalmia-9 Bilateral microphthalmia, IUGR, short stature, bilateral pulmonary hypoplasia/agenesis, diaphragmatic hernia, mental retardation, hypotonia, early death MIRAGE Adrenal hypoplasia, myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy

FOXC2

AD

153400

NFIX

AD

602535

MKS1

AR

249000

KAT6A

AD

616268

NONO

X-linked

300967

USP9X

X-linked

300968

BCOR

X-linked

300166

SOX2

AD

206900

STRA6

AR

601186

SAMD9

AD, de novo

617053

Mowat–Wilson

ZEB2 gene

AD, de novo

235730

Distinctive facial appearance, Hirschsprung disease or chronic constipation, fleshy upturned ear lobules

CHAPTER 1 

Cardiac Defecta

Syndrome Name

Congenital Heart Defects

Cardinal Features

Multiple congenital Neonatal hypotonia, lack of psyanomalies-hychomotor development, seizures, potonia-seizures dysmorphic features, and variable syndrome congenital anomalies Myhre Short stature, joint limitations, thick skin, muscular hypertrophy, autism spectrum disorder, mental retardation Neu–Laxova Lethal, ichthyosis, marked intrauterine growth restriction, microcephaly, central nervous system anomalies, limb deformities, hypoplastic lungs, edema, and abnormal facial features Noonan/Noonan Short stature, pectus excavatum/carilike natum, hypertelorism, low-set ears, mild mental retardation

Opitz G/BBB

Etiology

Inheritance

OMIM

PIGN PIGT

AR

614080 615398

SMAD4

AD

139210

PHGDH

AR

256520

PTPN11, AD SOS1, KRAS, RAF1, SOS2, NRAS, RIT1, PPP1CB, BRAF, CBL, PPP1CB MID1 X-linked SPECC1L AD

163950

X-linked

300373

Sporadic

601803

AD

146510

AD

600001

Hypertelorism, hypospadias, cleft lip/ palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay Osteopathia striata Sclerosing bone dysplasia, male AMER1 with cranial sclelethal, macrocephaly, cleft palate, rosis (OSCS) mild learning disabilities, sclerosis of the long bones and skull, longitudinal striations visible on radiographs of the long bones, pelvis, and scapulae Pallister–Killian Severe mental retardation, seizures, Mosaic 12p short stature, coarse face, frontal tetrasomy bossing, temporal balding, upturned nose, full cheeks, droopy mouth, patchy hypopigmented skin, diaphragmatic hernia, supernumerary nipples Pallister–Hall Hypothalamic hamartoma, pituitary GLI3 dysfunction, central polydactyly, and visceral malformations Pancreatic agenesis and congenital heart defects

Pancreatic hypoplasia

43

GATA6

300000 145410

Continued

44 Cardiac Defecta

SECTION 1 

Cardiovascular Disorders

Syndrome Name Periventricular nodular heterotopia

Primary hypertrophic osteoarthropathy Renal-hepatic-pancreatic dysplasia (RHPD) Restrictive dermopathy

Ritscher–Schinzel syndrome-2  Roberts

Robinow

Rubenstein–Taybi

Severe congenital neutropenia-4 (SCN4) Short-rib thoracic dysplasia 13 with or without polydactyly Short-rib thoracic dysplasia 15 Short stature, developmental delay, and congenital heart defects

Cardinal Features

Etiology

Inheritance

OMIM

Majority female with in utero male lethality, BAV, aortic dilation, periventricular heterotopic nodules, seizures, mild mental retardation, coagulopathy, strokes Digital clubbing and osteoarthropathy, variable features of pachydermia, delayed closure of the fontanels Potter facies, oligohydramnios, cystic malformations of the kidneys, liver, and pancreas Lethal, thin, tightly adherent translucent skin with erosions at flexure sites, superficial vessels, typical facial dysmorphism, generalized joint ankyloses, polyhydramnios Intellectual disability, posterior fossa defects, and minor abnormalities of the face and distal extremities Variable-reduction limb defects, growth delay, cleft lip and palate, hypertelorism, delay, renal, defects, neonatal death, premature centromere separation Mesomelia, normal intellect, genital hypoplasia, and distinctive facial features  Mental retardation, postnatal growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features Congenital neutropenia, prominent superficial venous patterning

FLNA

X-linked

300049

HPGD

AR

259100

NPHP3

AR

208540

ZMPSTE24 LMNA

AR

275210

CCDC22

X-linked

300963

ESCO2

AR

269000

DVL3

AD

616894

CREBBP

AD, de novo

180849

G6PC3

AR

612541

Short-rib thoracic dysplasia and polydactyly

CEP120

AR

616300

Short-rib thoracic dysplasia and polydactyly Short stature, intellectual disability

DYNC2LI1

AR

617088

TKT

AR

617044

CHAPTER 1 

Cardiac Defecta

Syndrome Name Simpson–Golabi– Behmel

Congenital Heart Defects

Cardinal Features

Pre- and postnatal overgrowth, coarse facies, hypertelorism, broad nose, wide mouth, macroglossia, prominent jaw, broad hands, cleft/high palate, extra nipples, occasional, hypoplastic fingernails, polydactyly, hernias, renal tract abnormalities, mild mental retardation, embryonal tumors Smith–Lemli–Opitz Mental retardation, failure to thrive, feeding, difficulties, premature death, microcephaly, micrognathia, ptosis, anteverted nostrils, 2/3 syndactyly of toes, broad alveolar ridges, short stature, genital anomalies; occasional, polydactyly, cleft palate, various other, visceral malformations, cataract Sotos Pre- and postnatal overgrowth, macrocephaly, prominent forehead, down-slanting palpebral, fissures, pointed chin, mental retardation Spinal muscular Severe neuromuscular disorder atrophy with characterized by onset of severe congenital bone hypotonia in utero resulting in confractures 1 genital contractures and increased incidence of prenatal fracture of the long bones Stankiewicz–Isidor Intellectual disability, behavioral disorders, mild craniofacial anomalies, and variable congenital defects of the cardiac and/or urogenital systems Takenouchi–Kosaki Intellectual disability, dysmorphic syndrome facial features, genitourinary, and hematologic or lymphatic defects Townes–Brocks Imperforate anus, dysplastic ears, hearing loss, thumb malformations, renal impairment/anomalies Transaldolase Variable cardiac defects, wrinkly skin, deficiency and dysmorphic facial features  VATER/VACTERL Vertebral defects (V), anal atresia (A), tracheoesophageal fistula with esophageal atresia (TE), and radial or renal dysplasia (R), cardiac malformations (C) and limb anomalies (L) three or more of the above is suggestive of the diagnosis

45

Etiology

Inheritance

OMIM

GPC3

X-linked

312870

DHCR7

AR

270400

NSD1

AD, de novo

117550

TRIP4

AR

616866

PSMD12

AD

617516

CDC42

AD

616737

SALL1

AD

107480

TALDO1

AR

606003

Unknown

Unknown, sporadic

192350

Continued

46

SECTION 1 

Cardiac Defecta

Cardiovascular Disorders

Syndrome Name Weill–Marchesani

Zellweger

Zimmermann– Laband

aSpace

Cardinal Features

Etiology

Inheritance

OMIM

Microspherophakia, ectopia lentis, short stature, brachydactyly, joint stiffness Failure to thrive, facial dysmorphism, hearing loss, cataracts, glaucoma, liver dysfunction

FBN1 ADAMTS10

AD AR

608328

PEX1, 2, 3, 5, AR 6, 10, 12, 13, 14, 16, 19, 26 KCNH1 AD

214100

Gingival fibromatosis, dysplastic or absent nails, hypoplasia of the distal phalanges, scoliosis, hepatosplenomegaly, hirsutism, and abnormalities of the cartilage of the nose and/or ears

135500

does not permit the inclusion of every case report or occasional observation. 

APPENDIX 7 Cardiac Defecta

Syndrome Name

Pulmonary valve

17q21.31 deletion

9q subtelomeric deletion (Kleefstra) Adams–Oliver Cardiofaciocutaneous Carpenter

CHARGE

Cardinal Features

Etiology

Inheritance

OMIM

Mental retardation, hypotonia, and characteristic face (pulmonary stenosis) Moderate to severe mental retardation, hypotonia, facial dysmorphisms, urogenital defects, seizures, behavior problems Scalp defects, terminal transverse defects, CL/P Noonan-like, sparse curly hair, short stature, mental retardation

Deletion 17q21.31

AD

610443

9q34.3 deletion AD, sporadic resulting in haploinsufficiency of EHMT1 Unknown AD, AR

610253

BRAF, MAP2K1, MAP2K2, and KRAS genes RAB23

AD, de novo mutation

115150

AR

201000

AD—variable expressivity

214800

Craniosynostosis, preaxial polydactyly, brachysyndactyly, ptosis, obesity Colobomata (iris and/or retina), heart CHD7 gene defects, atresia choanae, retardation of growth and development and/or central nervous system anomalies, genital hypoplasia in males, ears cup shaped and hearing loss (pulmonary valve stenosis)

100300

CHAPTER 1 

Cardiac Defecta

Syndrome Name Costello

Keutel LEOPARD

Microphthalmia-9

Neurofibromatosis type I Noonan spectrum disorders

Simpson–Golabi– Behmel

Townes–Brocks

Weil–Marchesani

Williams

Congenital Heart Defects

47

Cardinal Features

Etiology

Inheritance

OMIM

Polyhydramnios, mental retardation, coarse face, thick lips, deep palmer/ plantar creases Brachytelephalangism, calcification of cartilages Lentigenes, ECG abnormalities, ocular hypertelorism, pulmonic stenosis, abnormal genitalia, retardation of growth, and sensorineural deafness Bilateral microphthalmia, IUGR, short stature, bilateral pulmonary hypoplasia/agensis, diaphragmatic hernia, mental retardation, hypotonia, early death Cafe au lait macules, Lisch nodules in the eye, fibromatous tumors of the skin Variable phenotype: Short stature, pectus excavatum/carinatum, hypertelorism, low-set ears, mild mental retardation

HRAS gene

AD—de novo mutation

218040

MGP

AR

245150

PTPN11 RAF1 BRAF

AD

151100 611554 613707

STRA6

AR

601186

NF1

AD

162200

BRAF, KRAS, LZTR1, NS2, PTPN11, RAF1, RIT1, SHOC2, SOS1 GPC3 CXORF5

AD

163950

X-linked

312870

SALL1

AD

107480

FBN1 ADAMTS10

AD AR

608328

Deletion chromosome 7q11.23

AD

194050

Pre- and postnatal overgrowth, coarse facies, hypertelorism, broad nose, wide mouth, macroglossia, prominent jaw, broad hands, cleft/ high palate, extra nipples, occasional, hypoplastic fingernails, polydactyly, hernias, renal tract abnormalities, mild mental retardation, embryonal tumors Imperforate anus, dysplastic ears, hearing loss, thumb malformations, renal impairment/ anomalies Microspherophakia, ectopia lentis, short stature, brachydactyly, joint stiffness (pulmonary valve stenosis) Distinctive facial characteristics, mental retardation, unique personality, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism)

ECG, electrocardiography; IUGR, intrauterine growth restriction. aSpace does not permit the inclusion of every case report or occasional observation. 

48

SECTION 1 

Cardiovascular Disorders

APPENDIX 8 Cardiac Defecta

Syndrome Name

Mitral valve anomalies

Adams–Oliver

Axenfeld–Rieger syndrome type 3 Beals

Cardinal Features

Etiology

Inheritance OMIM

Scalp defects, terminal transverse defects

Unknown

AD, AR

100300

FOXC1

AD

602482

FBN2

AD

121050

ZNF469

AR

229200

COH1

AR

216550

HRAS

AD—de novo

218040

COL5A1 COL5A2 COL3A1

AD

130000

AD

130050

GLA

X-linked

301500

FMR1

X-linked

300624

TKS4

AR

249420

CHST3

AD

143095

IDUA

AR

607014 607016

Axenfeld–Rieger anomaly, sensorineural hearing loss Arachnodactyly, large joint contractures, camptodactyly, “crumpled” ears, kyphoscoliosis Brittle cornea Blue sclerae, corneal rupture, keratoconus or keratoglobus, hyperelastic skin, hypermobile joints Cohen Truncal obesity, mental retardation, hypotonia, microcephaly, delayed puberty, distinctive face, chorioretinal dystrophy, neutropenia Costello Polyhydramnios, mental retardation, coarse face, thick lips, deep palmer/ plantar creases Ehlers Danlos—Clas- Joint hypermobility, increased skin elassic type ticity, abnormal wound healing Ehlers Danlos—vas- Connective tissue fragility with spontacular type neous rupture of arteries, bowel, poor wound healing Fabry disease Acroparesthesia, abdominal pain, hypertrophic cardiomyopathy, angiokeratomas, corneal opacities, renal failure, myocardial ischemia Fragile X Mental retardation, long face, large ears, enlarged testes Frank–ter Haar Brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea, glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers Humerospinal Congenital dislocations of knees and/ dysostosis (sponor hips, clubfoot, elbow joint dysplasia dyloepiphyseal with subluxation, limited extension, dysplasia with short stature congenital joint dislocations) Hurler (MPS IH;) Coarse facial features, cloudy cornea, Scheie (MPS IS;) stiff joints Hurler–Scheie (MPS IH/S)

CHAPTER 1 

Cardiac Defecta

Syndrome Name

Congenital Heart Defects

Cardinal Features

Etiology

Inheritance OMIM

Mental retardation, short stature, characteristic face with tented eyebrows and everted lower palpebral fissures, prominent ears, occasional skeletal and visceral malformations Loeys–Dietz Arterial tortuosity and aneurysms, hypertelorism, bifid uvula or cleft palate Marfan Ectopia lentis, dilated aorta, skeletal features including pectus, scoliosis Morquio (mucopoly- Coarse face, short stature, severe saccharidosis type kyphoscoliosis, genu valgum, odontoid IVA, IVB) corneal clouding, hearing loss Myotonic dystrophy Myotonia, cardiac arrythmia, cataracts, type 1 frontal balding Oculofaciocardioden- Congenital cataracts, microphthalmia, tal (OFCD) palate abnormalities Osteogenesis imper- Multiple fractures, osteopenia, wormian fecta (type 1) bones, blue sclerae, abnormal tooth enamel, progressive hearing loss Otopalatodigital (Mel- Skeletal dysplasia, facial dysmorphism, nick–Needles) cleft palate Progressive external Adult-onset weakness of the external ophthalmoplegia eye muscles, exercise intolerance Pseudoxanthoma Flexural cutaneous yellowish papular elasticum lesions, mild skin redundancy, retinal angioid streaks, chorioretinopathy

MLL2 gene

AD

147920

TGFBR1 TGFBR2

AD

609192 610168

Shprintzen–Goldberg Craniosynostosis, exophthalmos, maxillary and mandibular hypoplasia, arachnodactyly, camptodactyly Stickler High myopia, hearing loss, Pierre Robin sequence, cleft palate, vitreous anomaly

FBN1

Kabuki

Weill–Marchesani

Williams

aSpace

49

FBN1

Autosomal dominant GALNS (IVA) AR GLB1 (IVB)

154700

DMPK

AD

160900

BCOR

X-linked

300166

COL1A1 COL1A2

AD

166200

FLNA

X-linked

309350

POLG

AR

258450

ABCC6

AR with mild 264800 manifestations in carriers AD 182212

COL2A1 COL11A1 COL11A2 COL9A1 Microspherophakia, ectopia lentis, short FBN1 stature, brachydactyly, joint stiffness ADAMTS10 (pulmonary valve stenosis) Distinctive facial characteristics, mental Deletion retardation unique personality, growth chromoabnormalities, and endocrine abnorsome malities (hypercalcemia, hypercalciuria, 7q11.23 hypothyroidism)

does not permit the inclusion of every case report or occasional observation. 

253000 253010

AD AR

108300

AD AR

608328

AD

194050

50

SECTION 1 

Cardiovascular Disorders

APPENDIX 9 Cardiac Syndrome Defecta Name

Cardinal Features

Septal 1p36 deletion Defects

Intrauterine growth restriction, failure to thrive, microcephaly, dysmorphic facial features, hearing loss, CL/P, seizures 17q21.31 deleMental retardation, hypotonia, and tion characteristic face 18q deletion Mental retardation, microcephaly, short stature, hypotonia, hearing loss 2q37 deletion Short stature, brachydactyly, mental retardation 22q11 deletion Immune deficiency, palate abnormalities, hypocalcemia, psychiatric illness 3MC Facial dysmorphism, cleft lip and palate, postnatal growth deficiency, mental retardation, hearing loss, craniosynostosis, radioulnar synostosis, genital and vesicorenal anomalies  Recombinant Postnatal growth retardation, chromosome 8 microcephaly, dysmorphic facial features, hearing loss, skeletal anomalies, genitourinary anomalies, mental retardation 9p deletion Mental retardation, trigonocephaly, dysmorphic facial features, myopia, scoliosis, hypotonia  9q deletion

Adams– Oliver Agenesis of the corpus callosum with mental retardation, ocular coloboma, and micrognathia Alagille

Moderate to severe mental retardation, hypotonia, facial dysmorphisms, urogenital defects, seizures, behavior problems Scalp defects, terminal transverse defects, CL/P Agenesis of the corpus callosum, mental retardation, coloboma, micrognathia

Etiology

Inheritance

Deletion 1p36

Autososmal 607872 dominant (AD), sporadic

Deletion 17q21.31

AD

610443

Deletion 18q

AD, sporadic

601808

Contiguous gene deletion 22q11 deletion

AD, sporadic

600430

AD

188400 192430

MASP1

Autosomal 257920 recessive (AR)

Duplication of 8q22.1qter and deletion of 8pter-p23.1 

OMIM

179613

9p deletion

De novo, 158170 inherited from parental translocation 9q34.3 deletion result- AD, sporadic 610253 ing in haploinsufficiency of EHMT1 Unknown

AD, AR

100300

IGBP1

X-linked

300472

AD

118450 610205

Intrahepatic cholestasis (95%); JAG1, NOTCH1 defects of the arterior chamber of the eye (80%), mainly posterior embryotoxon; abnormal facies (90%); vertebral anomalies (70%)

CHAPTER 1 

Cardiac Syndrome Defecta Name

Cardinal Features

Alveolar capillary Failure of formation and in-growth dysplasia with of alveolar with medial muscular misalignment thickening of small pulmonary of pulmonary arterioles presenting as persistent veins (ACD/ pulmonary hypertension of the MPVs) newborn, multiple congenital anomalies: Gastrointestinal, genitourinary, musculoskeletal, and/or disruption of the normal right-left asymmetry of intrathoracic or intraabdominal organs Antley–Bixler Coronal and lambdoid suture synostosis, frontal bossing, severe midface hypoplasia, proptosis, choanal stenosis, bowed femora and ulnae vaginal atresia, renal anomalies Apert Severe craniosynostosis, flat face, hypertelorism syndactyly (mitten hands), occasional cleft palate, deafness, mental retardation, renal and genitourinary anomalies Arthrogryposis, Arthrogryposis multiplex congenita renal dyswith jaundice and renal dysfuncfunction, and tion, dysmorphic features cholestasis-1 (ARCS1) Athabaskan Horizontal gaze palsy, sensorineural brainstem deafness, central hypoventilation, dysgenesis developmental delay Axenfeld–Rieger Axenfeld–Rieger anomaly, sensorisyndrome neural hearing loss type 3 Baller–Gerold Craniosynostosis, radial aplasia, missing thumbs, anal anomalies, skeletal defects, central nervous system defects, urogenital defects Bardet–Biedl Mental retardation, ulnar polydactyly, obesity, retinal dystrophy, hypogenitalism, kidney disease, occasional short stature, hearing loss, vaginal atresia

Congenital Heart Defects

51

Etiology

Inheritance

OMIM

FOX transcription factor gene cluster on chromosome 16q24.1q24.2

AD

265380

POR

AR

207410

FGFR2

AD

101200

VPS33B

AR

208085

HOXA1

AR

601536

FOXC1

AD

602482

RECQL4

AR

218600

Fourteen genes: BBS1, BBS2, ARL6/ BBS3, BBS4, BBS5, MKKS/BBS6, BBS7, TTC8/BBS8, B1/ BBS9, BBS10, TRIM32/BBS11, BBS12, MKS1/ BBS13, CEP290/ BBS14

AR

209900

Continued

52

SECTION 1 

Cardiac Syndrome Defecta Name Beals

C (opitz trigonocephaly) Campomelic dysplasia

Cardiofaciocutaneous Carpenter

Cat eye Cerebrocostomandibular CHARGE

CHILD

CHIME

CHOPS

Coffin–Siris Congenital disorders of glycosylation type IIa

Cardiovascular Disorders

Cardinal Features

Etiology

Inheritance

OMIM

Arachnodactyly, large joint contractures, camptodactyly, “crumpled” ears, kyphoscoliosis Facial dysmorphism, mental retardation, redundant skin, omphalocele, hepatomegaly Pierre Robin sequence with cleft palate, shortening and bowing of long bones, and club feet, sex reversal Noonan-like, sparse curly hair, short stature, mental retardation Craniosynostosis, preaxial polydactyly, brachysyndactyly, ptosis, obesity Iris coloboma, anal atresia, preauricular tags renal malformations Severe micrognathia, rib defects, and mental retardation Colobomata (iris and/or retina, heart defects, atresia choanae, retardation of growth and development and/or central nervous system anomalies, genital hypoplasia in males, ears cup shaped and hearing loss (pulmonary valve stenosis) Congenital hemidysplasia, ichthyosiform nevus, limb defects; occasional visceral hypoplasia, CNS lesions and mental retardation Colobomas, congenital heart defects, migratory ichthyosiform dermatosis, mental retardation, and ear anomalies Cognitive impairment, coarse facies, heart defects, obesity, pulmonary involvement, short stature, and skeletal dysplasia Growth deficiency, mental retardation, microcephaly Facial dysmorphism, stereotypic hand movements, seizures, mental retardation variable

FBN2

AD

121050

CD96

AR

211750

SOX9

AD

114290

BRAF, MAP2K1, MAP2K2, KRAS RAB23 MEGF8

AD, de novo mutation AR

115150

Chromosome 22 partial tetrasomy SNRPB

Sporadic

115470

AD

117650

CHD7 gene

AD- variable expressivity

214800

NSDHL

X-linked

308050

PIGL

AR

280000

AFF4

AD

616368

Unknown

AR

135900

ALG2

AR

212066

201000 614976

CHAPTER 1 

Cardiac Syndrome Defecta Name Chondrodysplasia punctata 2

Cardinal Features

Asymmetrical shortening of limbs, stippled epiphysis, contractures, patchy skin changes, epiphysis, contractures, patchy skin changes, sparse hair, flat facies Cohen Truncal obesity, mental retardation, hypotonia, microcephaly, delayed puberty, distinctive face, chorioretinal dystrophy, neutropenia Cornelia de Mental retardation, growth failure, Lange microbrachycephaly, hirsutism, synophrys, variable upper limb Reduction defects Costello Polyhydramnios, mental retardation, coarse face, thick lips, deep palmar/plantar creases CranioectoderCraniosynostosis facial dysmormal dysplasia-2 phism, ectodermal and skeletal anomalies Cri du chat (5p-) Growth deficiency, catlike cry, developmental delay, microcephaly, round face, hypertelorism Diamond-Black- Growth retardation, normochromic, fan anemia macrocytic, anemia, craniofacial, upper-limb, or genitourinary malformations Down Hypotonia, mental retardation, up-slanting palpebral fissures, epicanthal folds, brachycephaly, single palmar crease Duane-radial ray Upper limb anomalies, ocular anomalies, renal anomalies Edwards Growth failure, hypertonia, small palpebral fissures, clenched hands with overlapping digits, omphalocele, neural tube defect Ellis–van Creveld Short stature, postaxial polydactyly, miso/acromelic shortening of limbs, short ribs Emanuel Multiple congenital anomalies, craniofacial dysmorphism, mental retardation Goldenhar Hemifacial microsomia, epibulbar dermoid, preauricular ear tags, deafness, microtia, eyelid coloboma, cleft palate, vertebral anomalies

Congenital Heart Defects

53

Etiology

Inheritance

OMIM

EBP

X-linked

302960

COH1

AR

216550

NIPBL SMC1A

AD X-linked

122470 300590

HRAS gene

AD- de novo mutation

218040

WDR35

AR

613610

Deletion 5p

Sporadic; 5p translocation in 10%–15% AD

123450

RPS19, RPL5, RPL11, RPL35A, RPS24, RPS17, RPS7, RPS10, RPS26 Trisomy 21

105650

SALL4

Nondisjunction, 190685 unbalanced robertsonian translocations AD 607323

Trisomy 18

Sporadic

EVC1 and EVC2

AR

Malsegregation of the t(11;22) (q23;q11.2) translocation Unknown Sporadic, AD, AR

225500

609029

164210

Continued Continued

54

SECTION 1 

Cardiac Syndrome Defecta Name

Cardiovascular Disorders

Cardinal Features

Etiology

Inheritance

OMIM

Severe psychomotor retardation, poor overall growth, and dysmorphic facial features

FTO

AR

612938

Pancytopenia, leukemia, short stat- FANCA, FANCB, ure, café au lait macules absent/ FANCC, BRCA2 hypoplastic thumb, small genita(FANCD1), FANCD2, lia, microcephaly, renal abnormalFANCE, FANCF, ities, mental retardation, small FANCG (XRCC9), eyes, hearing loss, no physical FANCI, BRIP1(manifestations in ∼25%–40% FANCJ or BACH1), FANCL, FANCM, PALB2 (FANCN), RAD51C (FANCO), SLX4 (FANCP) FG Macrocephaly (absolute and relaMED12 tive), congenital hypotonia, small ears, agenesis of the corpus callosum, constipation, mental retardation Fontaine proPrenatal and postnatal growth SLC25A24 geroid retardation, decreased subcutaneous fat tissue, sparse hair, triangular face, widely open anterior fontanel, convex and broad nasal ridge, micrognathia, craniosynostosis Fryns Diaphragmatic defects, corneal Unknown clouding, hypoplastic distal digits Goltz (Focal der- Focal dermal hypoplasia, oligodac- PORCN gene mal hypoplasia) tyly, hypoplastic teeth, microphthalmos, coloboma, alopecia, mental retardation

AR

227650

X-linked

305450

AD

612289

Presumed AR

229850

X-linked

305600

H Syndrome

AR

612391

Sporadic

234100

AD

102500

Growth retardation, developmental delay, facial dysmorphism Fanconi anemia

Hallermann– Streiff

Hajdu–Cheney

Cutaneous hyperpigmentation, SLC29A3 hypertrichosis, hepatosplenomegaly, hypogonadism hearing loss, short stature Microphthalmia, cataract, small Unknown jaw, frontal prominence, thin pointed nose, dental anomalies, hypotrichosis, skin atrophy, short stature Short stature, coarse and dysmor- NOTCH2 phic facies, bowing of the long bones, and vertebral anomalies

CHAPTER 1 

Cardiac Syndrome Defecta Name Hennekam lymphangiectasia-lymphedema

Holt–Oram

Jacobsen

Johanson–Blizzard

Kabuki

Keutel Linear skin defects with multiple congenital anomalies Lujan–Fryns

Lymphedema-distichiasis

Congenital Heart Defects

55

Cardinal Features

Etiology

Inheritance

OMIM

Early-onset lymphedema, intestinal, lymphangiectasia, growth retardation, mental retardation, seizures, flat midface, epicanthus, hypertelorism, ear anomalies, tooth anomalies, renourinary malformations, deafness, skeletal anomalies Triphalangeal or hypoplastic to absent thumb bifid thumb, variable hypoplasia of first metacarpal, radius or whole limy, narrow shoulders. Growth retardation, mental retardation, dysmorphic features, strabismus, thrombocytopenia Failure to thrive, pancreatic insufficiency, hypothyroidism, aplasia cutis congenital, abnormal hair, hypoplastic alae nasi, mental retardation, sensorineural deafness Mental retardation, short stature, characteristic face with tented eyebrows and everted lower palpebral fissures, prominent ears, occasional skeletal and visceral malformations Brachytelephalangism, calcification of Linear skin defects with multiple congenital anomalies

CCBE1

AR

235510

TBX5

AD

142900

Terminal deletion 11q

AD

147791

UBR1 gene

AR

243800

MLL2 gene

AD

147920

MGP

AR

245150

COX7B

X-linked

300887

Marfanoid habitus, sharp nose, hypernasal voice, behavior problems

MED12

Extra row of eyelashes, late-onset FOXc2 lymphedema; occasional cleft palate, micrognathia, pterygium colli, ptosis, Arnold–Chiari malformation, urinary tract malformations, spinal extradural cysts, vertebral anomalies, double uterus

309520

AD

153400

Continued

56

SECTION 1 

Cardiac Syndrome Defecta Name Meckel–Gruber

Marshall–Smith

Mental retardation, AD 32 Mental retardation, X-linked, syndromic 34

Mental retardation, X-linked 99, syndromic, female-restricted McKusick– Kaufman Microcephalic osteodysplastic primordial dwarfism (MOPD) I Microphthalmia-2 Microphthalmia-3 

Microphthalmia-7 (microphthalmia with linear skin defects) Microphthalmia-9

Cardiovascular Disorders

Cardinal Features

Etiology

Inheritance

OMIM

Renal cysts, CNS anomalies (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly Accelerated linear growth, failure to thrive, mental retardation, and characteristic facial appearance (prominent forehead, shallow orbits, blue sclerae, depressed nasal bridge, and micrognathia) Intellectual disability, microcephaly, poor growth, absent speech Intellectual disability, poor speech, dysmorphic facial features, and mild structural brain abnormalities, including thickening of the corpus callosum Mild to moderate intellectual disability, scoliosis, postaxial polydactyly, mild cardiac or urogenital anomalies, dysmorphic facial features, and mild structural brain abnormalities  Postaxial polydactyly, hydrometrocolpos Primordial dwarfism

MKS1

AR

249000

NFIX

AD

602535

KAT6A

AD

616268

NONO

X-linked

300967

USP9X

X-linked

300968

MKKS

AR

236700

Unknown

AR

210710

Microphthalmia, microcephaly, BCOR short stature, congenital cataract, dysmorphic facial features Anophthalmia/microphthalmia, SOX2 brain anomalies, seizures, mental retardation, sensorineural hearing loss, esophageal atresia, growth hormone deficiency, gonadotropin deficiency

X-linked

300166

AD

206900

Unilateral or bilateral microphthalmia and linear skin defects

X-linked

309801

AR

601186

HCCS

Bilateral microphthalmia, intrauterine STRA6 growth restriction, short stature, bilateral pulmonary hypoplasia/ agenesis, diaphragmatic hernia, mental retardation, hypotonia, early death

CHAPTER 1 

Cardiac Syndrome Defecta Name Miller

Cardinal Features

Severe micrognathia, cleft lip and/ or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids, and supernumerary nipples Mowat–Wilson Distinctive facial appearance, Hirschsprung disease or chronic constipation, fleshy upturned ear lobules Multiple congeni- Neonatal hypotonia, lack of psytal anomalieschomotor development, seizures, hypotoniadysmorphic features, and variable seizures congenital anomalies syndrome Myhre Short stature, joint limitations, thick skin, muscular hypertrophy, autism spectrum disorder Neu–Laxova Lethal, ichthyosis, marked intrauterine growth restriction, microcephaly, central nervous system anomalies, limb deformities, hypoplastic lungs, edema, and abnormal facial features Noonan Short stature, pectus excavatum/ carinatum, hypertelorism, low-set ears, mild mental retardation Oculofaciocardi- Congenital cataracts, microphthalodental (OFCD) mia, palate abnormalities Ohdo Mental retardation, blepharophimosis, ptosis, hypoplastic teeth, dysplastic ears, characteristic nose, small mouth, hearing loss Opitz G/BBB Hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay Osteopathia Sclerosing bone dysplasia, male striata with cra- lethal, macrocephaly, cleft palate, nial sclerosis mild learning disabilities, sclero(OSCS) sis of the long bones and skull, longitudinal striations visible on radiographs of the long bones, pelvis, and scapulae Pallister–Hall Hypothalamic hamartoma, pituitary dysfunction, central polydactyly, and visceral malformations

Congenital Heart Defects

57

Etiology

Inheritance

OMIM

DHODH gene

AR

263750

ZEB2 gene

AD de novo mutation

235730

PIGN PIGT

AR

614080 615398

Unknown

?AR

139210

PHGDH

AR

256520

PTPN11, SOS1, KRAS, RAF1

AD

163950

BCOR

X-linked

300166

Unknown

AD

249620

MID1 gene

X-linked

300000

AMER1

X-linked

300373

GLI3

AD

146510

Continued

58

SECTION 1 

Cardiac Syndrome Defecta Name

Cardiovascular Disorders

Cardinal Features

Etiology

Severe mental retardation, seizures, short stature, coarse face, frontal bossing, temporal balding, upturned nose, full cheeks, droopy mouth, patchy hypopigmented skin, diaphragmatic hernia, supernumerary nipples Pancreatic hypoplasia

Mosaic 12p tetrasomy Sporadic

601803

GATA6

AD

600001

Mental retardation, incomplete development of forebrain, polydactyly, microcephaly, microphthalmia, cleft lip, cleft palate, deafness, cryptorchidism, scalp defects Anterior body wall defect, short or bifid sternum, diaphragmatic pericardium defect Peters anomaly, short stature, short limbs, brachydactyly, round face, thin lips, long philtrum, mental retardation, occasional cleft lip/ palate, renal abnormalities Potter facies, oligohydramnios, cystic malformations of the kidneys, liver, and pancreas

Trisomy 13

Sporadic

Unknown with some cases linked to Xq26.1 B3GALTL

Sporadic

313850

AR

261540

Renal-hepatic-pancreatic dysplasia (RHPD) Renpenning Mental retardation, microcephaly, (Golabi-Ito-Hall) short stature, and small testes Restrictive derLethal, thin, tightly adherent mopathy translucent skin with erosions at flexure sites, superficial vessels, typical facial dysmorphism, generalized joint ankyloses, polyhydramnios Ritscher– Intellectual disability, posterior Schinzel fossa defects, and minor abnormalities of the face and distal extremities

NPHP3

AR

208540

PQBP1 gene

X-linked

309500

ZMPSTE24 LMNA

AR

275210

WSHC5 CCDC22

AR X-linked

220210 300963

Roberts

ESCO2

AR

269000

Pallister–Killian

Pancreatic agenesis and congenital heart defects Pateau (trisomy 13)

Pentalogy of Cantrell Peters-plus

Variable-reduction limb defects, growth delay, cleft lip and palate, hypertelorism, delay, renal, defects, neonatal death, premature centromere separation

Inheritance

OMIM

CHAPTER 1 

Cardiac Syndrome Defecta Name Robinow

Cardinal Features

Mesomelia, normal intellect, genital hypoplasia, and distinctive facial features  Rubenstein– Mental retardation, postnatal Taybi growth deficiency, microcephaly, broad thumbs and halluces, and dysmorphic facial features Schinzel–Giedion Mental retardation, severe midface hypoplasia, hirsutism, hydronephrosis, genital, anomalies, skeletal anomalies, choanal stenosis, brain malformations, sacrococcygeal tumors Short stature, Short stature, intellectual disability developmental delay, and congenital heart defects Sifrim–Hitz– Intellectual disability syndrome Weiss associated with variable congenital defects affecting other systems, including cardiac, skeletal, and urogenital.  Simpson– Pre- and postnatal overgrowth, Golabi–Behmel coarse facies, hypertelorism, broad nose, wide mouth, macroglossia, prominent jaw, broad hands, cleft/high palate, extra nipples, occasional, hypoplastic fingernails, polydactyly, hernias, renal tract abnormalities, mild mental retardation, embryonal tumors Smith–Lemli– Mental retardation, failure to thrive, Opitz feeding, difficulties, premature death, microcephaly, micrognathia, ptosis, anteverted nostrils, 2/3 syndactyly of toes, broad alveolar ridges, short stature, genital anomalies; occasional, polydactyly, cleft palate, various other, visceral malformations, cataract

Congenital Heart Defects

59

Etiology

Inheritance

OMIM

DVL3

AD

616894

CREBBP EP300

AD, de novo

180849

SETBP1

AD de novo

269150

TKT

AR

617044

CHD4

AD

617159

GPC3

X-linked

312870

DHCR7

AR

270400

Continued

60

SECTION 1 

Cardiac Syndrome Defecta Name Sotos

Spinal muscular atrophy type I

Spinal muscular atrophy with congenital bone fractures 1 Stankiewicz– Isidor

Structural heart defects and renal anomalies Takenouchi–Kosaki syndrome Thanatophoric dysplasia

Thrombocytopenia–absent radius (TAR) Timothy

Townes–Brocks

Cardiovascular Disorders

Cardinal Features

Etiology

Inheritance

OMIM

Pre- and postnatal overgrowth, macrocephaly, prominent forehead, downslanting palpebral, fissures, pointed chin, mental retardation Muscle weakness, symmetric, proximal (lower limbs more affected than upper limbs), muscle atrophy, EMG shows neurogenic abnormalities, areflexia Severe neuromuscular disorder characterized by onset of severe hypotonia in utero resulting in congenital contractures and increased incidence of prenatal fracture of the long boneS Intellectual disability, behavioral disorders, mild craniofacial anomalies, and variable congenital defects of the cardiac and/or urogenital systems Heart defects and renal anomalies

NSD1

AD de novo

117550

SMN1, SMN2

AR

253300

TRIP4

AR

616866

PSMD12

AD

617516

TMEM260

AR

617478

Intellectual disability, dysmorphic facial features, genitourinary, and hematologic or lymphatic defects Severe short-limbed dwarfism, narrowed chest, neonatal death, macrocephaly, depressed nasal bridge, curved short femurs, metaphyseal flaring, H-shaped flattened vertebrae, brain anomalies; occasional cloverleaf skull Bilateral absent radius, (thumbs are present) ulnar hypoplasia, thumbs present, occasionally mentally retarded, squint Lethal arrhythmias, syndactyly, facial dysmorphology, immune deficiency, intermittent hypoglycemia, mental retardation, autism Imperforate anus, dysplastic ears, hearing loss, thumb malformations, renal impairment/anomalies

CDC42

AD

616737

FGFR3

AD de novo

187600

RBM8A

AR

274000

CACNA1C

AD, de novo

601005

SALL1

AD

107480

CHAPTER 1 

Cardiac Syndrome Defecta Name

Cardinal Features

Transaldolase deficiency

Variable cardiac defects, wrinkly skin, and dysmorphic facial features  Uniparental Asymmetry, hypertelorism, small disomy chrohands and feet, 5th finger clinomosome 16 dactyly, microcephaly (maternal) Hypospadias, scoliosis Neonatal proLow birth weight, aged appearance geria from birth, pinched features, development delay, sparse hair, lack of subcutaneous fat apart from pads over buttocks VATER/VACTERL Vertebral defects (V), anal atresia (A), tracheoesophageal fistula with esophageal atresia (TE), and radial or renal dysplasia (R), cardiac malformations (C) and limb anomalies (L) three or more of the above is suggestive of the diagnosis Weill–Marches- Microspherophakia, ectopia lentis, ani short stature, brachydactyly, joint stiffness Williams Distinctive facial characteristics, mental retardation unique personality, growth abnormalities, and endocrine abnormalities (hypercalcemia, hypercalciuria, hypothyroidism) Wolf–Hirschhorn Growth deficiency, severe mental retardation, microcephaly, seizures, hypertelorism, prominent glabella, highly arched eyebrows, proptosis, strabismus, cleft lip/ palate, agenesis of corpus of cases callosum, talipes, hypospadias, cryptorchidism Yunis–Varon Dolichocephaly, wide anterior fontanelles, sparse hair, dysmorphic, thin lips, short philtrum, micrognathia, absent thumbs, hypoplastic clavicles Zellweger Failure to thrive, facial dysmorphism, hearing loss, cataracts, glaucoma, liver dysfunction aSyndromes

may be associated with multiple types of cardiac defects. 

Congenital Heart Defects

61

Etiology

Inheritance

OMIM

TALDO1

AR

606003

Maternal uniparental disomy chromosome 16

Sporadic

Unknown

AR

264090

Unknown

Sporadic

192350

FBN1 ADAMTS10

AD AR

608328

Deletion chromosome AD 7q11.23

194050

Deletion in 165-kb critical region chromosome 4p Translocations in 10%–15%

Sporadic; de novo

194190

AR

216340

AR

214100

PEX1, 2, 3, 5, 6, 10, 12, 13, 14, 16, 19, 26

62

SECTION 1 

Cardiovascular Disorders

APPENDIX 10 Cardiac Defecta

Syndrome Name

Cardinal Features

Transposition 1q21.1 microdele- Microcephaly, mild facial dysof the great tion morphism, autism, various arteries heart defects 22q11 deletion Immune deficiency, palate abnormalities, hypocalcemia, psychiatric illness Antley–Bixler Coronal and lambdoid suture synostosis, frontal bossing, severe midface hypoplasia, proptosis, choanal stenosis, bowed femora and ulnae, vaginal atresia, renal anomalies Congenital Developmental delay, hypotodisorders of nia, failure to thrive, hepatic glycosylation Ia dysfunction, coagulopathy, abnormal subcutaneous fat, seizures, cerebellar hypoplasia/ atrophy and small brain stem Ellis–van Creveld Short stature, postaxial polydactyly, meso/acromelic shortening of limbs, short ribs aSpace

Etiology

Inheritance

OMIM

1q21.1 deletion

AD, reduced penetrance

612474

22q11 deletion AD

188400 192430

POR

AR

207410

PMM2

AR

212065

EVC1 and EVC2

AR

225500

does not permit the inclusion of every case report or occasional observation. 

APPENDIX 11 Cardiac Defect*

Syndrome Name

Cardinal Features

Truncus 1q21.1 Microcephaly, mild facial dysmorarteriosus microdeletion phism, autism, various heart defects

Etiology

Inheritance

OMIM

1q21.1 deletion

Autosomal dominant (AD), reduced penetrance AD

612474

22q11 deletion Immune deficiency, palate abnormali- 22q11 deletion ties, hypocalcemia, psychiatric illness Adams–Oliver Aplasia cutis congenita of the scalp DLL4 syndrome 6 vertex and terminal transverse limb defects Congenital Developmental delay, hypotonia, PMM2 disorders of failure to thrive, hepatic dysfunction, glycosylation coagulopathy, abnormal subcutaneIa ous fat, seizures, cerebellar hypoplasia/atrophy and small brain stem

AD

188400 192430 616589

Autosomal reces- 212065 sive (AR)

CHAPTER 1 

Cardiac Defect*

Syndrome Name

Cardinal Features

Structural Heart defects and renal anomalies heart defects and renal anomalies Emanuel Multiple congenital anomalies, craniofacial dysmorphism, mental retardation Goltz (Focal Focal dermal hypoplasia, oligodactyly, dermal hypohypoplastic teeth, microphthalmos, plasia) coloboma, alopecia, mental retardation Holt–Oram Triphalangeal or hypoplastic to absent thumb bifid thumb, variable hypoplasia of first metacarpal, radius or whole limy, narrow shoulders. MicrophthalBilateral microphthalmia, intrauterine mia-9 growth restriction, short stature, bilateral pulmonary hypoplasia/agenesis, diaphragmatic hernia, mental retardation, hypotonia, early death Pancreatic Pancreatic hypoplasia agenesis and congenital heart defects Renal-hepatThe main organs affected include the ic-pancreatic kidney, liver, and pancreas, although dysplasia 2 other abnormalities, including cardiac, skeletal, and lung defects, may also be present Stankiewicz– Isidor

Congenital Heart Defects

Etiology

Inheritance

OMIM

TMEM260

AR

617478

Malsegregation of the t(11;22) (q23;q11.2) translocation PORCN gene

X-linked

305600

TBX5

AD

142900

STRA6

AR

601186

GATA6

AD

600001

NEK8

AR

615415

AD

617516

Unknown

274000

AD

107480

Intellectual disability, behavioral disor- PSMD12 ders, mild craniofacial anomalies, and variable congenital defects of the cardiac and/or urogenital systems ThrombocyBilateral absent radius, (thumbs are 200 kb deletion, topenia– present) ulnar hypoplasia, thumbs chromosome absent radius present, occasionally mentally 1q21.1 (TAR) retarded, squint Townes– Imperforate anus, dysplastic ears, SALL1 Brocks hearing loss, thumb malformations, renal impairment/anomalies

 

63

609029

64

SECTION 1 

Cardiovascular Disorders

APPENDIX 12 Cardiac Defect*

Syndrome Name

Cardinal Features

Etiology

Total/partial 22q11.2 microdu- Highly variable phenotype from normal anomalous plication to mental retardation, growth retarpulmonary dation, and/or hypotonia venous return Athabaskan brain- Horizontal gaze palsy, sensorineural stem dysgenesis deafness, central hypoventilation, developmental delay Cat eye Iris coloboma, anal atresia, preauricular tags renal malformations Desmosterolosis Microcephaly, microcephaly, cleft palate, facial dysmorphic features, osteosclerosis Holt–Oram Triphalangeal or hypoplastic to absent thumb bifid thumb, variable hypoplasia of first metacarpal, radius or whole limy, narrow shoulders Smith–Lemli– Mental retardation, failure to thrive, Opitz feeding, difficulties, premature death, microcephaly, micrognathia, ptosis, anteverted nostrils, 2/3 syndactyly of toes, broad alveolar ridges, short stature, genital anomalies; occasional, polydactyly, cleft palate, various other, visceral malformations, cataract Structural heart Heart defects and renal anomalies defects and renal anomalies

Inheritance

3-Mb or 1.5-Mb Autosomal 22q11 duplication dominant (AD)

OMIM 608363

HOXA1

Autosomal 601536 recessive (AR)

Chromosome 22 partial tetrasomy DHCR24

Sporadic

115470

AR

602398

TBX5

AD

142900

DHCR7

AR

270400

TMEM260

AR

617478

 

APPENDIX 13: SYNDROMES TETRALOGY Cardiac Defecta

Syndrome Name

Cardinal Features

Etiology

Tetralogy 1p36 deletion Short stature, facial 1p36 deleof Fallot dysmorphism, tion microcephaly, hearing loss, hypotonia, developmental delay, facial clefting 15q13.3 Mental retardation, 15q13.3 deletion seizures, autism, deletion schizophrenia

Gene Inheritance OMIM Reviews Reference Photo Autosomal dominant (AD)

607872

Click link

AD

612001

Click link

CHAPTER 1 

Cardiac Defecta

Syndrome Name 16p11.2 deletion 22q11 deletion

Cardinal Features

Mental retardation, autism Immune deficiency, palate abnormalities, hypocalcemia, psychiatric illness 9q subModerate to severe telomeric mental retardadeletion tion, hypotonia, facial dysmorphisms, urogenital defects, seizures, behavior problems Adams–Oliver Scalp defects, terminal transverse defects, CL/P Alagille Intrahepatic cholestasis (95%); defects of the anterior chamber of the eye (80%), mainly posterior embryotoxon; abnormal facies (90%); vertebral anomalies (70%) Athabaskan Horizontal gaze brainstem palsy, sensoridysgenesis neural deafness, central hypoventilation, developmental delay Baller–Gerold Craniosynostosis, radial aplasia, missing thumbs, anal anomalies, skeletal defects, central nervous system defects, urogenital defects

Etiology

Congenital Heart Defects

Gene Inheritance OMIM Reviews Reference Photo

16p11.2 deletion 22q11 deletion TBX1 mutation

AD

611913

Click link

[87]

AD

188400 192430

Click link

[35]

9q34.3 deletion resulting in haploinsufficiency of EHMT1

AD, sporadic 610253

[88]

Unknown

AD, autosomal recessive (AR) AD

100300

[89]

HOXA1

AR

601536

RECQL4

AR

218600

JAG1, NOTCH1

65

118450 610205

Click link

[42,90]

[91]

Click link

Continued

66 Cardiac Defecta

SECTION 1 

Cardiovascular Disorders

Syndrome Name

Cardinal Features

C syndrome

Mental retardation, metopic ridge, broad alveolar ridges, up-slanting eyes, epicanthus, forehead hemangioma, upturned nose; joint, kidney, genital, and brain anomalies Pierre Robin sequence with cleft palate, shortening and bowing of long bones, and club feet, sex reversal Craniosynostosis, preaxial polydactyly, brachysyndactyly, ptosis, obesity Colobomata (iris and/or retina, heart defects, atresia choanae, retardation of growth and development and/ or central nervous system anomalies, genital hypoplasia in males, ears cup shaped and hearing loss Growth deficiency, mental retardation, microcephaly

Campomelic dysplasia

Carpenter

CHARGE

Coffin–Siris

Etiology

Gene Inheritance OMIM Reviews Reference Photo

CD96

AR

605039

SOX9

AD

114290

RAB23 gene

AR

201000

CHD7 gene

AD- variable expressivity

214800

Unknown

?AR

135900

AR

212065

Congenital Developmental PMM2 disorders of delay, hypotonia, glycosylafailure to thrive, tion Ia hepatic dysfunction, coagulopathy, abnormal subcutaneous fat, seizures, cerebellar hypoplasia/ atrophy, and small brain stem

[92]

Click link

[93]

Click link

[94]

Click link

[95]

CHAPTER 1 

Cardiac Defecta

Syndrome Name

Cardinal Features

Cornelia de Lange

Mental retardation, NIPBL growth failure, SMC1A microbrachycephaly, hirsutism, synophrys, variable upper limb reduction defects Growth retardation, RPS19, normochromic, RPL5, macrocytic, RPL11, anemia, craniofaRPL35A, cial, upper-limb, RPS24, or genitourinary RPS17, malformations RPS7, RPS10, RPS26 Hypotonia, mental Trisomy 21 retardation, up-slanting palpebral fissures, epicanthal folds, brachycephaly, single palmar crease Growth failure, Trisomy 18 hypertonia, small palpebral fissures, clenched hands with overlapping digits, omphalocele, neural tube defect Hypertelorism, ALX3 broad nasal root, median nasal cleft, short stature, microcephaly Hemifacial microUnknown somia, epibulbar dermoid, preauricular ear tags, deafness, microtia, eyelid coloboma, cleft palate, vertebral anomalies

DiamondBlackfan Anemia

Down

Edwards

Frontonasal dysplasia

Goldenhar

Etiology

Congenital Heart Defects

67

Gene Inheritance OMIM Reviews Reference Photo AD X-linked

122470 300590

Click link

[96]

AD

105650

Click link

[97]

Nondis190685 junction, unbalanced robertsonian translocations

[98]

Sporadic

[28]

Sporadic

136760

Sporadic, AD, AR

164210

[99]

Click link

[100]

Continued

68 Cardiac Defecta

SECTION 1 

Cardiovascular Disorders

Syndrome Name

Cardinal Features

Hallermann– Streiff

Microphthalmia, Unknown cataract, small jaw, frontal prominence, thin pointed nose, dental anomalies, hypotrichosis, skin atrophy, short stature Triphalangeal or TBX5 hypoplastic to absent thumb bifid thumb, variable hypoplasia of first metacarpal, radius or whole limy, narrow shoulders. HOS excluded with malformations involving: ulnar ray only, kidney, vertebra, craniofacies, hearing loss or ear malformations, lower limb, anus, or eye HypoparathyroidMicrodeleism, sensorineural tion of 10p deafness, renal including disease GATA3

Sporadic

234100

AD

142900

AD

146255

[102]

Mental retardation, MLL2 gene short stature, characteristic face with tented eyebrows and everted lower palpebral fissures, prominent ears, occasional skeletal and visceral malformations

AD

147920

[103]

Holt–Oram

Hypoparathyroidism, sensorineural deafness, and renal disease (HDR) Kabuki

Etiology

Gene Inheritance OMIM Reviews Reference Photo [101]

Click link

Yes

CHAPTER 1 

Cardiac Defecta

Syndrome Name Lymphedema-distichiasis

Cardinal Features

Etiology

Distichiasis, late-on- FOXc2 set lymphedema; occasional cleft palate, micrognathia, pterygium colli, ptosis, Arnold–Chiari malformation, urinary tract malformations, spinal extradural cysts, vertebral anomalies, double uterus McKusick– Postaxial polydacMKKS Kaufman tyly, hydrometrocolpos Microcephalic Primordial dwarfUnknown osteodysism plastic primordial dwarfism (MOPD) I Microphthal- Bilateral microphSTRA6 mia-9 thalmia, intrauterine growth restriction (, short stature, bilateral pulmonary hypoplasia/agenesis, diaphragmatic hernia, mental retardation, hypotonia, early death Miller–Dieker Lissencephaly type Deletions at I, severe retar17p13.3 dation, seizures, including growth failure, LIS1, tall furrowed foresequence head, bitemporal variations narrowing, short LIS1 upturned nose Nager Acrofacial dysosUnknown acrofacial tosis resembling dysostosis Treacher Collins syndrome combined with predominantly radial limb defects

Congenital Heart Defects

69

Gene Inheritance OMIM Reviews Reference Photo AD

153400

Click link

AR

236700

Click link

AR

210710

AR

601186

AD

247200

AD

154400

[104]

[105]

Click link

Continued

70 Cardiac Defecta

SECTION 1 

Syndrome Name Opitz G/BBB

Cardiovascular Disorders

Cardinal Features

Hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay Pentalogy of Anterior body wall Cantrell defect, short or bifid sternum, diaphragmatic pericardium defect Renpenning Mental retardation, (Golabi-Itomicrocephaly, Hall) short stature, and small testes Smith–Lemli– Mental retardation, Opitz failure to thrive, feeding, difficulties, premature death, microcephaly, micrognathia, ptosis, anteverted nostrils, 2/3 syndactyly of toes, broad alveolar ridges, short stature, genital anomalies; occasional, polydactyly, cleft palate, various other, visceral malformations, cataract ThromboBilateral absent cytoperadius, (thumbs nia–absent are present) radius (TAR) ulnar hypoplasia, thumbs present, occasionally mentally retarded, squint

Etiology

Gene Inheritance OMIM Reviews Reference Photo

MID1 gene

X-linked

300000

Click link

Unknown Sporadic with some cases linked to Xq26.1 PQBP1 gene X-linked

313850

DHCR7

AR

270400

Click link

200 kb deletion, chromosome 1q21.1

Unknown

274000

Click link

309500

[106]

[107]

[108]

CHAPTER 1 

Cardiac Defecta

Syndrome Name

Cardinal Features

Timothy

Lethal arrhythCACNA1C mias, syndactyly, immune deficiency, intermittent hypoglycemia, mental retardation, autism Imperforate anus, SALL1 dysplastic ears, hearing loss, thumb malformations, renal impairment/anomalies Vertebral defects Unknown (V), anal atresia (A), tracheoesophageal fistula with esophageal atresia (TE), and radial or renal dysplasia (R), cardiac malformations (C) and limb anomalies (L) three or more of the above is suggestive of the diagnosis Dolichocephaly, wide anterior fontanelles, sparse hair, dysmorphic, thin lips, short philtrum, micrognathia, absent thumbs, hypoplastic clavicles

Townes– Brocks

VATER/VACTERL

Yunis–Varon

aSpace

Etiology

Congenital Heart Defects

71

Gene Inheritance OMIM Reviews Reference Photo AD, de novo

601005

Click link

[109]

AD

107480

Click link

[110]

Sporadic

192350

[111]

AR

216340

[112]

does not permit the inclusion of every case report or occasional observation.

72

SECTION 1 

Cardiovascular Disorders

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[53] FitzPatrick DR. Zellweger syndrome and associated phenotypes. J Med Genet 1996;33(10):863–8. [54] Brosius U, Gartner J. Cellular and molecular aspects of Zellweger syndrome and other peroxisome biogenesis disorders. Cell Mol Life Sci 2002;59(6):1058–69. [55] Robin NH, Shprintzen RJ. Defining the clinical spectrum of deletion 22q11.2. J Pediatr 2005;147(1):90–6. [56] Lin AE, et al. Cardiovascular malformations in Smith-Lemli-Opitz syndrome. Am J Med Genet 1997;68(3):270–8. [57] Tint GS, et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 1994;330(2):107–13. [58] Jira PE, et al. Smith-Lemli-Opitz syndrome and the DHCR7 gene. Ann Hum Genet 2003;67(Pt 3):269–80. [59] Satoda M, et al. Mutations in TFAP2B cause Char syndrome, a familial form of patent ductus arteriosus. Nat Genet 2000;25(1):42–6. [60] Garg V, et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 2003;424(6947):443–7. [61] Robinson SW, et al. Missense mutations in CRELD1 are associated with cardiac atrioventricular septal defects. Am J Hum Genet 2003;72(4):1047–52. [62] Beekman RH, Robinow M. Coarctation of the aorta inherited as an autosomal dominant trait. Am J Cardiol 1985;56(12):818–9. [63] Gerboni S, et al. Coarctation of the aorta, interrupted aortic arch, and hypoplastic left heart syndrome in three generations. J Med Genet 1993;30(4):328–9. [64] Mone SM, et al. Effects of environmental exposures on the cardiovascular system: prenatal period through adolescence. Pediatrics 2004;113(4 Suppl. l):1058–69. [65] Lisowski LA, et al. Congenital heart disease in pregnancies complicated by maternal diabetes mellitus. An international clinical collaboration, literature review, and meta-analysis. Herz 2010;35(1):19–26. [66] Kinsley B. Achieving better outcomes in pregnancies complicated by type 1 and type 2 diabetes mellitus. Clin Ther 2007;29(Suppl. D):S153–60. [67] Randhawa PK, et al. The Ras activator RasGRP3 mediates diabetes-induced embryonic defects and affects endothelial cell migration. Circ Res 2011;108(10):1199–208. http://dx.doi:10.1161/CIRCRESAHA.110.230888. Epub 2011 Apr 7. [68] Malik S, et al. Maternal smoking and congenital heart defects. Pediatrics 2008;121(4):e810–6. [69] Grewal J, et al. Maternal periconceptional smoking and alcohol consumption and risk for select congenital anomalies. Birth Defects Res A Clin Mol Teratol 2008;82(7):519–26.

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[87] Hempel M, et al. Microdeletion syndrome 16p11.2-p12.2: clinical and molecular characterization. Am J Med Genet A 2009;149A(10):2106–12. [88] Kleefstra T, et al. Further clinical and molecular delineation of the 9q subtelomeric deletion syndrome supports a major contribution of EHMT1 haploinsufficiency to the core phenotype. J Med Genet 2009;46(9):598–606. [89] Baskar S, et al. Adams-Oliver syndrome: additions to the clinical features and possible role of BMP pathway. Am J Med Genet A 2009;149A(8):1678–84. [90] Ropke A, et al. Identification of 36 novel Jagged1 (JAG1) mutations in patients with Alagille syndrome. Hum Mutat 2003;21(1):100. [91] Holve S, et al. Athabascan brainstem dysgenesis syndrome. Am J Med Genet A 2003;120A(2):169–73. [92] Kaname T, et al. Mutations in CD96, a member of the immunoglobulin superfamily, cause a form of the C (Opitz trigonocephaly) syndrome. Am J Hum Genet 2007;81(4):835–41. [93] Alessandri JL, et al. RAB23 mutation in a large family from Comoros Islands with Carpenter syndrome. Am J Med Genet A 2010;152A(4):982–6. [94] Fleck BJ, et al. Coffin-Siris syndrome: review and presentation of new cases from a questionnaire study. Am J Med Genet 2001;99(1):1–7. [95] Romano S, et al. Conotruncal heart defects in three patients with congenital disorder of glycosylation type Ia (CDG Ia). J Med Genet 2009;46(4):287–8. [96] Oliver C, et al. Cornelia de Lange syndrome: extending the physical and psychological phenotype. Am J Med Genet A 2010;152A(5):1127–35. [97] Lipton JM, Ellis SR. Diamond-Blackfan anemia: diagnosis, treatment, and molecular pathogenesis. Hematol Oncol Clin N Am 2009;23(2):261–82. [98] Feingold M, Geggel RL. Health supervision for children with Down syndrome. Pediatrics 2001;108(6):1384. author reply 1385. [99] Meinecke P, Blunck W. Frontonasal dysplasia, congenital heart defect, and short stature: a further observation. J Med Genet 1989;26(6):408–9. [100] Digilio MC, et al. Congenital heart defects in patients with oculo-auriculo-vertebral spectrum (Goldenhar syndrome). Am J Med Genet A 2008;146A(14):1815–9. [101] Cohen Jr MM. Hallermann-Streiff syndrome: a review. Am J Med Genet 1991;41(4):488–99. [102] Skrypnyk C, et al. Molecular cytogenetic characterization of a 10p14 deletion that includes the DGS2 region in a patient with multiple anomalies. Am J Med Genet 2002;113(2):207–12. [103] Ng SB, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 2010;42(9):790–3.

CHAPTER 1  [104] Slavotinek AM, Biesecker LG. Phenotypic overlap of McKusick-Kaufman syndrome with bardet-biedl syndrome: a literature review. Am J Med Genet 2000;95(3):208–15. [105] Segel R, et al. Pulmonary hypoplasia-diaphragmatic hernia-anophthalmia-cardiac defect (PDAC) syndrome due to STRA6 mutations—what are the minimal criteria? Am J Med Genet A 2009;149A(11):2457–63. [106] De Falco F, et al. X-linked Opitz syndrome: novel mutations in the MID1 gene and redefinition of the clinical spectrum. Am J Med Genet A 2003;120A(2):222–8. [107] Lubs H, et al. Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene. J Med Genet 2006;43(6):e30. [108] Klopocki E, et al. Complex inheritance pattern resembling autosomal recessive inheritance involving a microdeletion in thrombocytopenia-absent radius syndrome. Am J Hum Genet 2007;80(2):232–40. [109] Splawski I, et al. Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism. Cell 2004;119(1):19–31.

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[110] Powell CM, Michaelis RC. Townes-Brocks syndrome. J Med Genet 1999;36(2):89–93. [111] Solomon BD, et al. Analysis of component findings in 79 patients diagnosed with VACTERL association. Am J Med Genet A 2010;152A(9):2236–44. [112] Ades LC, et al. Congenital heart malformation in YunisVaron syndrome. J Med Genet 1993;30(9):788–92.

FURTHER READING Mitchell SC, Korones SB, Berendes HW. Congenital heart disease in 56,109 births. Incidence and natural history. Circulation 1971;43(3):323–32. Nielsen J, Wohlert M. Chromosome abnormalities found among 34,910 newborn children: results from a 13year incidence study in Arhus, Denmark. Hum Genet 1991;87(1):81–3.

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2 Genetic Cardiomyopathies Ronald M. Paranal,1 Polakit Teekakirikul,2 Carolyn Y. Ho,3 Diane Fatkin,4 Christine E. Seidman5,6 1Department

of Genetics, Harvard Medical School, Boston, MA, United States, of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital and Chinese University of Hong Kong, Hong Kong, 3Cardiovascular Genetics Center and Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States, 4Cardiology Department, St Vincent’s Hospital, Molecular Cardiology Division, Victor Chang Cardiac Research Institute, Sydney, Australia, 5Department of Genetics, Harvard Medical School, Cardiovascular Genetics Center and Cardiovascular Division, Brigham and Women’s Hospital, Howard Hughes Medical Institute, Boston, MA, United States, 6Howard Hughes Medical Institute, Chevy Chase, MD, United States

2Division

Cardiomyopathies are disorders of the myocardium that arise from a variety of etiologies and culminate in hypertrophic or dilated remodeling of the heart. While compensatory forms of cardiac remodeling are recognized, inherited and de novo genetic variants are the most prevalent causes for primary cardiomyopathies. Important insights into the genetic cause and molecular pathophysiology have had a profound effect on our understanding of basic myocyte biology and the personalized approach to managing the disease. This chapter will discuss the clinical significance of genetic cardiomyopathies, the pathogenic and likely pathogenic variants that are identified in cardiomyopathy patients, and how these genetic dependencies contribute to disease pathophysiology.

2.1 INTRODUCTION Insights into the genetic architecture of cardiomyopathies have advanced our knowledge of the complex cellular and molecular events that trigger cardiac remodeling. Despite similar clinical presentations, there is considerable genetic heterogeneity underlying cardiomyopathies—a complexity that is further increased by the many distinct variants in disease genes that cause

cardiomyopathy. To improve standards and to guide the interpretation of sequence variants, the American College of Medical Genetics and Genomics has standardized a five-tier terminology system to describe the spectrum of pathogenicity for genes involved in Mendelian disorders, including cardiomyopathies. Five variant categories are defined consisting of pathogenic, likely pathogenic, unknown significance, likely benign, and benign [1]. Classification according to this system employs scoring rules based on population-based and disease-based databases that inform the frequency of gene variants; computational, predictive, or functional data; segregation or de novo data; and evidence for cis or trans effects on other variants. For example, a variant is considered pathogenic in a dominant cardiomyopathy gene where loss of function (LOF) is a known mechanism when it is (1) a null variant (due to nonsense, frameshift, canonical splice donor or acceptor sites, initiation codon, and single or multi-exon deletion mutations) and (2) exhibits familial segregation or is de novo in an affected patient without family history. A variant is classified as benign when there is evidence of allele frequency >5% in ancestry-matched reference data sets. “Likely pathogenic” and “likely benign” variants are

Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics. https://doi.org/10.1016/B978-0-12-812532-8.00002-1 Copyright © 2020 Elsevier Inc. All rights reserved.

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more nuanced designations, but these indicate a likelihood >90% certainty of their disease-causing status and as such, likely pathogenic and pathogenic variants are clinically actionable. Variants are considered to be of “unknown significance” (VUS) when these criteria are unmet or contradictory. While this classification system provides uniformity in annotating variants, these descriptors fail to capture important parameters such as penetrance and variable expressivity of genetic disorders. Consideration of these issues may be very relevant when incorporating genotype into the clinical management of patients. In the discussions that follow, pathogenic and likely pathogenic variants in the relevant genes would be considered likely to account for a patient’s cardiomyopathy. An important discovery from the identification of many pathogenic variants in cardiomyopathy patients is that disease genes often encode the protein constituents of the sarcomere. Pathogenic variants in sarcomere proteins are the most common genetic causes for both hypertrophic and dilated cardiomyopathy. However, pathogenic variants in different protein constituents of the sarcomere evoke distinct biophysical consequences. Therefore, we begin this chapter with a brief review of sarcomere biology. The sarcomere is the fundamental unit of contraction of all muscle cells. Sarcomere proteins are organized into thick (myosin heavy and light chains) and thin (actin, the troponin complex, and α-tropomyosin) filaments that interdigitate during muscle fiber shortening and lengthening. The detachment and attachment of actin and the myosin head drive contraction and relaxation at the molecular level. Contraction occurs when the myosin head hydrolyzes ATP and undergoes conformational changes that allow the myosin head to be propelled against the thin filament. This chemomechanical cycle initiates with ATP binding the actin-bound myosin head resulting in myosin dissociation from the actin filament. Myosin ATPase-mediated hydrolysis results in a myosin head’s converter domain changing into the pre-power stroke conformation. Myosin rebinds to a new position along the actin filament with release of the Pi, followed by the myosin power stroke responsible for sarcomere shortening and gross muscle contraction. Release of ADP permits new ATP binding and continued sarcomere shortening. In addition to ATP hydrolysis, the chemomechanical cycle is dependent on carefully orchestrated

fluxes in intracellular Ca2+ concentration to coordinate thick- and thin-filament interaction. Membrane depolarization by the action potential elicits calcium influx through cell membrane L-type calcium channels. Ryanodine receptors on the sarcoplasmic reticulum (SR) are then activated to trigger calcium-induced calcium release. The resultant rise in intracellular Ca2+ concentration leads to calcium binding of troponin C and causes conformational changes in the troponin complex, releasing troponin I and tropomyosin blockade of actin that permits actin–myosin cross-bridge formation. Coordinated allosteric alteration in protein confirmation allows for thick and thin filaments to drive cardiac contractility. During diastole, particular structural interactions occur between pairs of myosin heads via an interacting heads motif (IHM) that result in steric inhibition of one or both ATPases and two levels of ATP cycling [2]. These dynamic IHM interactions have structural and functional implications on relaxation that are disrupted by pathogenic variants that cause hypertrophic cardiomyopathy (HCM). In addition, intracellular calcium concentration is decreased during diastole by a variety of mechanisms including efflux by sodium calcium exchangers, sequestration into the SR and mitochondria by uniporters, and calcium transport into the SR by SR calcium ATPase (SERCA). SERCA activity is directly regulated by phospholamban. cAMP-dependent protein kinase A and Ca2+/calmodulin-dependent protein kinase II (CaMKII), which are responsible for regulating many calcium handling proteins, phosphorylate phospholamban (PLN). This posttranslational modification induces a phosphorylation-mediated conformational change that relieves phospholamban-mediated inhibition of SERCA to permit calcium reuptake into the SR. Ultimately, low myofilament calcium concentrations permit steric inhibition by the troponin–tropomyosin complex and relaxation ensues. Several of these calcium-dependent relaxation processes are altered by pathogenic variants that cause dilated cardiomyopathy. 

2.2 HYPERTROPHIC CARDIOMYOPATHY HCM was first described centuries ago, but modern clinical descriptions appeared in the mid-1950s and over the past 30 years, the molecular genetic basis of HCM has been elucidated. HCM is defined by the presence of

CHAPTER 2  (A)

(B)

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(C)

Figure 2.1  Normal and Pathologic Myocardial Gross Anatomy.  A comparison of normal cardiac anatomy and cardiac remodeling. (A) Normal myocardium with left ventricular (LV) wall thickness ≤11 mm and normal LV volume. (B) Hypertrophic cardiomyopathy cause increased LV wall thickness without cavity dilation. (C) DCM causes enlargement of LV and occasionally right, ventricular cavity size. (Reproduced with permission from Ahmad F, Seidman, JG, Seidman CE. The genetic basis for cardiac remodeling. Annu Rev Genomics Hum Genet 2005;6:185–216.)

unexplained cardiac hypertrophy in a nondilated ventricle (Fig. 2.1). “Unexplained” indicates that left ventricular hypertrophy (LVH) develops in the absence of any systemic or cardiac condition (such as hypertension or valvular heart disease) that may impose an increased load on the heart. HCM is often familial and inherited as an autosomal dominant trait. Genetic studies have defined HCM to be a disease of the sarcomere caused by mutations in eight major genes that encode different components of the contractile apparatus. Many historical descriptions of HCM have reported severe morphologic manifestations of the condition, including profound hypertrophic remodeling, marked left ventricular outflow tract (LVOT) obstruction, and adverse clinical outcomes, most notably sudden death. However, with the contemporary widespread use of robust noninvasive imaging techniques, HCM is now recognized to be a prevalent cardiovascular disorder with highly variable manifestations. Clinical presentation can occur throughout life, including late in adulthood. Hypertrophy is usually modest and typically involves the interventricular septum. Significant outflow tract obstruction occurs in ∼25% of patients, although a gradient can be provoked in many patients by administering medications or through maneuvers that impact preload or cardiac contractility. Although life expectancy is near normal, symptoms are usually progressive and can be punctuated by adverse events that may necessitate critical interventions.

2.2.1 Prevalence In a general population of young adults, the prevalence of unexplained LVH, the prototypic clinical feature of HCM, is 1:500 [3]. Epidemiologic data support the claim that HCM is one of the most common genetic cardiovascular disorders [4,5]. The prevalence of HCM in the general population may explain why this diagnosis accounts for most nonviolent sudden deaths in individuals under the age of 35 and is the most common cause of sudden death in athletes, occurring in one-third of these events [6]. 

2.2.2 Pathology HCM causes several patterns of hypertrophy, including asymmetric involvement of the interventricular septum (Fig. 2.1), concentric hypertrophy, and apical hypertrophy [7]. There is significant variation in both the location and extent of LVH in affected individuals and no evidence to support correlation between genetic etiology and cardiac morphology [8]. The histopathologic hallmarks of HCM are myocyte enlargement, myocyte disarray, and increased amounts of myocardial fibrosis (Fig. 2.2). Although small amounts of myocyte disarray may be seen in other forms of cardiac disease, the degree of disarray in HCM is distinctively higher. The distribution of disarray may be patchy and typically affects the deeper myocardial layers; therefore, catheter-based endomyocardial biopsy is often nondiagnostic. Small vessel disease with thickening of the walls of intramural arteries is also seen in HCM and correlates with clinical ischemia. 

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Figure 2.2  Normal and Pathologic Myocardial Histology.  Left. Hypertrophic cardiomyopathy is characterized by marked myocyte disarray, hypertrophy, and interstitial fibrosis. Increased interstitial fibrosis (blue) is evident by the Masson trichrome stain. Right. Dilated cardiomyopathy is characterized by nonspecific abnormalities (i.e., mildly increased interstitial fibrosis) but not by myocyte and myofibrillar disarray. Additionally, myocyte nuclei with abnormal morphologic characteristics are also observed (arrowheads). (Left: Reproduced with permission from Ahmad F, Seidman JG, Seidman CE. The genetic basis for cardiac remodeling. Annu Rev Genomics Hum Genet 2005;6:185–216. Right: Reproduced with permission from Kamisago M, et al. Mutations in sarcomere protein genes as a cause of dilated cardiomyopathy. N Engl J Med 2000;343(23):1688–96. Herman DS, et al. Truncations of titin causing dilated cardiomyopathy. N Engl J Med 2012;366(7):619–28.)

2.2.3 Phenotype The clinical spectrum of HCM is extremely diverse. Whereas some individuals experience only minor symptoms and are diagnosed incidentally or in the course of family screening, others may develop refractory symptoms of pulmonary congestion or end-stage heart failure requiring cardiac transplantation. In a small subset of patients, sudden cardiac death (SCD) is the presenting event [9–12]. Left ventricular systolic function is typically preserved in HCM and ejection fraction is often increased [13]. Dyspnea, particularly on exertion, is the most common symptom of HCM, occurring in ∼90% of patients. In the absence of LVOT obstruction or valvular dysfunction, abnormal diastolic function may largely account for symptoms of pulmonary congestion and exercise intolerance [13–15]. HCM patients may have an abnormal fall in blood pressure in response to exercise possibly due to abnormal vasomotor tone or inability to augment stroke volume in response to increased demand, potentially indicating a worse prognosis with a higher risk for sudden death [16–18]. Other common clinical manifestations include exertional chest pain (∼30% of patients), palpitations, atrial fibrillation (∼25%) with associated risk of stroke, orthostatic lightheadedness, presyncope (>50%), syncope (15%–25%), orthopnea/paroxysmal nocturnal dyspnea, and fatigue [12,19]. Symptoms and the incidence of atrial fibrillation typically increase with disease duration. In patients with outflow tract obstruction, cold weather leading to reflex vasoconstriction can lessen

symptoms due to increased arterial pressure and subsequently decreased outflow obstruction, while the opposite occurs in patients with coronary artery disease [7]. Although there is limited correlation between morphologic findings and clinical manifestations, significant outflow tract obstruction >50 mmHg is an important determinant of adverse outcomes in HCM [18]. Typical findings on physical examination include a prominent left ventricular apical impulse or lift, a fourth heart sound (S4), and a brisk, occasionally bifid, carotid upstroke. If obstruction is present, there may be a harsh crescendo–decrescendo systolic murmur that is typically best heard at the lower left sternal border and apex, radiating to the axilla and base, but usually not to the neck as classically audible in valvular aortic stenosis. A separate murmur of mitral regurgitation may also be present, related either to concomitant intrinsic structural abnormalities of the mitral valve or as a consequence of systolic anterior motion of the mitral apparatus if obstructive physiology is present. Maneuvers that alter preload and afterload are recommended for discriminating of HCM and valvular aortic stenosis. Preload or afterload reduction from these maneuvers enhances the dynamic gradient and accentuates the intensity of systolic murmur. Conversely, increased preload and afterload in response to these maneuvers decreases murmur intensity. Although Valsalva maneuver, leg raising, and amyl nitrite inhalation can change murmur intensity, the classically recommended maneuver is standing–squatting–standing. Standing to squatting decreases murmur

CHAPTER 2 

intensity due to increased preload and afterload, while squatting to standing accentuates murmur intensity as a result of rapidly decreased afterload. 

2.2.4 Natural History The natural history of HCM varies, even between family members who have inherited the same causal mutation. Although it is not uncommon for HCM to present in infancy or early childhood, development of LVH typically occurs in adolescence in conjunction with the pubertal growth spurt. Overall, patients with pathogenic mutations in sarcomere proteins are diagnosed with HCM 11.7 years earlier compared to patients who are genotype negative [20]. The age of onset of hypertrophy may be determined to some extent by the specific nature of the underlying gene defect [20,21]. For example, disease caused by mutations in the β-myosin heavy chain gene is associated with obvious clinical manifestations and nearly uniform development of LVH by the second decade of life. In contrast, clinically evident hypertrophy may not be present until the fourth or fifth decade of life in disease caused by mutations that introduce a premature truncation in the cardiac myosin binding protein C (MyBPC) that is encoded by the MYBPC3 gene. MYBPC3 mutations are also associated with elderly onset HCM [22]. Known causes of premature morbidity and mortality in HCM include SCD, progressive heart failure, atrial fibrillation associated with an increased risk of thromboembolism and stroke, and heart failure; however, annual mortality remains imprecisely defined. Evaluation of populations drawn from specialized referral centers suggests a significant annual mortality rate of 4%–6%. In contrast, community-based studies, which may be less subject to selection bias, demonstrate a more benign course with a projected annual mortality rate of 1%–2% [19]. There is no difference in mortality compared to the general population between the ages of 30–49; however, there is a three- and fourfold higher rate in patients between 20–29 years and 50–69 years, respectively [20]. Sudden death is the most feared complication of HCM, and accurate estimation of an individual’s risk for sudden death is a considerable clinical challenge. The annual risk for sudden death in the overall HCM population varies from 1% to 5% with ∼10%– 20% of patients at the highest risk [9,10,23]. Previous studies reported SCD to account for up to half of deaths associated with HCM [24,25]; however, recent data

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suggest SCD to be attributable to only 15% of deaths with a majority of mortality secondary to heart failure and noncardiac death [20]. HCM patients with pathogenic and likely pathogenic sarcomere variants have a higher degree of phenotypic severity than HCM patients with a negative genetic test [26,27]. While patients diagnosed earlier demonstrate poor outcomes, the presence of single and multiple sarcomere mutations are still independent predictors of a worse clinical status that includes atrial fibrillation, stroke, ventricular arrhythmia and heart failure morbidity and morality, and overall death [20]. Of the potential morbidities associated with HCM, heart failure and atrial fibrillation typically occur between the ages of 50 and 70 years and are the most common complications. Heart failure is associated with an annual mortality of 0.5% [28]. Fewer than 10%–20% of the patients progress to the “burnt-out” phase of HCM, which is marked by worsening symptomatic heart failure, left ventricular systolic dysfunction, progressive LV wall thinning, and chamber dilatation [9–11]. These patients may ultimately require cardiac transplantation for end-stage heart failure. 

2.2.5 Diagnosis The identification of unexplained LVH via echocardiographic imaging has traditionally formed the basis for the diagnosis of HCM. LV wall thickness in excess of two standard deviations above normal or >13 mm in the adult population is considered diagnostic. LVH is not uniformly present in all individuals with sarcomere gene mutations, particularly early in life due to age-dependent penetrance [22,29]. Furthermore, the severity of symptoms associated with HCM is not directly related to the magnitude of hypertrophy [9,11]. Although a pattern of asymmetric septal hypertrophy is most common, any pattern of LVH may be seen, including isolated apical hypertrophy, concentric hypertrophy, or asymmetric hypertrophy involving other myocardial segments [21]. Cardiac magnetic resonance (CMR) imaging can complement echocardiography when findings are inconclusive. CMR permits visualization of focal hypertrophy in the anterolateral free wall, apex, or posterior septum that would otherwise go undetected during standard echocardiography [30,31]. Furthermore, CMR provides higher resolution imaging capable of more precisely determining left ventricular wall thickness, an independent risk factor that can be

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Figure 2.3  Cardiac magnetic resonance imaging (CMR) with gadolinium enhancement in a normal individual (left) and a patient with hypertrophic cardiomyopathy (HCM, right). CMR provides high resolution of cardiac dimensions due to the sharp contrast between the myocardial border and blood pool, as well as tomographic coverage of the entire myocardium without obliquity. In comparison to the normal heart, there is prominent left ventricular wall thickness and smaller ventricular volume in the HCM heart. The addition of gadolinium contrast to CMR allows tissue characterization and identification and quantification of focal myocardial fibrosis (right, arrow), which is prevalent in HCM patients. (Courtesy of Carolyn Ho, MD, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA.)

underestimated when full interrogation by echocardiography is limited due to body habitus or because hypertrophy is restricted to a discrete region [32]. CMR with gadolinium provides additional information about myocardial fibrosis (Fig. 2.3), which is suggested to be prognostic of adverse events [33]. While further data may demonstrate the utility of broader use, current recommendations indicate that CMR be utilized by individuals with cardiac imaging expertise and limited to patients with suspected HCM who have inadequate echocardiographic testing [34]. Electrocardiographic changes are present in ∼90% of affected individuals and may be detected prior to the development of echocardiographic manifestations. Q waves and repolarization abnormalities (QST) occur in 25% of individuals with pathogenic variants prior to the onset of clinically overt hypertrophy, but in only 3% of controls (P G, produces a new exon: high frequency in Spanish cystic fibrosis chromosomes and association with severe phenotype. Am J Hum Genet 1995;56:623–9. [264] Sosnay PR, Castellani C, Corey M, Dorfman R, Zielenski J, Karchin R, Penland CM, Cutting GR. Evaluation of the disease liability of CFTR variants. Methods Mol Biol 2011;742:355–72. [265] Sosnay PR, Siklosi KR, Van Goor F, Kaniecki K, Yu H, Sharma N, Ramalho AS, Amaral MD, Dorfman R, Zielenski J, Masica DL, Karchin R, Millen L, Thomas PJ, Patrinos GP, Corey M, Lewis MH, Rommens JM, Castellani C, Penland CM, Cutting GR. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet 2013;45:1160–7. [266] Genetics EWGoC. Gradient of distribution in Europe of the major CF mutation and of its associated haplotype. Hum Genet 1990;85:436–45. [267] Consortium CFGA. Population variation of common cystic fibrosis mutations. Hum Mutat 1994;4:167–77.

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[268] Cystic Fibrosis Foundation Patient Registry Annual Data Report 1997 (1997). [269] Estivill X, Bancells C, Ramos C. Geographic distribution and regional origin of 272 cystic fibrosis mutations in european populations. The Biomed CF Mutation Analysis Consortium. Hum Mutat 1997;10:135–54. [270] Zielenski J, Fujiwara TM, Markiewicz D, Paradis AJ, Anacleto AI, Richards B, Schwartz RH, Klinger KW, Tsui LC, Morgan K. Identification of the M1101K mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene and complete detection of cystic fibrosis mutations in the hutterite population. Am J Med Genet 1993;52:609–15. [271] Rozen R, De Braekeleer M, Daigneault J, Ferreira-Rajabi L, Gerdes M, Lamoureux L, Aubin G, Simard F, Fujiwara TM, Morgan K. Cystic fibrosis mutations in French Canadians: three CFTR mutations are relatively frequent in a Quebec population with an elevated incidence of cystic fibrosis. Am J Med Genet 1992;42:360–4. [272] Stuhrmann M, Dork T, Fruhwirth M, Golla A, Skawran B, Antonin W, Ebhardt M, Loos A, Ellemunter H, Schmidtke J. Detection of 100% of the CFTR mutations in 63 CF families from Tyrol. Clin Genet 1997;52:240–6. [273] Mercier B, Raguénès O, Estivill X, Morral N, Kaplan GC, McClure M, Grebe TA, Kessler D, Pignatti PF, Marigo C, Bombieri C, Audrézet MP, Verlinguie C, Férec C. Complete detection of mutations in cystic fibrosis patients of Native American origin. Hum Genet 1994;94:629–32. [274] Cheadle JP, Goodchild MC, Meredith AL. Direct sequencing of the complete CFTR gene: the molecular characterisation of 99.5% of CF chromosomes in Wales. Hum Mol Genet 1993;2:1551–6. [275] Férec C, Audrézet MP, Mercier B, Guillermit H, Moullier P, Quere I, Verlingue C. Detection of over 98% cystic fibrosis mutations in a Celtic population. Nat Genet 1992;1:188–91. [276] Abeliovich D, Lavon IP, Lerer I, Cohen T, Springer C, Avital A, Cutting GR. Screening for five mutations detects 97% of cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the Jewish Ashkenazi population. Am J Hum Genet 1992;51:951–6. [277] Dörk T, Mekus F, Schmidt K, Bobhammer J, Fislage R, Heuer T, Dziadek V, Neumann T, Kälin N, Wulbrand U, Wulf B, von der Hardt H, Maab G, Tümmler B. Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients. Hum Genet 1994a;94:533–42. [278] Mercier B, Lissens W, Audrézet MP, Bonduelle M, Liebaers I, Férec C. Detection of more than 94% cystic fibrosis mutations in a sample of Belgian population and identification of four novel mutations. Hum Mutat 1993;2:16–20.

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[643] Werner A, Bongers ME, Bijvelds MJ, De Jonge HR, Verkade HJ. No indications for altered essential fatty acid metabolism in two murine models for cystic fibrosis. J Lipid Res 2004;45:2277–86. [644] Freedman SD, Katz MH, Parker EM, Laposata M, Urman MY, Alvarez JG. A membrane lipid imbalance plays a role in the phenotypic expression of cystic fibrosis in cftr(-/-) mice. Proc Natl Acad Sci USA 1999;96:13995–4000. [645] Jelalian E, Stark LJ, Reynolds L, Seifer R. Nutrition intervention for weight gain in cystic fibrosis: a meta analysis. J Pediatr 1998;132:486–92. [646] Foundation CF. Cystic fibrosis foundation patient registry annual data report 2000. 2001. Bethesda, MD. [647] Colombo C, Petroni ML. Prevention and treatment of liver disease in cystic fibrosis. In: Dodge JA, Brock DJH, Widdicombe JH, editors. Cystic fibrosis - current topics. New York: John Wiley & Sons Ltd; 1994. p. 327–42. [648] Grubb BR, Boucher RC. Pathophysiology of gene-targeted mouse models for cystic fibrosis. Physiol Rev 1999;79:S193–214. [649] Wilke M, Buijs-Offerman RM, Aarbiou J, Colledge WH, Sheppard DN, Touqui L, Bot A, Jorna H, De Jonge HR, Scholte BJ. Mouse models of cystic fibrosis: phenotypic analysis and research applications. J Cyst Fibros 2011;10:S152–71. [650] Clarke LL, Grubb BR, Gabriel SE, Smithies O, Koller BH, Boucher RC. Defective epithelial chloride transport in a gene-targeted mouse model of cystic fibrosis. Science 1992;257:1125–8. [651] Dorin JR, Dickinson P, Alton EWFW, Smith SN, Geddes DM, Stevenson BJ, Kimber WL, Fleming S, Clarke AR, Hooper ML, Anderson L, Beddington RSP, Porteous DJ. Cystic fibrosis in the mouse by targeted insertional mutagenesis. Nature 1992;359:211–5. [652] Snouwaert JN, Brigman KK, Latour AM, Malouf NN, Boucher RC, Smithies O, Koller BH. An animal model for cystic fibrosis made by gene targeting. Science 1992;257:1083–8. [653] Durie PR, Kent G, Phillips MJ, Ackerley CA. Characteristic multiorgan pathology of cystic fibrosis in a long-living cystic fibrosis transmembrane regulator knockout murine model. Am J Pathol 2004;164:1481–93. [654] Haston CK, Corey M, Tsui LC. Mapping of genetic factors influencing the weight of cystic fibrosis knockout mice. Mamm Genome 2002;13:614–8. [655] Clarke LB, Grubb BR, Yankaskas JR, Cotton CU, McKenzie A, Boucher RC. Relationship of a non-cystic fibrosis transmembrane conductance regulator-mediated chloride conductance to organ-level disease in CFTR (-/-) mice. Proc Natl Acad Sci USA 1994;91:479–83.

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13 Genetic Underpinnings of Asthma and Related Traits Christopher J. Cardinale,1 Michael E. March,1 Patrick M.A. Sleiman,1 Hakon Hakonarson1,2 1Center

for Applied Genomics, Children’s Hospital of Philadelphia, Abramson Research Center, Philadelphia, PA, United States, 2Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Abramson ­Research Center, Philadelphia, PA, United States

GLOSSARY Bronchial Hyperresponsiveness  A condition of lung airways characterized by easily induced and/or exaggerated constriction of airways following some triggering event. Candidate Gene Study  A hypothesis-driven form of genetic study in which genes suspected in disease pathology are examined for variations between cases and control individuals. Candidate gene studies require a previous understanding of disease biology, as candidate genes are selected largely on the basis of biological plausibility. Forced Expiratory Volume in 1 s (FEV1)  A measure of lung function in which the amount of air a patient can expel in one second following a deep inhalation is measured by spirometry. Forced Vital Capacity (FVC)  A measure of lung function in which the full volume of air a patient can expel following a deep inhalation is measured by spirometry. Gene–Environment Interaction  Phenotypic effects resulting from effects of the environment on given genotypes. In context of asthma genetics, this would refer to the influence of environmental factors upon both susceptibility to asthma and the severity of disease.

Gene–Gene Interaction  Also called epistasis. Refers to phenotypes that arise only when specific alleles are present at two or more different loci. Genome-Wide Association Study (GWAS)  A hypothesis-free (and often hypothesis-generating) form of genetic study in which hundreds of thousands of single-nucleotide polymorphisms are genotyped in large cohorts of cases and controls. The large panel of polymorphisms is analyzed for variations in frequency between cases and controls, allowing for identification of disease susceptibility loci. Genome-Wide Linkage Study  A hypothesis-free (and often hypothesis-generating) form of genetic study in which the genomes of disease-affected and disease-unaffected family members are screened with a panel of genetic markers. Due to the smaller amount of recombination expected between family members, regions containing susceptibility loci can be identified with a comparatively small number of genetic markers. Peak Expiratory Flow (PEF)  A measure of lung function in which the speed of a patient’s exhalation is measured, through the use of a peak flow meter. Pharmacogenetics  The study of genetic variation that affects the responses of individuals to medication. 

Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics. https://doi.org/10.1016/B978-0-12-812532-8.00013-6 Copyright © 2020 Elsevier Inc. All rights reserved.

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NOMENCLATURE FEV1  Forced expiratory volume in one second FVC  Forced vital capacity GWAS  Genome-wide association screen PEF  Peak expiratory flow SNP  Single-nucleotide polymorphism 

13.1 INTRODUCTION 13.1.1 Definition Asthma is a common, chronic respiratory disorder featuring episodic shortness of breath, often at night and usually accompanied by a nonproductive cough. Wheezing is usually observed upon clinical examination during exacerbations, with normal breath sounds when asthma is well controlled. Asthma is characterized by episodic airway obstruction accompanied by airway inflammation and, in some cases, irreversible structural alterations to airways. There are many different definitions of asthma. The most recent Global Initiative for Asthma’s Global Strategy for Asthma Management and Prevention report (updated in 2009) provides the following definition, which integrates symptoms and addresses the underlying cellular mechanisms of asthma: Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role. The chronic inflammation is associated with airway hyperresponsiveness that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing, particularly at night or in the early morning. These episodes are usually associated with widespread, but variable, airflow obstruction within the lung that is often reversible either spontaneously or with treatment [1]. Acute asthma attacks are episodes in which patients experience difficulty breathing, usually as a result of constriction in the airways of the lung. Symptoms of acute attacks can usually be alleviated through the use of inhaled bronchodilators. These medications relax the smooth muscle of the airways, opening the airways and alleviating the increased work of breathing. Over the long term, structural changes can occur in the lungs that impact lung function, including excess mucus production, infiltration of cells of the immune system mediating chronic inflammation, and thickening of the walls of the airway irreversibly limiting air space. Some of these

changes can be irreversible, permanently reducing lung function. Others, such as immune-mediated inflammation can be controlled through medication. Although asthma is usually recognized through the acute episodes of asthma attacks, including wheezing and sometimes irreversible declines in lung function, asthma has an important immune system component as well. Roles for many immune cells and mediators have been described. There is a clear connection between asthma and atopy, although this connection is not absolute. Atopic individuals are more prone to developing asthma, and much of the prevalence of asthma can be linked to specific allergies [2]. However, not all atopic individuals develop asthma, and not all asthmatics have detectably elevated allergic responses. Nonetheless, dysregulated immunity appears important in the development of asthma, with elevated serum IgE levels, excess release of allergic mediators from mast cells, infiltration of eosinophils into the lungs and inflammation in the airways, and with skewed TH1 and TH2 responses being frequently observed in asthmatics. Reduction of chronic inflammation in the lungs is part of the strategy for long-term control of asthma, through the use of anti-inflammatory agents like inhaled glucocorticoids. 

13.1.2 Asthma Diagnosis Asthma sufferers can present with a variety of symptoms, and the transient nature of the acute attacks (the most obvious symptom) can make actual diagnosis difficult. Most asthmatics will report recurrent episodes of difficulty breathing, and wheezing is usually (although not always) observed upon examination. A series of secondary characteristics can be evaluated to aid in diagnosis. Bronchial hyperresponsiveness (BHR), the tendency of asthmatic airways to overreact to irritants or stimuli, can be measured by either direct or indirect methods [3]. Direct challenges are the most commonly performed tests, and they specifically target the sensitivity of responsiveness of airway smooth muscle. These involve exposure of the airways to a substance such as methacholine that binds to receptors on smooth muscle cells and promotes muscle contraction, leading to constricting the airways. The reduction in lung function measures, which is typically assessed by the reduction in forced expiratory volume in one second (FEV1), can be assayed as can the response to treatment with bronchodilators that subsequently reverse the airway narrowing. Most asthmatics will display larger than

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expected reactions in direct challenge tests [4]. Indirect challenge tests involve stimuli that will cause activation of the immune cells that are resident in the asthmatic lung. These immune cells will release mediators that act on smooth muscle in the airways causing constriction [5]. Common indirect stimuli include exercise, dry or cold air, and adenosine monophosphate. Indirect tests mimic the triggers of most asthma attacks in daily life, and therefore may be more clinically relevant [3]. Overreactions to indirect challenges indicate the presence of immune cells like mast cells and eosinophils in the lung, indicative of asthma. Several measures of lung function are commonly used [1]. Peak expiratory flow rate is a measurement of the patient’s maximum airflow rate during expiration. It is measured with a peak flow meter; modern meters are inexpensive, portable plastic devices, which enable home measurement and recording of peak expiratory flow rate, aiding in the monitoring of early deterioration and response to therapy. FEV1 is the amount of air exhaled in one second following a deep inhalation, while forced vital capacity (FVC) is the maximal amount of air that can be expelled following a full inhalation. Both FEV1 and FVC are measured by spirometry. The reversibility of FEV1 by treatment indicates a diagnosis of asthma [6]. There is a clear but imperfect connection between asthma and allergy. As such, it is often useful to determine a patient’s allergy status, either through skin tests or measurement of allergen-specific or total IgE levels in serum. Allergies and allergic disease (especially allergic rhinitis) increase the probability of an asthma diagnosis. Additionally, identifying allergens to which a patient reacts can aid in identifying environmental exposures that trigger asthma attacks. In the description of asthma genetic studies that follows below, many different phenotypes are considered endpoints for studies. Some studies consider actual asthma diagnoses, but others rely on different criteria. Measurements of lung function, allergic reactions, levels of serum IgE, and eosinophilia are cited as endpoints. In this chapter, these other criteria that serve somewhat as surrogates for asthma will be described as “asthma-­ related phenotypes.” 

in practice from country to country complicate worldwide estimates. In the United States, it is estimated that at least 22.9 million Americans suffer from asthma. Asthma is the leading chronic illness in US children, with 6.8 million affected in 2006 [2]. Global rates of asthma range from 1% to 18% of the population from different countries [1]. Prevalence is rising in locations where rates were previously low, and variation in rates from country to country appears to be diminishing [7]. Asthma was previously categorized based on severity of symptoms in untreated individuals. Four groups were recognized: intermittent, mild persistent, moderate persistent, and severe persistent [8]. However, these classifications did not account for the difficulty of controlling symptoms with treatment. Mild persistent asthma in one individual might be resistant to treatment, while severe persistent asthma in another person might respond well and be thoroughly controlled with proper medication. Current consensus is to classify asthma on the basis of both severity of symptoms and the level of control of those symptoms [8,9]. Mild asthma is therefore well controlled with low-intensity treatment, while severe asthma requires high-intensity treatment for full, and sometimes only partial, control. The advent of new treatments, allowing better control in certain situations, will hopefully allow currently severe forms of asthma to be reclassified as mild asthma in the future. Further characterization of severe asthma continues, with lower lung function, more frequent sinopulmonary infections, more persistent symptoms, and higher health-care requirements in severe asthmatics [10]. Additional work has shown the existence of multiple distinct groups among severe asthma sufferers; differences between groups are apparent in age, age of onset of disease, presence of atopy, requirements for medication and health care, and impairment and reversibility of lung function [11]. Appreciation of these groups will likely aid in care, as the underlying causes and therefore the most appropriate treatments for each type of severe asthma are likely to be different. 

13.1.3 Asthma Prevalence and Severity

Twin studies have shown that there is a genetic element to asthma susceptibility, with heritability of the condition estimated at between 0.36 and 0.77 [12–15]. The first study to link a genetic locus (chromosome 11q13)

Due to the variability of the disease and a lack of generally agreed-upon standards for diagnosis, it can be difficult to estimate the prevalence of asthma, and variations

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to asthma was published in 1989 [16]. Since then more than 600 candidate genes described in more than 1000 publications have been found in connection to asthma or an associated phenotype, like elevated IgE levels, BHR, or eosinophilia.

13.2.1 An Overview of the Analysis of the Genetic Contributions in Asthma

Researchers have been successful in identifying the genetic underpinning of nearly 3000 single-gene disorders. However, it has been comparatively difficult to identify the genetic basis of complex genetic disorders, such as asthma, allergic disorders, and autoimmune diseases, due to polygenic inheritance and significant environmental contributors. Three study designs are routinely employed to investigate genetic contributions in complex diseases: candidate gene association studies, genome-wide linkage studies, and genome-wide association studies (GWASs).

13.2.1.1 Candidate Gene Studies In a candidate gene association study, a particular gene (or set of genes) is selected for study based on its biological plausibility or suspected role in the phenotype of interest. The incidence of variants in this gene is compared between a group of individuals affected with the phenotype (cases) and a group of controls. The strength of such a design lies in the statistical power and relative ease of recruiting large cohorts, compared to family-based studies. The main limitations of such a design are its inability to identify novel or unsuspected genes and pathways contributing to the pathogenesis of a disorder, and its susceptibility to unknown population structures in cases or controls. Candidate gene association studies are best suited to identifying common genetic variants of modest effect [17]. More than 1000 papers have been published with candidate gene studies examining asthma and related phenotypes, identifying more than 600 candidate genes. However, surprisingly few of these candidate gene discoveries have been rigorously replicated, and many have been examined and failed replication in subsequent studies [18–20]. Among genes identified in candidate studies are receptors for detection of microbial products (TLRs, CD14, NOD2, among others); various cytokines and cytokine signaling proteins involved in T cell survival, proliferation, and differentiation; genes involved in lung function, development, and response to stimuli

(ADRB2, CFTR, SPINK5, etc.); genes involved in epithelial barrier function and innate immunity (FLG and DEFB1) [21,22]; genes believed to be involved in the responses to environmental exposures (GSTM1, GSTP1, and GSTT1) [19,23–25]. Genes that have been extensively replicated include the β2 adrenergic receptor gene [26–28]; the cytokines, receptors, signaling proteins, and transcription factors involved in TH1 and TH2 differentiation of T cells like IL4, IL4RA, IFNG, IFNGR1, STAT6, GATA3, and TBX21 [29–36]; and genes involved in the cellular responses that characterize atopic disease, such as IL13 and its receptor and the FCER1B gene [37–41]. Genes that have been identified in five or more candidate gene studies as having a positive association with asthma, or asthma-related phenotypes, are listed in Table 13.1. 

13.2.1.2 Linkage Studies A genome-wide linkage study design focuses on families affected by the disease of interest. With less genetic recombination occurring between closely related individuals, it is possible to screen the entire genome with a panel of relatively few, evenly spaced markers, searching for variants that are either unique to or overrepresented in affected individuals. If such a region is found, it is said to be linked with the disease trait, and the genes within this region can become candidates for further analysis, including association studies followed by positional cloning of the gene. Unlike the candidate gene association study, this study design allows for the identification of genes and pathways previously not suspected of contributing to the disease in question. However, because large families of affected individuals are needed, these studies are expensive and difficult to conduct. Moreover, while they are effective at identifying genes with low-frequency variants with high penetrance and large effects, they often lack the statistical power to identify genes of modest effect that are attributed to common alleles. This is in contrast to GWASs (discussed below), which are best suited to the identification of common variants with lower penetrance and smaller effects. In this way, linkage studies and association studies are used to address different questions, and are, in fact, complementary. Approximately 20 genome-wide linkage screens have been reported in different populations investigating chromosomal regions that are linked to asthma and atopy, or related phenotypes like elevated IgE levels,

CHAPTER 13 

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345

TABLE 13.1  Summary of Well-Replicated Loci Identified Through Candidate Gene Studies Gene

Chromosomal Locus

Function

Immune Function IL10 CTLA4

1q31-q32 2q33

IL13 IL4 CD14

5q31 5q31.1 5q31.1

HAVCR1 LTC4S LTA TNF HLA-DRB1 HLA-DQB1 HLA-DPB1 FCER1B IL18 STAT6 CMA1 IL4R

5q33.2 5q35 6p21.3 6p21.3 6p21 6p21 6p21 11q13 11q22.2-q22.3 12q13 14q11.2 16p12.1-p12.2

Cytokine—immune regulation Control/inhibition of T cell responses/ immune regulation Induces TH2 effector functions TH2 differentiation Microbe detection— recognizes pathogenassociated molecular patterns T Cell responses—hepatitis A virus receptor Leukotriene synthase—inflammatory mediator Inflammatory mediator Inflammatory mediator Major histocompatibilty complex class II— antigen presentation

Barrier Function/Innate Immunity FLG 1q21.3 SPINK5 5q32 CC16 11q12.3-q13.1 NOS1 CCL11 CCL5

12q24.2-q24.31 17q21.1-q21.2 17q11.2-q12

Tissue Response GSTM1

1p13.3

ADRB2 GPRA

5q31-q32 7p14.3

NAT2 GSTP1

8p22 11q13

ACE TBXA2R TGFB1

17q23.3 19p13.3 19q13.1

ADAM33 GSTT1

20p13 22q11.23

Receptor for IgE—atopy Inflammation IL-4 and IL-13 signaling Chymase—mast cell–expressed serine protease Alpha chain of receptors for IL-4 and IL-13 Epithelial integrity and barrier function Epithelial serine protease inhibitor Potential immunoregulatory function— epithelial expression Nitric oxide synthase—cellular communication Eotaxin-1—eosinophil chemoattractant RANTES—chemoattactant for T cells, eosinophils, basophils Detoxification, removal of products of oxidative stress Smooth muscle relaxation Regulation of metalloprotease expression, neuronal effects Detoxification Detoxification, removal of products of oxidative stress Regulation of inflammation Platelet aggregation Influences cell growth, differentiation, proliferation, apoptosis Cell–cell and cell–matrix interactions Detoxification, removal of products of oxidative stress

Genes identified as asthma susceptibility loci in candidate gene studies. Genes are grouped loosely based on their functions in immunity, epithelial barrier function, or tissue response and remodeling.

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TABLE 13.2  Table of Loci Identified

Though Linkage Studies and Positional Cloning Gene

Chromosomal Locus

Reference

CYFIP2 DPP10 HLAG PHF11 GPRA ADAM33

5q33.3 2q14.1 6p21.33 13q14.3 7p14.3 20p13

[42] [43] [44] [45] [46] [47]

wheezing, and BHR. A number of chromosomal regions have been repeatedly identified across multiple studies that contain genes of biological relevance to asthma and allergic disease (Table 13.2), including the cytokine cluster on chromosome 5q [containing interleukin 3 (IL3), IL5, and granulocyte/macrophage colony-stimulating factor (GMCSF)], FCER1B on 11q, IFNG (interferon γ) and STAT6 on 12q, and IL4R (the IL-4Rα chain, also part of the IL-13R) on 16p. Linkage studies followed by positional cloning approaches have resulted in the identification of a handful of novel asthma susceptibility genes, including CYFIP2 [42], DPP10 [43], HLAG [44], PHF11 [45], GPRA [46], and ADAM33 [47]. GPRA (G protein–coupled receptor for asthma) and ADAM33 (a disintegrin and metalloproteinase domain-containing protein 33) have generated considerable interest, as their expression in bronchial smooth muscle cells suggests roles in the pathobiology of asthma and pulmonary allergic disease [46]. 

13.2.1.3 Genome-Wide Association Studies Rapid advances in microarray technology permit the high-throughput genotyping of hundreds of thousands of single-nucleotide polymorphisms (SNPs). This development has enabled the execution of GWASs. In this design, many SNPs (hundreds of thousands) are compared across the entire genome between cases and controls. Like the candidate gene association study, this design requires the collection of a large number of cases and controls for analysis to achieve statistical power. In contrast to the candidate gene approach, however, it permits a hypothesis-free search for gene variants

associated with disease, revealing new and unexpected targets for researchers. As mentioned above, GWASs are well suited for discovery of common alleles with relatively small effects [17]. The results of GWAS targeting asthma or related phenotypes are summarized in Table 13.3. In 2007, the first GWAS focusing on bronchial asthma as an endpoint was reported [48], identifying multiple markers on chromosome 17q21 reproducibly associated with childhood-onset asthma. The findings were replicated in German and British cohorts. Independent replication of the 17q21 association has been reported in multiple populations of diverse ethnic backgrounds [49–53]. Variable expression of two genes within this region, ORMDL3 and GSDMB, was linked to asthma susceptibility [48]. ORMDL3 is a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum [54]. GSDMB encodes a member of the gasdermin proteins that are expressed in epithelial cells and regulate apoptosis. Both sequencing and functional data will be required to identify the causal gene; however, this finding does represent the first step in unraveling the complex genetics underlying asthma susceptibility in a hypothesis-independent manner. A case-control GWAS of North American asthmatics of European ancestry from the Childhood Asthma Management Program (CAMP) cohort was reported subsequently. Whereas no loci reached genome-wide significance in their discovery cohort, the strongest association was to variants of the PDE4D gene on chromosome 5q12. In seven Caucasian replication cohorts, two out of seven PDE4D SNPs were marginally associated. No significant associations were observed at the PDE4D locus in populations of African ancestry [55]. PDE4D is a lung-expressed phosphodiesterase that has been implicated in airway contractility. In a separate study, genome-wide association data from the CAMP cohort were investigated for replication of previously reported candidate gene associations. Approximately 30 genes were investigated with five SNP-based associations replicating to a nominal significance in the IRAK-3, PHF11, IL10, ITGB3, and IL4R genes [56]. Association of asthma with SNPs in multiple genes was reported in a study containing more than 10,000 individuals with physician-diagnosed asthma and

CHAPTER 13 

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347

TABLE 13.3  Summary of GWAS Loci Referenced in This Review, Including Chromosome

Location, the Most Significant SNP Identified, and the Endpoint of the Study Reported Gene

Locus

Top SNP

Endpoint Analyzed

Reference

RAD50 HLA-DR/DQ DENND1B TLE4 PDE4D ORMDL3 PDE11A CHI3L1

5q31.1 6p21.32 1q31.3 9q21.31 5q12.1 17q12 2q31.2 1q32.1

rs2244012 rs3998159 rs2786098 rs2378383 rs2548659 rs7216389 rs11684634 rs4950928

Asthma

[84] [58] [160] [55] [48] [161] [71]

FCER1A STAT6 RAD50 IL1RL1 IKZF2 GATA2 IL5 SH2B3 CHRNA 3/5 HHIP TNS1 GSTCD HTR4 AGER THSD4 GPR126 ADAM19 AGER-PPT2 FAM13A PTCH1 PID1 HTR4 INTS12-GSTCD-NPNT IL1RL1/IL18R1 HLA-DQ IL33 SMAD3 IL2RB ORMDL3/GSDMB GLCCI1

1q23.2 12q13 5q31.1 2q12.1 5q31.1 3q21.3 2q12.1 12q24.12 15q24 4q31.22 2q35 4q24 5q33.1 6p21.32 15q23 6q24.1 5q33 6p21.3 4q22.1 9q22.32 2q36.3 5q33.1 4q24 2q12.1 6p21.32 9p24.1 15q22.33 22q12.3 17q12 7p21.3

rs2251746 rs12368672 rs2040704 rs1420101 rs12619285 rs4857855 rs4143832 rs3184504 rs8034191 rs13147785 rs2571445 rs10516526 rs3995090 rs2070600 rs12899618 rs3817928 rs2277027 rs2070600 rs2869967 rs16909898 rs1435867 rs7735184 rs17331332 rs3771166 rs9273349 rs1342326 rs744910 rs2284033 rs2305480 rs37972

Asthma Asthma Asthma Asthma Asthma Asthma/YKL-40 serum levels Serum IgE levels

Blood eosinophil count/ asthma

[73]

COPD FEV1/FVC FEV1 FEV1 FEV1 FEV1/FVC FEV1/FVC FEV1/FVC FEV1/FVC FEV1/FVC FEV1/FVC FEV1/FVC FEV1/FVC FEV1/FVC FEV1 Asthma

[76] [162] [78]

IL6R LRRC32

1q21.3 11q13.5 3p26.2

rs4129267 rs7130588 rs9815663

6q14.1

rs1361549

FAM46A

Childhood onset asthma Inhaled glucocorticoid response Asthma Asthma age of onset

[72]

[77]

[57]

[159] [61] [163]

African-American asthma [70] Continued

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TABLE 13.3  Summary of GWAS Loci Referenced in This Review, Including Chromosome

Location, the Most Significant SNP Identified, and the Endpoint of the Study—cont’d Reported Gene

Locus

Top SNP

Endpoint Analyzed

Reference

USP38 TSLP NOTCH4

rs7686660 rs1837253 rs404860 rs10508372 rs1701704 rs6967330

Japanese asthma

[66]

IKZF4 CDHR3

4q31.21 5q22.1 6p21.32 10p14 12q13.2 7q22.3

[65]

TEK GRM4 PTGES JMJD1C

9p21.2 6p21.31 9q34.11 10q21.3

rs72721168 rs1776883 rs11788591 rs75446656

Early childhood asthma with severe exacerbations Asthma

16,000 unaffected persons matched for ancestry [57]. SNPs in several loci achieved genome-wide significance, including a block on chromosome 2 that includes IL1RL1 and IL18R, HLA-DQ on chromosome 6, IL33 on chromosome 9, SMAD3 on chromosome 15, and IL2RB on chromosome 22. The authors observed association with the previously reported ORMDL3/GSDMB locus on chromosome 17 only in childhood-onset asthma. Many of these genes have direct or indirect roles in T cell responses (IL2RB, HLA-DQ) and the development of TH1 (IL18R1) or TH2 (IL33) responses. SMAD3 is a second messenger in the signaling pathway for transforming growth factor β, which has numerous biological roles, notably the induction of Treg and TH17 types of helper T cells. Our group conducted a GWAS on a series of pediatric asthma patients consisting of North American cases of European ancestry with persistent asthma requiring daily inhaled glucocorticoids for symptom control, and matched controls without asthma. In addition to the previously reported 17q21 locus, we uncovered an association to a novel asthma locus on chromosome 1q31 in the discovery cohort and replicated the finding in an independent cohort of Northern European ancestry. The locus contains DENND1B, a gene that is expressed by natural killer cells and dendritic cells [58]. To determine whether the 1q31 locus also contributes to asthma in children of African ancestry, we also tested for association of the chromosome 1q31 locus and asthma in African-American cases and ancestrally matched controls.

[62]

Asthma with allergy

A total of 17 of 20 SNPs were significantly associated with asthma, although the associated allele at each SNP was the alternate allele to that associated with asthma in the discovery set. Allele reversal at shared risk loci can be attributed to differences in the underlying genomic architecture at the loci between populations of different ancestry and as a result are being tagged differently. The DENND1B gene has since been replicated in inflammatory bowel disease, in separate studies of both Crohn disease and ulcerative colitis [59], and in primary biliary cirrhosis [60]. More recent GWASs have added to the tally of known associations by expanding the size of cohorts and sampling diverse populations. Loci identified through these efforts include those for IL6R, LRRC32 [61], TEK, GRM4, PTGES, and JMJD1C [62]. The interleukin-6 receptor is noteworthy because this cytokine has been implicated in several inflammatory diseases and is a target of blocking monoclonal antibodies for rheumatoid arthritis [63]. PTGES encodes a prostaglandin E synthase, producing a hormone-like compound of the lipid-derived family of eicosanoids. The PGE2 signal mediates bronchoconstriction, bronchodilation, as well as inflammatory processes [64]. A GWAS on early childhood asthma with severe exacerbation recapitulated many known loci as well as adding a novel locus for CHDR3, a cadherin-related gene [65]. In order to uncover more loci, some investigators have expanded the scope of their GWAS cohorts to include non-European ancestries. In the Japanese

CHAPTER 13 

Genetic Underpinnings of Asthma and Related Traits

population, five loci were identified as specific to that background. These loci were near the genes for USP38, NOTCH4, IKZF4, and TSLP [66]. NOTCH4 is a receptor expressed in the vascular endothelium that is involved in the development of blood vessels and which has been identified in GWAS for a spectrum of autoimmune and inflammatory disorders [67]. IKZF4 encodes a transcription factor of the Ikaros family known as Eos, which is necessary for the function of regulatory T cells (Treg) [68]. TSLP codes for thymic stromal lymphopoietin, a cytokine implicated in allergy, atopic dermatitis, eosinophilic esophagitis, and T helper type 2 function [69]. These immunoregulatory genes have the potential to be therapeutic targets. A GWAS on the African-American population found an association with a locus for FAM46A, a gene with unknown function [70]. Numerous GWASs have been reported using intermediate phenotypes and quantitative traits, rather than asthma itself, as study endpoints. The first report used genome-wide associations to identify variants that modulate serum protein levels [71]. A promoter SNP in the CHI3L1 gene that encodes the chitinase-like protein YKL-40 was shown to influence serum YKL40 levels and was also shown to be weakly associated with asthma, bronchial responsiveness, and pulmonary function in the Hutterite population. A GWAS showed significant association of the FCER1A and RAD50 genes with expression of CHI3L1, and evidence for association of the STAT6 gene with IgE levels. IgE levels are closely correlated with the clinical expression and severity of both asthma and allergy. The RAD50 variants were further shown to be associated with increased risk of asthma and atopic eczema [72]. Eosinophils are leukocytes that play an important role in the initiation and propagation of inflammatory signals. This makes them likely mediators of inflammatory disease and a GWAS was performed examining blood eosinophil counts. Five loci reached genome-wide association significance, one of which, IL1RL1, was also shown to be associated with asthma in a collection of 10 different populations [73]. One GWAS focused on chronic obstructive pulmonary disease (COPD), and three other studies performed GWAS on lung function using a quantitative metric of lung function as a measure of airflow obstruction. Altered lung function, and airflow obstruction in particular, is associated with both asthma and COPD.

349

Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) surpassed genome-wide significance in the study and replicated in two of three independent cohorts. The CHRNA 3/5 locus had previously been associated with lung cancer and nicotine dependence [74,75]. The authors also reported that SNPs at the HHIP locus on chromosome 4 showed association and were consistently replicated across the study cohorts but did not reach genome-wide significance [76]. In the first of the three lung-function GWASs that included 7691 Framingham heart study participants, the only locus to surpass genome-wide significance for association with FEV1/FVC ratio and replicate in an independent cohort of 835 Family Heart Study participants was HHIP [142]. The final two studies resulted in the identification of 11 novel loci associated with measures of lung function; both studies also replicated the previously reported association of the HHIP locus [77,78]. These novel loci will not only shed further light on the pathways associated with pulmonary function but may also provide potential targets for respiratory disease such as asthma and COPD. 

13.2.2 Themes Revealed by Genetic Analysis of Asthma Susceptibility

The numerous genome-wide linkage, candidate gene, and GWASs performed on asthma and asthma-related phenotypes have resulted in an increasingly large list of genes implicated in asthma susceptibility and pathogenesis. This list can be categorized into four broad functional groups [19,79–81], from which several themes have emerged, as summarized in Fig. 13.1.

13.2.2.1 TH2-Mediated Cell Response TH2 cell-mediated adaptive immune responses have been widely recognized as a crucial component of allergic disease. Genes involved in TH2 cell differentiation and function have been extensively studied in asthma candidate-gene association studies, and as one might expect, SNPs in many of these genes have been associated with asthma and other allergic phenotypes. Genes important for TH1 versus TH2 T cell polarization, like GATA3, TBX21, IL4, IL4RA, STAT6, and IL12B, have been implicated with asthma and allergy [29–38,82,83]. The genes encoding IL-13 and the beta-chain of the IgE receptor FcεR1 are well-replicated contributors to asthma susceptibility [37,39–41,82,84]. These two molecules play critical roles in allergic disease. 

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Figure 13.1  Genes implicated in asthma susceptibility and pathogenesis.

13.2.2.2 Environmental Sensing and Immune Detection A second class of associated genes is involved in detection of pathogens and allergens. These genes include pattern recognition receptors and extracellular receptors, such as CD14, toll-like receptor 2 (TLR2), TLR4, TLR6, TLR10; and intracellular receptors, such as nucleotide-binding oligomerization domain containing 1 (NOD1/CARD4) [85–90]. Additional studies have strongly associated variations in the HLA class II genes with asthma and allergen-specific IgE responses [84]. These molecules are important in the immune response and shaping of the T cell repertoire; their involvement in an immune-mediated inflammatory disorder like asthma is unsurprising. 

13.2.2.3 Tissue Response A variety of genes involved in mediating the response to allergic inflammation and oxidant stress on the tissue level appear to be important contributors to asthma susceptibility. Examples include ADAM33, a disintegrin and metalloprotease expressed in lung fibroblasts and smooth muscle cells; the alpha-1 chain of type 29 collagen (COL29A1); leukotriene C4 synthase (LTC4S); glutathione-S-transferase (GSTP1, GSTM1); arachidonate 5-lipoxygenase (ALOX-5); and nitric oxide synthase 1 (NOS1) [47,91–97].  13.2.2.4 Epithelial Barrier Function Studies of asthma genetics have raised new interest in the body’s first line of immune defense, the epithelial

CHAPTER 13 

Genetic Underpinnings of Asthma and Related Traits

barrier, in the pathogenesis of asthma. Mutations in the filaggrin gene (FLG) were initially identified in the rare single-gene disorder ichthyosis vulgaris [98], but subsequently loss-of-function variants were reported to be strongly associated with atopic dermatitis, eczema, and asthma, both dependent and independent of atopic dermatitis [22,99–101]. FLG, a protein involved in keratin aggregation, is not expressed in the bronchial mucosa [102], which has led others to suggest that asthma susceptibility in patients with loss-of-function FLG variants may be due to allergic sensitization that occurs after breakdown of the epithelial barrier [103]. Several epithelial genes with important roles in innate and adaptive immune function have also been implicated in asthma. These genes include defensin beta1 (an antimicrobial peptide), uteroglobin/Clara cell 16-kD protein (CC16) (an inhibitor of dendritic cell-mediated TH2-cell differentiation), and several chemokines (CCL-5, -11, -24, and -26) involved in the recruitment of T cells and eosinophils [21,104–109]. Variations in SPINK5, a serine protease inhibitor limited to the epithelium and the causative factor in Netherton syndrome [110], have been associated with asthma, but with conflicting results [82,88,111,112]. 

13.3.3 The Future of Asthma Genetics The many studies that have been aimed at asthma and allergies have revealed considerable new information about the genetic variants that underlie susceptibility to the condition as well as its severity. It is through this work that we have come to appreciate the importance of the barrier function of the epithelium and molecules involved in the sensing and effector arms of innate immunity. Additionally, we have a much better picture of the critical roles played by both TH2 skewing and the molecules involved in development and remodeling of the lungs. The application of GWAS to asthma, with the possibility of discovering new genes that are currently unsuspected in asthma pathobiology, has the potential to greatly and rapidly expand our knowledge of the genetic and biological factors contributing to this complex genetic disease. However, challenges remain in the understanding of the genetic contribution to asthma and only a relatively small proportion of its heritability is explained despite recent advances. Although the other contributing factors are not necessarily specific to asthma genetics, they are worth illuminating here.

351

13.3.3.1 Gene–Environment Interactions Asthma, as an immune-mediated disease, involves the response of the body to the environment, including pollutants, allergens, viruses, and other pathogens and irritants. These environmental factors interact with genetic variation to influence the development or severity of disease. Researchers are finding that specific genetic variants affect susceptibility to, and the severity of, asthma in different ways depending on the environments of the individuals carrying those variants, a phenomenon known as gene–environment interaction. Several examples of gene–environment interaction exist in asthma, with perhaps the best characterized being CD14. Interest in CD14 as an asthma susceptibility locus originates with linkage studies identifying an association between asthma (and related phenotypes) and chromosome 5q, where CD14 resides [113–117]. The protein product of CD14 acts to optimize the immune response to molecular pathogens, such as LPS/endotoxin [118,119]. This function made CD14 an interesting candidate gene within the chromosome 5q region linked to asthma. A functional SNP (rs2569190, denoted CD14/-260C>T) in the promoter of CD14 was associated with increased CD14 protein levels in serum and reduced serum IgE levels [120,121]. This polymorphism has been examined in candidate gene association studies of asthma, with conflicting results. Studies have demonstrated a protective role for the T allele at this SNP, including reduced serum IgE levels and allergic symptoms in individuals bearing this allele [122,123]. Conversely, studies have also shown that the T allele does not protect from asthma or allergy, with association of this allele with higher IgE levels in laboratory workers [124], increased positive skin tests [125], and food allergies [126] in different study populations. In two German cohorts, CD14/-260T was not associated with asthma, atopy, or IgE levels [127,128]. The reasons for such conflicting results were unclear, until studies of potential environmental influences were performed. The CD14/-260C allele was associated with higher IgE levels in children with pets like cats and dogs, while the opposite allele was associated with the same phenotype in children exposed to stable animals such as horses [129]. Homozygotes for CD14/-260T were found to be at lower risk for asthma if exposed to comparatively low levels of house dust endotoxin, but at higher risk at higher endotoxin exposures [130]. These alleles

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have opposite effects on allergic reactions in individuals of Karelian ethnicity that live in either Finland or Russia [131], suggesting key environmental differences between these locales. This SNP has also been associated with effects on IgE by alcohol consumption [132] and Helicobacter pylori [133]. Other polymorphisms at the CD14 locus have been associated with different outcomes in specific populations, depending on environmental exposure [124]. Given the large number of identified asthma susceptibility loci, and the daunting amount of environmental variables that may influence complex diseases, much work remains before we have a reasonable understanding of the roles of gene–environment interactions in asthma. 

13.3.3.2 Gene–Gene Interactions A comparatively small number of studies have been published to date examining the role in asthma of gene– gene interactions, where variation at one locus alters the effects of variations at a second locus, reflecting epistasis between two or more genes. The existing literature consists mainly of studies in which researchers have chosen two or more specific genes (and occasionally specific variants of those genes) to examine in the context of asthma, looking for evidence of interactions between the two loci. Examples of gene–gene interactions that have been observed in association with asthma include IL9 and IL9R polymorphisms in Koreans [134], TGFBR2 and FOXP3 in specific IgE production [135], IL13 and IL4 in Dutch cohorts [136], and LTA4H and ALOX5AP in Latinos [97]. Larger scale analysis examining 169 SNPs in 29 genes identified a number of gene–gene interactions affecting both total and antigen-specific IgE levels [137]. Methods are actively being developed to enable large-scale and unbiased analysis of gene–gene interactions [138] and visualization of the resulting networks [139], but these efforts are in their relative infancy. Given the number of previously identified relevant genes, and the possibilities for discovery of new loci, the combinatorial potential for interactions between gene effects is daunting. Much work remains in the development of methods and tools before we will truly grasp these vast possibilities.  13.3.3.3 Replication It has been a long-term concern for the field of asthma genetics (and for the study of many other common, complex diseases) that many discoveries fail to be

replicated in subsequent studies [140,141]. While concerns about poorly constructed or statistically underpowered studies are constant, an appreciation has developed for other issues that may affect study results [142]. Heterogeneity among cases and controls is the most basic confounder of genetic analyses. While tools have been developed to address the most obvious source of heterogeneity, racial and ethnic diversity [143–145], other less apparent sources may remain. As described above, asthma is influenced by gene–environment interactions, with genetic and environmental variability interacting in unexpected ways. The search for statistical power has led to studies with increasingly large sample sizes; large populations are required to detect the common variants with small effect sizes that are hypothesized to underlie complex diseases like asthma. However, these growing study populations carry risks as well as benefits, as it becomes more difficult to account for diversity among large populations. While computational tools exist to deal with racial stratification in study groups, less attention has historically been paid to geographic and environmental diversity. And while genetic analyses like GWAS often inherently include the information required to identify racial stratification, accounting for environmental variations requires additional effort in the form of questionnaires or surveys answered by study participants, or observation and sampling of the participants’ environments. These concerns may directly affect the issue of replication, as the assembly of ever larger cohorts may result in the mixing of environmental influences, diluting the effects of gene–environment interactions, and making the detection of the connected loci difficult if not impossible. In fact, the example of CD14 described above demonstrates that studies focused on smaller groups can yield informative results, if the smaller cohorts are accompanied by reports on environmental influences. However, in the case of asthma the list of environmental influences may be extraordinarily long. Endotoxin, various allergens, cigarette smoke, airborne pollutants, and indoor pets or stable animals have all been considered environmental factors for asthma, as have less obvious connections, such as whether and for how long an infant was breastfed [146,147]. Controlling for these impacts will be increasingly laborious, and lack of accounting for some of these factors may account for failures of genes to be replicated.

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Genetic Underpinnings of Asthma and Related Traits

Replication in asthma studies faces an additional complication in the varying phenotypes that can be considered asthma-associated, and the degree to which a specific locus needs to be identified to be considered replicated. Both phenotypes and genotypes can be subjected to criteria of varying stringency, generally referred to as strict or loose replication [148]. For phenotypes, strict replication would involve studies that consider only the same endpoint (i.e., diagnosis of asthma, BHR, serum IgE levels, allergic skin test responses), while loose replication would consider studies that identified the same locus using varying but related endpoints. For genotypes, strict replication would require identification of precisely the same variant of a gene (SNP, copy number variation, insertion or deletion) in multiple studies, while loose replication considers the gene itself to be the unit of replication, including all variants identified at a locus. Use of the gene as the unit of replication has been advocated [18,149] and is becoming more common, but worries persist that this is too permissive a standard and may lead to inappropriate conclusions of replication [148]. Obviously, convincing demonstration of replicated results will be difficult if research cannot agree on even the standard of replication required. 

13.3.3.4 Pharmacogenetics Pharmacogenetics, in which variations in genotype are examined for their effects on the response to treatments, is of growing interest with asthma, with the hope that it will increase efficacy and reduce toxic side-effects of medications. It is a nascent field, and as such there are still few studies that involve more than a few hundred subjects, and most are limited to only one or two candidate genes selected for their known or suspected roles in response to specific medication. The best example at this time is provided by β-adrenergic receptor agonists (or simply β agonists), which are prescribed to treat bronchoconstriction and provide long-term symptom control for asthmatics. The ARDB2 locus encodes the β2-adrenergic receptor, which binds to and is activated by beta agonists. This activation leads to several downstream effects, including relaxation of airway smooth muscle, thereby alleviating the acute symptoms of an asthma attack. Two studies have implicated variations in ARDB2 as modulators of response to inhaled bronchodilators [150,151]. However, a recent randomized, double-blind study was performed in which subjects were genotyped before being enrolled, so that they could

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be stratified by genotype before receiving prescriptions [152]. This study showed no association of genotype with the response to beta agonists. One study showed that an arginine/glycine polymorphism at position 16 of the ARDB2 protein influences the response to regularly administered albuterol, with the Arg/Arg genotype receiving less relief from regular, long-term use of short-acting beta agonists [153]. Yet another group has shown that genotype ARDB2 does not affect the response to combined beta agonist and inhaled corticosteroid treatment [154]. While several other genes that are targeted by current asthma treatments have been identified as asthma susceptibility loci, very few have actually been analyzed for the effects of variations in genotype on treatment. Genes involved in the biosynthesis of leukotrienes, such as ALOX-5, ALOX5AP, and LTC4S, have been identified as asthma susceptibility loci; drugs targeting the leukotriene pathway, like 5-lipoxygenase inhibitors and cysteinyl leukotriene receptor 1 antagonists have been approved for treatment of asthma. One group has shown that variations at ALOX5 correlate with the response to a 5-lipoxygenase inhibitor [155], while another demonstrated that an SNP in the gene LTA4H, which encodes a leukotriene cleaving enzyme (LTA4 hydrolase), associate with variability in the response to a cysteinyl leukotriene receptor 1 antagonist [156]. Two studies have shown that variants of genes involved in the synthesis of or the response to glucocorticoids impact the response to inhaled glucocorticoids in asthmatics. Polymorphisms in corticotrophin-releasing hormone receptor (CRHR1) [157] and the STIP1 gene (involved in the signaling initiated by glucocorticoids) [158] associate with variable FEV1 response after inhaled glucocorticoid treatment, as do polymorphisms in TBX21, encoding a transcription factor important in the generation of TH1 cells [35]. This last study demonstrates that variations in genes not directly involved in the metabolism or signaling cascades of a drug can be important modulators of the response to that drug. This point will be critical in the future of pharmacogenetics, as researchers design the studies and tools necessary to examine drug–gene interactions in an unbiased way. Just as GWAS and linkage studies allow identification of susceptibility loci that would not have been suspected based on known function, unbiased pharmacogenetic studies could allow identification of variants that affect the response to treatment that cannot be predicted based on current information. One

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such hypothesis-free study was a GWAS on the efficacy of inhaled glucocorticoids. It showed that an SNP in GLCCI1, a glucocorticoid-induced gene, is associated with poor glucocorticoid response [159]. 

13.4 CONCLUSION Despite the progress that has been made in understanding the genetic contribution to asthma and allergic disease in recent years, much work remains to be done before this information can be used to improve the diagnosis and management of individuals suffering from these conditions. Today’s discoveries unfortunately only explain a fraction of the heritability of asthma. Referred to as ‘missing heritability’, this difficult to fill void in our understanding has become a common theme in the analysis of complex genetic traits. As more GWAS of increasingly greater size are performed, it is likely that additional loci will be identified that will close a portion of this gap. However, GWAS are not well suited to detection of rare variants with potentially large effects. More importantly, the development of techniques to describe gene–gene and gene–environment interactions, which likely play a key role in the susceptibility to allergic disease, is only in its infancy. Very little is known how epigenetic phenomena, hereditable but reversible changes to DNA (such as methylation) that are not detected by standard genotyping, may contribute to asthma and allergy pathogenesis. Advancement in sequencing technologies is likely to enable strategies capable of thoroughly examining the entire genome, including all genic and epigenetic variations and their complex interaction. Together with transcriptome sequencing and in silico, in  vitro, and in  vivo models of human-derived tissues through induced pluripotent stem cell cultures, eventually we will be able to complete the journey from genetic discovery to improvements in asthma patient care. 

SUPPORT Supported by an Institute Development Award from Children’s Hospital of Philadelphia (to Dr. Hakonarson) and by NIH eMERGE grant U01HG006830 (to Dr. Hakonarson).

CONFLICT OF INTEREST The authors report no potential conflicts of interest with this work.

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[103] Hudson TJ. Skin barrier function and allergic risk. Nat Genet 2006;38(4):399–400. [104] Laing IA, de Klerk NH, Turner SW, Judge PK, Hayden CM, Landau LI, et al. Cross-sectional and longitudinal association of the secretoglobin 1A1 gene A38G polymorphism with asthma phenotype in the Perth Infant Asthma Follow-up cohort. Clin Exp Allergy 2009;39(1):62–71. [105] Lee JH, Moore JH, Park SW, Jang AS, Uh ST, Kim YH, et al. Genetic interactions model among Eotaxin gene polymorphisms in asthma. J Hum Genet 2008;53(10):867–75. [106] Min JW, Lee JH, Park CS, Chang HS, Rhim TY, Park SW, et al. Association of eotaxin-2 gene polymorphisms with plasma eotaxin-2 concentration. J Hum Genet 2005;50(3):118–23. [107] Raby BA, Van Steen K, Lazarus R, Celedon JC, Silverman EK, Weiss ST. Eotaxin polymorphisms and serum total IgE levels in children with asthma. J Allergy Clin Immunol 2006;117(2):298–305. [108] Sengler C, Heinzmann A, Jerkic SP, Haider A, Sommerfeld C, Niggemann B, et al. Clara cell protein 16 (CC16) gene polymorphism influences the degree of airway responsiveness in asthmatic children. J Allergy Clin Immunol 2003;111(3):515–9. [109] Zhang YG, Huang J, Zhang J, Li XB, He C, Xiao YL, et al. RANTES gene polymorphisms and asthma risk: a meta-analysis. Arch Med Res 2010;41(1):50–8. [110] Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD, et al. Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 2000;25(2):141–2. [111] Liu Q, Xia Y, Zhang W, Li J, Wang P, Li H, et al. A functional polymorphism in the SPINK5 gene is associated with asthma in a Chinese Han Population. BMC Med Genet 2009;10:59. [112] Walley AJ, Chavanas S, Moffatt MF, Esnouf RM, Ubhi B, Lawrence R, et al. Gene polymorphism in Netherton and common atopic disease. Nat Genet 2001;29(2):175–8. [113] Martinez FD, Holberg CJ, Halonen M, Morgan WJ, Wright AL, Taussig LM. Evidence for Mendelian inheritance of serum IgE levels in Hispanic and non-Hispanic white families. Am J Hum Genet 1994;55(3):555–65. [114] Meyers DA, Postma DS, Panhuysen CIM, Xu J, Amelung PJ, Levitt RC, et al. Evidence for a locus regulating total serum Ige levels mapping to chromosome-5. Genomics 1994;23(2):464–70. [115] Noguchi E, Shibasaki M, Arinami T, Takeda K, Maki T, Miyamoto T, et al. Evidence for linkage between asthma/atopy in childhood and chromosome 5q31-q33 in a Japanese population. Am J Respir Crit Care Med 1997;156(5):1390–3.

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Genetic Underpinnings of Asthma and Related Traits

[116] Postma DS, Bleecker ER, Amelung PJ, Holroyd KJ, Xu J, Panhuysen CI, et al. Genetic susceptibility to asthma–bronchial hyperresponsiveness coinherited with a major gene for atopy. N Engl J Med 1995;333(14):894– 900. [117] Xu J, Levitt RC, Panhuysen CI, Postma DS, Taylor EW, Amelung PJ, et al. Evidence for two unlinked loci regulating total serum IgE levels. Am J Hum Genet 1995;57(2):425–30. [118] Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol 2003;21:335–76. [119] Triantafilou M, Triantafilou K. Lipopolysaccharide recognition: CD14, TLRs and the LPS-activation cluster. Trends Immunol 2002;23(6):301–4. [120] Baldini M, Lohman IC, Halonen M, Erickson RP, Holt PG, Martinez FD. A polymorphism* in the 5’ flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 1999;20(5):976–83. [121] Gao PS, Mao XQ, Baldini M, Roberts MH, Adra CN, Shirakawa T, et al. Serum total IgE levels and CD14 on chromosome 5q31. Clin Genet 1999;56(2):164–5. [122] Koppelman GH, Reijmerink NE, Stine OC, Howard TD, Whittaker PA, Meyers DA, et al. Association of a promoter polymorphism of the CD14 gene and atopy. Am J Resp Crit Care 2001;163(4):965–9. [123] Leung TF, Tang NL, Sung YM, Li AM, Wong GW, Chan IH, et al. The C-159T polymorphism in the CD14 promoter is associated with serum total IgE concentration in atopic Chinese children. Pediatr Allergy Immunol 2003;14(4):255–60. [124] Pacheco KA, Rose CS, Silveira LJ, Van Dyke MV, Goelz K, MacPhail K, et al. Gene-environment interactions influence airways function in laboratory animal workers. J Allergy Clin Immunol 2010;126(2):232–40. [125] Ober C, Tsalenko A, Parry R, Cox NJ. A second-generation genomewide screen for asthma-susceptibility alleles in a founder population. Am J Hum Genet 2000;67(5):1154–62. [126] Woo JG, Assa’ad A, Heizer AB, Bernstein JA, Hershey GK. The -159 C-->T polymorphism of CD14 is associated with nonatopic asthma and food allergy. J Allergy Clin Immunol 2003;112(2):438–44. [127] Heinzmann A, Dietrich H, Jerkic SP, Kurz T, Deichmann KA. Promoter polymorphisms of the CD14 gene are not associated with bronchial asthma in Caucasian children. Eur J Immunogenet 2003;30(5):345–8. [128] Sengler C, Haider A, Sommerfeld C, Lau S, Baldini M, Martinez F, et al. Evaluation of the CD14 C-159 T polymorphism in the German Multicenter Allergy Study Cohort. Clin Exp Allergy 2003;33(2):166–9. [129] Eder W, Klimecki W, Yu L, von Mutius E, Riedler J, Braun-Fahrlander C, et al. Opposite effects of

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CD 14/-260 on serum IgE levels in children raised in different environments. J Allergy Clin Immunol 2005;116(3):601–7. [130] Zambelli-Weiner A, Ehrlich E, Stockton ML, Grant AV, Zhang S, Levett PN, et al. Evaluation of the CD14/-260 polymorphism and house dust endotoxin exposure in the Barbados Asthma Genetics Study. J Allergy Clin Immunol 2005;115(6):1203–9. [131] Zhang G, Khoo SK, Laatikainen T, Pekkarinen P, Vartiainen E, von Hertzen L, et al. Opposite gene by environment interactions in Karelia for CD14 and CC16 single nucleotide polymorphisms and allergy. Allergy 2009;64(9):1333–41. [132] Campos J, Gude F, Quinteiro C, Vidal C, Gonzalez-Quintela A. Gene by environment interaction: the -159C/T polymorphism in the promoter region of the CD14 gene modifies the effect of alcohol consumption on serum IgE levels. Alcohol Clin Exp Res 2006;30(1):7–14. [133] Virta M, Pessi T, Helminen M, Seiskari T, Kondrashova A, Knip M, et al. Interaction between CD14159C>T polymorphism and Helicobacter pylori is associated with serum total immunoglobulin E.. Clin Exp Allergy 2008;38(12):1929–34. [134] Namkung JH, Lee JE, Kim E, Park GT, Yang HS, Jang HY, et al. An association between IL-9 and IL-9 receptor gene polymorphisms and atopic dermatitis in a Korean population. J Dermatol Sci 2011;62(1):16–21. [135] Bottema RW, Kerkhof M, Reijmerink NE, Thijs C, Smit HA, van Schayck CP, et al. Gene-gene interaction in regulatory T-cell function in atopy and asthma development in childhood. J Allergy Clin Immunol 2010;126(2):338–46. 46 e1–10. [136] Bottema RW, Nolte IM, Howard TD, Koppelman GH, Dubois AE, de Meer G, et al. Interleukin 13 and interleukin 4 receptor-alpha polymorphisms in rhinitis and asthma. Int Arch Allergy Immunol 2010;153(3):259– 67. [137] Reijmerink NE, Bottema RW, Kerkhof M, Gerritsen J, Stelma FF, Thijs C, et al. TLR-related pathway analysis: novel gene-gene interactions in the development of asthma and atopy. Allergy 2010;65(2):199–207. [138] De Lobel L, Geurts P, Baele G, Castro-Giner F, Kogevinas M, Van Steen K. A screening methodology based on Random Forests to improve the detection of gene-gene interactions. Eur J Hum Genet 2010;18(10):1127–32. [139] Chu JH, Weiss ST, Carey VJ, Raby BA. A graphical model approach for inferring large-scale networks integrating gene expression and genetic polymorphism. BMC Syst Biol 2009;3:55. [140] Anonymous. Framework for a fully powered risk engine. Nat Genet 2005;37(11):1153.

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[154] Bleecker ER, Postma DS, Lawrance RM, Meyers DA, Ambrose HJ, Goldman M. Effect of ADRB2 polymorphisms on response to longacting beta2-agonist therapy: a pharmacogenetic analysis of two randomised studies. Lancet 2007;370(9605):2118–25. [155] Drazen JM, Yandava CN, Dube L, Szczerback N, Hippensteel R, Pillari A, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet 1999;22(2):168–70. [156] Lima JJ, Zhang S, Grant A, Shao L, Tantisira KG, Allayee H, et al. Influence of leukotriene pathway polymorphisms on response to montelukast in asthma. Am J Respir Crit Care Med 2006;173(4):379–85. [157] Tantisira KG, Lake S, Silverman ES, Palmer LJ, Lazarus R, Silverman EK, et al. Corticosteroid pharmacogenetics: association of sequence variants in CRHR1 with improved lung function in asthmatics treated with inhaled corticosteroids. Hum Mol Genet 2004;13(13):1353–9. [158] Hawkins GA, Lazarus R, Smith RS, Tantisira KG, Meyers DA, Peters SP, et al. The glucocorticoid receptor heterocomplex gene STIP1 is associated with improved lung function in asthmatic subjects treated with inhaled corticosteroids. J Allergy Clin Immunol 2009;123(6):1376–83. e7. [159] Tantisira KG, Lasky-Su J, Harada M, Murphy A, Litonjua AA, Himes BE, et al. Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N Engl J Med 2011;365(13):1173–83. [160] Hancock DB, Romieu I, Shi M, Sienra-Monge JJ, Wu H, Chiu GY, et al. Genome-wide association study implicates chromosome 9q21.31 as a susceptibility locus for asthma in mexican children. PLoS Genet 2009;5(8):e1000623. [161] DeWan AT, Triche EW, Xu X, Hsu LI, Zhao C, Belanger K, et al. PDE11A associations with asthma: results of a genome-wide association scan. J Allergy Clin Immunol 2010;126(4):871–3. e9. [162] Wilk JB, Chen TH, Gottlieb DJ, Walter RE, Nagle MW, Brandler BJ, et al. A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLoS Genet 2009;5(3):e1000429. [163] Forno E, Lasky-Su J, Himes B, Howrylak J, Ramsey C, Brehm J, et al. Genome-wide association study of the age of onset of childhood asthma. J Allergy Clin Immunol 2012;130(1):83–90. e4.

Relevant Web Pages

The Global Initiative for Asthma: http://www.ginasthma.org. The American Lung Association: http://www.lungusa.org/.

14 Hereditary Pulmonary Emphysema* Nestor A. Molfino US Medical Expert, Respiratory Medical Affairs, GlaxoSmithKline, Bethesda, MA, United States

ABBREVIATIONS AAT Alpha 1-antitrypsin CEPH Center d’Etude du Polymorphisme Humain COPD Chronic obstructive pulmonary disease COPDGene Genetic Epidemiology of COPD study CT Computed tomography DLCO Diffusing capacity for carbon monoxide ECLIPSE  Evaluation of COPD Longitudinally to Iden­ tify Predictive Surrogate End-points study EXACTLE  Exacerbations and CT scan as lung endpoints study FEF25–75  Forced expiratory flow rate between 25% and 75% of forced vital capacity FEV1 Forced expiratory volume in 1 s FVC Forced vital capacity GOLD Global initiative for chronic obstructive lung disease HPLC  High-performance liquid chromatography HRCT High-resolution computed tomography MMP Matrix metalloproteinase NAS Normative aging study NETT National Emphysema Treatment Trial PI Protease inhibitor SHARe SNP Health Association Resource SNP Single-nucleotide polymorphism SPEP Serum protein electrophoresis * This article is a revision of the previous edition article by Chad Oh and Nestor Molfino © 2013, Elsevier Ltd.

SPIROMICS  SubPopulations and InteRmediate Outcome Measures In COPD Study STR Short tandem repeat SVC Slow vital capacity 

14.1 INTRODUCTION Pulmonary emphysema has been a recognized clinical problem since Bonet described the condition of “voluminous lungs” in 1679. The first description of enlarged airspaces in emphysema was by Ruysh in 1721, and Baillie described the destructive character of the condition in 1789, which was followed by the comprehensive description by Laennec in 1819 [1]. In the 1893 edition of his Principles and Practice of Medicine, Osler described several forms of emphysema, including hypertrophic emphysema, which involved “distention of the air-cells and atrophy of their walls, and clinically by the imperfect aeration of the blood and more or less marked dyspnoea” [2]. In addition to this remarkably modern description of emphysema, Osler noted “the markedly hereditary character of the disease.” Chronic obstructive pulmonary disease (COPD) includes emphysema and chronic bronchitis. Because emphysema is encompassed within the diagnostic rubric of COPD, we focus our discussion on COPD in general and only refer to emphysema when specifically warranted. Since the mass production of cigarettes began in the early 1900s, the development of COPD has become increasingly common. COPD is the fourth leading cause of morbidity and mortality in the United States and is expected to rank third as the cause of death worldwide

Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics. https://doi.org/10.1016/B978-0-12-812532-8.00014-8 Copyright © 2020 Elsevier Inc. All rights reserved.

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by 2020 [3]. There are estimated to be 10 million individuals in the United States with physician-diagnosed COPD and many more affected individuals who are undiagnosed [4]. Although case reports of familial COPD were published in the 1950s [5], interest in the role of genetic factors in COPD largely began with the discovery of severe alpha 1-antitrypsin (AAT) deficiency by Laurell and Eriksson in 1963 [6]. AAT deficiency is a proven genetic determinant of COPD; therefore, we discuss the molecular and population genetics of AAT deficiency in detail. In addition, we review the evidence for genetic factors in non-AAT deficiency COPD, including assessment of risk to relatives, segregation analysis, linkage analysis, and association studies. We also discuss the utility of animal models in identifying the genetic determinants of COPD. 

14.2 DISEASES WITH AIRFLOW LIMITATION: DEFINITIONS Pulmonary emphysema is included with chronic bronchitis and small airway disease in the syndrome of COPD. COPD is defined as a “disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases” [7]. Thus, airflow limitation, also known as airflow obstruction, is central to the definition of COPD. Significant updates to this definition of COPD occurred in 2017. The GOLD 2017 definition of COPD added two critical elements to the one published in 2011: (1) Persistent respiratory symptoms are needed to diagnose COPD because they point to the need to conduct spirometry, while the latter should not be done in asymptomatic subjects. Moreover, studies such as COPDGene reference [8] and SPIROMICS reference [9] have shown that respiratory symptoms can precede the development of airflow limitation; (2) Alveolar changes suggesting emphysema may also be evident to diagnose COPD. In addition to chronic bronchitis, emphysema, and small airway disease, COPD has also been used to describe the subset of asthmatic subjects who have chronic airflow obstruction as well as subjects with less common conditions such as bronchiectasis. For this discussion, we restrict COPD to include individuals with chronic bronchitis, small airway disease, and/or pulmonary emphysema.

14.2.1 Pulmonary Emphysema Pulmonary emphysema is an anatomically defined condition characterized by abnormal airspace enlargement and destruction of airspaces beyond the terminal bronchioles but without obvious fibrosis [10]. This destructive process reduces elastic recoil of the lung, accounting for airflow obstruction. In addition, the surface available for gas exchange is reduced, which, in severe cases, limits the capacity for gas exchange to occur and results in hypoxemia. A cross-section of an emphysematous lung is shown in Fig. 14.1. 

14.2.2 Chronic Bronchitis Chronic bronchitis is a condition defined on a clinical basis by the presence of cough productive of phlegm for at least 3 months per year for at least two consecutive years [10]. This excess mucus production should

Figure 14.1  Paper-mounted whole lung section from a subject who died with chronic obstructive pulmonary disease. This subject had severe emphysema, which was primarily the centrilobular form. Destruction of respiratory bronchioles produced increased airspaces throughout the lung. (Reprinted from ­Thurlbeck WM. Internal surface area and other measurements in emphysema. Thorax 1967;22:483-496.)

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not be caused by other conditions, such as bronchiectasis or tuberculosis. Subjects with chronic bronchitis frequently do not have chronic airflow obstruction; for this discussion, we consider individuals with chronic bronchitis to have COPD only if they also have chronic airflow obstruction. 

14.2.3 Small Airway Disease COPD also includes small airway disease—a poorly understood entity that includes inflammation of the terminal and respiratory bronchioles as well as fibrosis with narrowing and destruction of airway walls [10] reference [12]. Some inflammation of the terminal and respiratory bronchioles is likely present in all cigarette smokers. However, only a subset of smokers develops fibrosis and narrowing of the small airways, with associated airflow obstruction. The classification of disease processes encompassed within COPD emphasizes the heterogeneity of this disorder. Some investigators have attempted to define subsets of COPD based on clinical and/or physiological criteria. For example, Burrows suggested that chronic airflow obstruction included a group of patients with emphysema, who were largely male smokers with progressive airflow limitation, and a group of patients with chronic asthmatic bronchitis, who were largely female with a more benign clinical course [13]. However, dissection of the syndrome of COPD will likely require improved understanding of the pathophysiological basis of disease, and, potentially, the genetic determinants of this condition [14]. 

14.3 PHENOTYPIC EVALUATION IN COPD A variety of phenotypes are useful in genetic and epidemiologic studies of COPD, including pulmonary function test data, chest computed tomography (CT) scan measurements, and questionnaire-derived assessments of respiratory symptoms. Development of biochemical markers that relate to the pathophysiology of COPD has been less successful.

14.3.1 Pulmonary Function Tests As noted above, fixed airflow obstruction is essential for the definition of COPD. Airflow obstruction is typically determined by spirometry, which includes forced expiratory maneuvers after the subject has inhaled to total lung capacity. Key phenotypes obtained from

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spirometry include the volume of air exhaled within the first second of the forced expiratory volume in 1 s (FEV1) and the total volume of air exhaled during the entire maneuver (forced vital capacity [FVC]). Subjects with airflow obstruction have a reduced ratio of FEV1/FVC; however, in addition to COPD, airflow obstruction can result from other diseases, such as asthma. Spirometric values are typically expressed as a percentage of predicted values, to adjust for known effects of age, gender, height, and ethnicity on these parameters. In normal subjects, maximally rapid vital capacity (i.e., FVC) is equal to the relaxed or slow vital capacity (SVC). In subjects with significant airflow limitation, SVC is often larger than FVC because airways in such subjects tend to close before the lung region that they serve has fully emptied. Therefore, airflow obstruction may be more sensitively determined by the use of the FEV1/SVC rather than FEV1/FVC. Other spirometric measures, such as the forced expiratory flow rate between 25% and 75% of the FVC (FEF25–75), may also be used as phenotypes in the study of COPD. Some investigators contend that FEF25–75 reflects obstruction in small airways, but the large coefficient of variation associated with this measurement may limit its utility. Reduced FEV1 has been repeatedly demonstrated to be a major risk factor for mortality from chronic lung disease [15,16] and from all causes [17,18]. Since reduced FEV1 can result from restrictive lung diseases (e.g., interstitial lung diseases, neuromuscular diseases) as well as obstructive lung diseases, analysis of the FEV1/ FVC ratio selects for conditions associated with airflow obstruction. The relationship between emphysema and airflow obstruction is controversial; some investigators suggest that emphysema is not the major cause of airflow obstruction in COPD [19]. FEV1 is particularly valuable in the assessment of COPD because it tends to track consistently throughout the life of an individual. FEV1 follows a pattern of growth, plateau, and then decline with increasing age. There are at least three mutually independent ways that one can reach a low level of FEV1 in later adult life. Specifically, one can have reduced growth, premature decline, or accelerated decline in lung function. A simplified graphic depiction of the natural history of COPD is shown as a function of the influences on tracking curves of FEV1 in Fig. 14.2 [20,21]. Death or disability can result from normal rate of decline after a reduced

FEV1 (% normal level at age 20)

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function tests were developed to assess early small airway disease, in an effort to identify a susceptible subpopulation of cigarette smokers who would develop severe COPD; such measurements, including the closing volume, tended to be abnormal in all smokers and were not useful in the identification of susceptible smokers [26]. 

20

14.3.2 Chest CT

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c

80

d

a

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0

b

0

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40 50 Age (yrs)

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Figure 14.2 Hypothetical tracking curves of FEV1 which can lead to chronic obstructive pulmonary disease. The normal pattern of growth and decline in FEV1 is shown by curve a. Significant reductions in FEV1 (below a threshold of 65% predicted) can occur by (1) normal rate of decline after a reduced maximally attained FEV1 (curve b); (2) early initiation of FEV1 decline following normal growth (curve c); and (3) accelerated decline in FEV1 following normal growth (curve d). (From Rijcken B. Bronchial responsiveness and COPD risk; an epidemiological study. University of Groningen; 1991. Adapted from Fletcher C, Peto R. The natural history of chronic airflow obstruction. Br Med J 1977;1:1645–8.)

growth phase (curve b), early initiation of pulmonary function decline after normal growth (curve c), or accelerated decline after normal growth (curve d). The rate of decline can be modified by changing environmental exposures (i.e., quitting smoking), with smoking cessation at an earlier age leading to a more beneficial effect than smoking cessation after disability has developed. Although rare individuals may experience precipitous declines in pulmonary function values, most individuals follow a steady trajectory of increased pulmonary function with growth during childhood and adolescence, followed by gradual decline with aging [22,23]. Children appear to track in their quantile of pulmonary function based on environmental, developmental, and familial factors that put them on different tracks at an early age. In addition to spirometry, other pulmonary function tests demonstrate abnormalities in COPD. Patients with emphysema tend to have increased total lung capacity and residual volume, related to the hyperinflation that accompanies alveolar destruction. Reduced diffusing capacity for carbon monoxide (DLCO) is also frequently noted in emphysema. However, DLCO is not reduced in some subjects with emphysema, and DLCO may be reduced in subjects with small airway disease rather than emphysema [24,25]. A variety of pulmonary

The development of high-resolution CT (HRCT) chest scans has provided a powerful, noninvasive tool for assessment of the anatomic presence of emphysema. HRCT scans are much more sensitive than conventional chest X-rays for the detection of emphysema. High-resolution (thin cut) images allow identification and quantification of the extent of emphysema, which was not possible with conventional (thick cut) chest CT scan images [27]. An example of the improved detection of emphysema by HRCT compared with conventional chest CT is shown in Fig. 14.3. Both qualitative (presence/absence or severity scales determined by radiologist scoring) and quantitative (computerized image analysis) approaches have been used to analyze the severity and distribution of emphysema on HRCT. Radiologist scoring typically involves grading the severity of emphysema in different lung regions and obtaining an overall emphysema score; independent scoring by multiple radiologists probably improves the quality of the emphysema scoring data. Using computerized image analysis of the frequency distribution of X-ray attenuation values within the lung, thresholds can be defined corresponding to the presence of emphysema, and the fraction of lung below those thresholds can be used to assess the percentage of emphysema within the lung [28,29]. Furthermore, Gupta et  al. demonstrated that various quantitative and qualitative HRCT features correlate with patients’ characteristics, spirometric indices, and health-related quality-of-life score, suggesting that HRCT is useful not only in detecting emphysema and its various subtypes but also in predicting the extent and severity of COPD [30]. Assessment of small airway disease using chest CT scanning has been quite challenging because the small airways responsible for airflow obstruction in COPD (