Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Cardiovascular, Respiratory, and Gastrointestinal Disorders

By Wayne W. Grody

Emery and Rimoin’s Principles and Practice of Medical Genetics and Genomics: Cardiovascular, Respiratory, and Gastrointestinal Disorders, Seventh Edition includes the latest information on seminal topics such as prenatal diagnosis, genome and exome sequencing, public health genetics, genetic counseling, and management and treatment strategies. This comprehensive, yet practical, resource emphasizes theory and research fundamentals relating to applications of medical genetics across the full spectrum of inherited disorders and applications to medicine. Updated sections in this release cover the genetics of cardiovascular, respiratory and gastrointestinal disorders, with an emphasis on genetic determinants and new pathways for diagnosis, prevention and disease management.

In addition, genetic researchers, students and health professionals will find new and fully revised chapters on the molecular genetics of congenital heart defects, inherited cardiomyopathies, hypertension, cystic fibrosis, asthma, hereditary pulmonary emphysema, inflammatory bowel disease, and bile pigment metabolism disorders among other conditions.

• Offers pathways for diagnosis, prevention and disease management
• Includes color images supporting identification, concept illustration and method processing
• Features contributions by leading international researchers and practitioners of medical genetics

• Language: English
• Publisher: Academic Press
• Release date: Sep 4, 2019
• ISBN: 9780128126806

Book preview

Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics

Cardiovascular, Respiratory, and Gastrointestinal Disorders

Seventh Edition

Editors

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

Table of Contents

Cover image

Title page

Copyright

List of Contributors

Preface to the Seventh Edition of Emery and Rimoin’s Principles and Practice of Medical Genetics AND GENOMICS

Preface to Cardiovascular, Respiratory, and Gastrointestinal Disorders

Section 1. Cardiovascular Disorders

1. Congenital Heart Defects

1.1. Introduction

1.2. The Evaluation of the Patient With Congenital Heart Defect

1.3. Embryology

1.4. Specific Syndromes With Congenital Heart Defect

1.5. Genes Responsible for Congenital Heart Malformations as Monogenic Traits

1.6. Environmental Causes and the Teratogen Syndromes

1.7. Maternal Diabetes

1.8. Maternal Cigarette Smoking

1.9. Maternal Drug Ingestion

1.10. Folic Acid Supplementation

1.11. The Adult With Congenital Heart Defect

1.12. Empirical Risks for Offspring

1.13. Future Developments

Appendix 1

Appendix 2

Appendix 3

Appendix 4

Appendix 5

Appendix 6

Appendix 7

Appendix 8

Appendix 9

Appendix 10

Appendix 11

Appendix 12

Appendix 13: Syndromes Tetralogy

2. Genetic Cardiomyopathies

2.1. Introduction

2.2. Hypertrophic Cardiomyopathy

2.3. Dilated Cardiomyopathy

2.4. Arrhythmogenic Right Ventricular Cardiomyopathy

2.5. Ventricular Noncompaction

2.6. Conclusion

3. Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

3.1. Introduction

3.2. Phenotype and Natural History

3.3. Genetics

3.4. Genotype–Phenotype Correlations in HHT

3.5. ALK1 Signaling and HHT Pathogenesis

3.6. Animal Models of HHT

3.7. Mechanistic Basis of AVM Pathogenesis

3.8. Diagnosis

3.9. Management

4. Genetics of Electrophysiologic Disorders

4.1. Long QT Syndrome

4.2. Brugada Syndrome

4.3. Catecholaminergic Polymorphic Ventricular Tachycardia

4.4. Arrhythmogenic Right Ventricular Cardiomyopathy

4.5. Medical Workup after Sudden Unexplained Death

5. Heritable Thoracic Aortic Disease: Single Gene Disorders Predisposing to Thoracic Aortic Aneurysms and Acute Aortic Dissections

5.1. Mechanisms of Heritable Thoracic Aortic Disease Due to Highly Penetrant, Pathogenic Variants in Single Genes

5.2. Gene-Based Clinical Management for Heritable Thoracic Aortic Disease

6. The Genetics of Blood Pressure Regulation

6.1. Introduction

6.2. History

6.3. Complexity of Blood Pressure Regulation

6.4. Single Gene Conditions with Hypertension or Hypotension

6.5. The GWAS Era

6.6. Conclusions

7. Genetics and Genomics of Atherosclerotic Cardiovascular Disease

7.1. Introduction

7.2. Mouse Models of Atherosclerosis

7.3. Candidate Gene Studies in Humans

7.4. Family-Based Studies in Humans

7.5. Association Studies in Humans

7.6. GWAS Findings for Atherosclerotic Traits

7.7. Mendelian Randomization

7.8. Genetic Risk Scores and Prediction Algorithms for Personalized Medicine

7.9. Summary and Future Directions

8. Genetic Disorders of the Lymphatic System

8.1. Introduction

8.2. Development of the Lymphatic System

8.3. Disorders of the Lymphatic System

8.4. Autosomal Dominant Inheritance

8.5. Autosomal Recessive Inheritance

8.6. Mosaic Disorders with Lymphatic Phenotype

8.7. Genetic Counseling

9. Disorders of the Venous System

9.1. Introduction

9.2. The Venous System

9.3. Disorders of the Venous System

10. Capillary Malformation/Arteriovenous Malformation

10.1. Introduction

10.2. Capillary Malformation

10.3. Sturge–Weber Syndrome

10.4. Capillary Malformation—Arteriovenous Malformation

11. Cerebral Cavernous Malformations, Molecular Biology, and Genetics

11.1. Introduction

11.2. Clinical Genetics

11.3. CCM Molecular Genetics

11.4. CCM Protein Partners and Signaling Pathways

11.5. Modeling Human CCM Disease in Mouse Models for the Development of Pre-clinical Trials

Section 2. Respiratory Disorders

12. Cystic Fibrosis

Summary

12.1. Incidence of Cystic Fibrosis

12.2. Clinical Features

12.3. Genetics

12.4. Diagnosis and Differential Diagnosis

12.5. Management

13. Genetic Underpinnings of Asthma and Related Traits

Glossary

Nomenclature

13.1. Introduction

13.2. The Genetics of Asthma and Allergic Diseases

13.4. Conclusion

Support

Conflict of Interest

14. Hereditary Pulmonary Emphysema

Abbreviations

14.1. Introduction

14.2. Diseases With Airflow Limitation: Definitions

14.3. Phenotypic Evaluation in COPD

14.4. Cigarette Smoking and COPD

14.5. Severe AAT Deficiency

14.6. Risk of COPD in Z Allele Heterozygotes

14.7. COPD and COPD-Related Phenotypes in Other Genetic Syndromes

14.8. Risk to Relatives for Non-AAT COPD∗

14.9. Linkage Analysis

14.10. Genetic Association Studies

14.11. Animal Models of COPD

14.12. Conclusions

15. Genetic Determinants of Interstitial Lung Diseases

15.1. Introduction

15.2. Idiopathic Interstitial Pneumonias

15.3. Genetic Basis of IIP

15.4. Systemic Diseases that can Cause ILD

15.5. Other Genetic Diseases that Can Cause ILD

15.6. Other Restrictive Lung Diseases

15.7. Conclusion

16. Heritable and Idiopathic Forms of Pulmonary Arterial Hypertension

16.1. Historical Perspectives and Introduction

16.2. Nomenclature

16.3. Incidence and Prevalence of HPAH and IPAH

16.4. Phenotype and Natural History of HPAH and IPAH

16.5. Inheritance and Genetics of PAH in Families

16.6. Connecting BMPR2 to PAH

16.7. Molecular and Cellular Pathogenesis

16.8. Diagnosis

16.9. Management

16.10. Counseling

Section 3. Gastrointestinal Disorders

17. Gastrointestinal Tract and Hepatobiliary Duct System

17.1. Introduction

17.2. Embryological Background

17.3. Classification of Gastrointestinal Disorders

17.4. The GI Microbiome

18. Inflammatory Bowel Disease

18.1. Introduction and Disease Definition

18.2. Phenotypic Heterogeneity

18.3. Racial and Ethnic Differences

18.4. Familial Aggregation

18.5. Twin and Spouse Studies

18.6. Inferences Regarding Mode of Inheritance

18.7. Association of Inflammatory Bowel Disease with Rare Genetic Syndromes

18.8. Associations With Other Diseases

18.9. Gene and Environmental Interactions

18.10. Gene Identification

18.11. Meta-Analysis Across all Genome Scans

18.12. Candidate Gene Studies (Table 18.10)

18.13. Clinical Application of Genetic Information

19. Bile Pigment Metabolism and Its Disorders

19.1. Introduction

19.2. Formation of Bilirubin

19.3. Structure of Bilirubin

19.4. Possible Physiologic Benefits of Biliverdin and Bilirubin

19.5. Bilirubin-Induced Neurological Dysfunctions

19.6. Disposition of Bilirubin

19.7. Bilirubin in Body Fluids

19.8. Disorders of Bilirubin Metabolism

Index

Copyright

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List of Contributors

Eric D. Austin,     Vanderbilt University Medical Center, Department of Pediatrics, Division of Allergy, Pulmonary and Immunology Medicine, Nashville

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

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

Christopher J. Cardinale,     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

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

Nisha Limaye,     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

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

Susan K. Mathai,     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

Douglas A. Marchuk,     Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC, United States

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

Dianna M. Milewicz,     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

Pia Ostergaard,     Associate Professor in Human Genetics, Molecular and Clinical Sciences, St George’s, University of London, London, United Kingdom

Ronald M. Paranal,     Department of Genetics, Harvard Medical School, Boston, MA, United States

Eberhard Passarge,     Institut für Humangenetik, Universitätsklinikum Essen, Essen, Germany

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

Reed E. Pyeritz,     Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, United States

Atif N. Qasim,     University of California, San Francisco, San Francisco, CA, United States

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

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

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

Preface to the Seventh 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.

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.

Preface to Cardiovascular, 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

Section 1

Cardiovascular Disorders

Outline

1. Congenital Heart Defects

2. Genetic Cardiomyopathies

3. Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)

4. Genetics of Electrophysiologic Disorders

5. Heritable Thoracic Aortic Disease: Single Gene Disorders Predisposing to Thoracic Aortic Aneurysms and Acute Aortic Dissections

6. The Genetics of Blood Pressure Regulation

7. Genetics and Genomics of Atherosclerotic Cardiovascular Disease

8. Genetic Disorders of the Lymphatic System

9. Disorders of the Venous System

10. Capillary Malformation/Arteriovenous Malformation

11. Cerebral Cavernous Malformations, Molecular Biology, and Genetics

1

Congenital Heart Defects

Rocio Moran ¹ , and Nathaniel H. Robin ²       ¹ Department of Pediatrics, Case Western Reserve University, MetroHealth Medical Center, Cleveland, OH, United States      ² Department of Genetics, Pediatrics, and Surgery, University of Alabama at Birmingham, Birmingham, AL, United States

Abstract

Congenital heart defects have always had a special place of significance among birth defects for clinical geneticists. They are often the first anomaly to present in a child with an underlying syndrome, and, as many are life-threatening, they also typically command the greatest attention. This chapter will provide an overview of congenital heart defects from a perspective most relevant to the clinical geneticist. Cardiac embryology will be reviewed with emphasis on known genes and associated heart defects. An approach to the patient with a congenital heart defect will be suggested. Common genetic syndromes with cardiac defects as major manifestations (categorized by etiology: chromosomal/ aneuploidy syndromes, segmental chromosomal deletion/duplication syndromes, single-gene mutations, and teratogenic) will be highlighted. Issues unique to the adult patient with congenital heart defects will be discussed as well as information regarding recurrence risks. In addition, tables of well-researched syndromes and genes associated with isolated and syndromic heart defects will be provided as a reference.

Keywords

Coarctation of the aorta; Congenital heart defect; Double outlet right ventricle; Hypoplastic left heart; septal defects; Tetralogy of Fallot; Total anomalous pulmonary venous return; Transposition of the great arteries; Truncus arteriosus

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 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.

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 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.

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 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.

Table 1.1

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 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 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.

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

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.

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

Table 1.2

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.

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

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, 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 low-set 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.

Figure 1.4 Partitioning of the bulbus cordis and truncus arteriosus.

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 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].

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

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].

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

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 they have the full picture, yet none has the complete pattern.

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

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 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 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].

Figure 1.10 Arcus juvenilis in Alagille syndrome.

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 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].

Figure 1.11 Mother and two affected daughters with Noonan syndrome.

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