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

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EMERY AND RIMOIN’S PRINCIPLES AND PRACTICE OF MEDICAL GENETICS AND GENOMICS
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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
		1.4.1 Chromosomal Disorders
			1.4.1.1 Trisomy 21 (Down Syndrome)
			1.4.1.2 Trisomy 18 (Edwards Syndrome)
			1.4.1.3 Trisomy 13 (Patau Syndrome)
			1.4.1.4 Turner Syndrome (Ulrich–Turner Syndrome)
		1.4.2 Microdeletions/Microduplication Syndromes
			1.4.2.1 22q11 Deletion Syndrome
			1.4.2.2 Williams Syndrome
			1.4.2.3 Alagille Syndrome
		1.4.3 Single-Gene Disorders
			1.4.3.1 Noonan Syndrome
			1.4.3.2 Holt–Oram Syndrome
			1.4.3.3 CHARGE Syndrome
		1.4.4 Heart Malformation and Metabolic Disorders
			1.4.4.1 Zellweger Syndrome
			1.4.4.2 Smith–Lemli–Opitz Syndrome
	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
		1.9.1 Alcohol
		1.9.2 Cocaine
		1.9.3 Lithium
		1.9.4 Maternal Phenylketonuria
	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
	Further Reading
2 - Genetic Cardiomyopathies
	2.1 Introduction
	2.2 Hypertrophic Cardiomyopathy
		2.2.1 Prevalence
		2.2.2 Pathology
		2.2.3 Phenotype
		2.2.4 Natural History
		2.2.5 Diagnosis
		2.2.6 Management
		2.2.7 Genetics
			2.2.7.1 Cardiac Myosin Binding Protein C
			2.2.7.2 Cardiac β-Myosin Heavy Chain (MYH7)
			2.2.7.3 Cardiac Troponin I (TNNI3)
			2.2.7.4 Cardiac Troponin T (TNNT2)
			2.2.7.5 α-Tropomyosin (TPM1)
			2.2.7.6 Myosin Light Chains
			2.2.7.7 α-Cardiac Actin (ACTC1)
			2.2.7.8 Putative HCM Genes
		2.2.8 Molecular and Experimental Models of HCM
			2.2.8.1 Interacting Heads Motif Disruption
			2.2.8.2 Calcium Dysregulation
			2.2.8.3 Energy Compromise
		2.2.9 Genetic Phenocopies of Hypertrophic Cardiomyopathy
			2.2.9.1 AMPK Dysfunction
			2.2.9.2 Fabry Disease
			2.2.9.3 Danon Disease
	2.3 Dilated Cardiomyopathy
		2.3.1 Prevalence
		2.3.2 Pathology
		2.3.3 Phenotype
		2.3.4 Natural History
		2.3.5 Diagnosis
		2.3.6 Management
		2.3.7 Genetics
			2.3.7.1 Sarcomere Mutations in DCM
				2.3.7.1.2 Troponin–tropomyosin complex. Pathogenic and likely pathogenic variants in α-tropomyosin (TPM1, <2%), cardiac troponin...
				2.3.7.1.3 Cardiac actin (ACTC1). Dominant pathogenic and likely pathogenic variants in ACTC1 account for less than 1% of DCM [75...
				2.3.7.1.4 β-Myosin heavy chain (MYH7). MYH7 mutations that cause DCM were identified from familial genetic linkage analyses [265...
				2.3.7.1.5 MYBPC3. While the majority of HCM mutations in MYBPC3 encode LOF, most pathogenic variants in MYBPC3 that cause DCM ar...
			2.3.7.2 Nonsarcomere Mutations in DCM
				2.3.7.2.2 Phospholamban. The PLN gene encodes phospholamban, a critical regulator of cardiac calcium homeostasis that modulates ...
				2.3.7.2.3 Metavinculin and vinculin. Splice variants of the 75-kb VCL gene give rise to metavinculin and vinculin. Vinculin is a...
				2.3.7.2.4  Dystrophin. Dystrophin is a large striated muscle cytoskeletal protein that functions in force transduction and membra...
				2.3.7.2.5 Desmin. The type III intermediate filament protein, design, is a 470-amino-acid muscle-specific protein that is expres...
				2.3.7.2.6 Desmoplakin. The desmosome is an intercellular junctional complex critical for tolerating mechanical stress and is lin...
				2.3.7.2.7  δ-Sarcoglycan. The DMD-associated glycoprotein complex is composed of α- and β-dystroglycans, α-, β-, γ- and δ-sarcogl...
				2.3.7.2.8 Other DCM genes. Additional pathogenic and likely pathogenic variants have been identified less commonly in DCM patien...
	2.4 Arrhythmogenic Right Ventricular Cardiomyopathy
		2.4.1 Prevalence
		2.4.2 Pathology
		2.4.3 Phenotype and Natural History
		2.4.4 Diagnosis and Management
		2.4.5 Genetics
			2.4.5.1 Cardiac Desmosomes
			2.4.5.2 Atypical ARVC Genes
	2.5 Ventricular Noncompaction
		2.5.1 Prevalence
		2.5.2 Pathology
		2.5.3 Phenotype and Natural History
		2.5.4 Diagnosis and Management
		2.5.5 Genetics
	2.6 Conclusion
3 - Hereditary Hemorrhagic Telangiectasia (Osler–Weber–Rendu Syndrome)*
	3.1 Introduction
		3.1.1 Historic Perspective
	3.2 Phenotype and Natural History
		3.2.1 Overview
		3.2.2 Phenotype
			3.2.2.1 Mucocutaneous Telangiectases
			3.2.2.2 Epistaxis
			3.2.2.3 Gastrointestinal
			3.2.2.4 Central Nervous System
			3.2.2.5 Lung
			3.2.2.6 Liver
			3.2.2.7 Other Manifestations
	3.3 Genetics
		3.3.1 HHT1 and Endoglin (ENG)
		3.3.2 HHT2 and ACVRL1
		3.3.3 HHT3
		3.3.4 HHT4
		3.3.5 Juvenile Polyposis–HHT
	3.4 Genotype–Phenotype Correlations in HHT
	3.5 ALK1 Signaling and HHT Pathogenesis
	3.6 Animal Models of HHT
		3.6.1 Mouse Models of HHT
			3.6.1.1 Acvrl1/HHT2 Mouse Models
			3.6.1.2 Eng/HHT1 Mouse Models
			3.6.1.3 Bmp9 and Bmp10 Mouse Models
		3.6.2 Zebrafish Models of HHT
			3.6.2.1 acvrl1/HHT2 Zebrafish Models
			3.6.2.2 eng/HHT1 Zebrafish Models
			3.6.2.3 bmp9 and bmp10 Zebrafish Models
	3.7 Mechanistic Basis of AVM Pathogenesis
		3.7.1 Arterial Identity in HHT Pathogenesis
		3.7.2 Impaired Pericyte/Vascular Smooth Muscle Cell Coverage in HHT Pathogenesis
		3.7.3 Enhanced Angiogenesis in HHT Pathogenesis
		3.7.4 Aberrant Endothelial Cell Migration in HHT Pathogenesis
		3.7.5 HHT-Associated AVMs as a Secondary Consequence of Altered Hemodynamic Environment
	3.8 Diagnosis
	3.9 Management
		3.9.1 Mucocutaneous Telangiectases
		3.9.2 Epistaxis
		3.9.3 Central Nervous System
		3.9.4 Lung
		3.9.5 Liver
		3.9.6 Gastrointestinal
		3.9.7 Anemia
		3.9.8 Circulation
		3.9.9 Pregnancy
		3.9.10 Counseling
		3.9.11 Life Expectancy
4 - Genetics of Electrophysiologic Disorders
	4.1 Long QT Syndrome
		4.1.1 Genetics of LQTS
		4.1.2 Diagnosis
		4.1.3 Genetic Testing
		4.1.4 Risk Stratification
		4.1.5 Treatment Strategies
	4.2 Brugada Syndrome
		4.2.1 Genetics of Brugada Syndrome
		4.2.2 Clinical Manifestations
		4.2.3 Diagnosis
		4.2.4 Genetic Testing
		4.2.5 Risk Stratification
		4.2.6 Treatment Strategies
	4.3 Catecholaminergic Polymorphic Ventricular Tachycardia
		4.3.1 Genetics of CPVT
		4.3.2 Clinical Manifestations
		4.3.3 Diagnosis
		4.3.4 Genetic Testing
		4.3.5 Risk Stratification
		4.3.6 Treatment Strategies
	4.4 Arrhythmogenic Right Ventricular Cardiomyopathy
		4.4.1 Genetics
		4.4.2 Clinical Manifestations
		4.4.3 Diagnosis
		4.4.4 Genetic Testing
		4.4.5 Risk Stratification
		4.4.6 Treatment Strategies
	4.5 Medical Workup after Sudden Unexplained Death
	Further Reading
5 - Heritable Thoracic Aortic Disease: Single Gene Disorders Predisposing to Thoracic Aortic Aneurysms and Acute Aortic Dissections
	5.1.1 HTAD Genes Encoding Proteins Involved in SMC Adhesion and Contraction Highlights the Importance of Maintaining the Elastin...
		5.1.2 Altered Genes That Disrupt the Extracellar Matrix
		5.1.3 Genes with Pathogenic Variants Disrupting SMC Contraction
		5.1.4 HTAD Genes Disrupting TGF-β Signaling
		5.1.5 HTAD Genes Disrupting Other Pathways
	5.2 Gene-Based Clinical Management for Heritable Thoracic Aortic Disease
		5.2.1 COL3A1
		5.2.2 ACTA2
		5.2.3 PRKG1
		5.2.4 MYLK
		5.2.5 FLNA
		5.2.6 TGFBR1 and TGFBR2
		5.2.7 TGFB2, SMAD3, and TGFB3
6 - The Genetics of Blood Pressure Regulation
	6.1 Introduction
	6.2 History
		6.2.1 Measurement of Blood Pressure
		6.2.2 Early Observations on Heredity and Blood Pressure
		6.2.3 Platt versus Pickering—Single Gene or Polygenic
	6.3 Complexity of Blood Pressure Regulation
	6.4 Single Gene Conditions with Hypertension or Hypotension
	6.5 The GWAS Era
		6.5.1 Chronology of GWAS Analyses of Blood Pressure
		6.5.2 Examples of Blood Pressure Genes Identified by GWAS
		6.5.3 Genetic Risk Scores and Hypertension
	6.6 Conclusions
7 - Genetics and Genomics of Atherosclerotic Cardiovascular Disease
	7.1 Introduction
	7.2 Mouse Models of Atherosclerosis
		7.2.1 Candidate Gene Approach Using Knock-Out Mice
		7.2.2 Unbiased Mapping in Mouse Models
		7.2.3 Challenges with Mouse Models
	7.3 Candidate Gene Studies in Humans
	7.4 Family-Based Studies in Humans
	7.5 Association Studies in Humans
		7.5.1 GWAS and RVAS
	7.6 GWAS Findings for Atherosclerotic Traits
		7.6.1 The 9p21 Locus
		7.6.2 Additional GWAS Loci for CHD
		7.6.3 SORT1
		7.6.4 ADAMTS7
		7.6.5 ABO
		7.6.6 CXCL12
		7.6.7 RVAS Findings for Atherosclerotic Traits
		7.6.8 Association Study Findings for CHD Risk Factors
		7.6.9 Next Steps for Novel CHD Risk Loci
	7.7 Mendelian Randomization
		7.7.1 PCSK9
		7.7.2 Lipoprotein(a)
		7.7.3 C-Reactive Protein
		7.7.4 LDL and HDL Cholesterol and Triglycerides
	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
		8.4.1 Congenital Primary Lymphedema
			8.4.1.1 Milroy Disease/Hereditary Lymphedema Type 1A—VEGFR3/FLT4
			8.4.1.2 Milroy-like Primary Lymphedema/Hereditary Lymphedema 1D—VEGFC
			8.4.1.3 Microcephaly-Chorioretinopathy-Lymphedema Syndrome—KIF11
		8.4.2 Autosomal Dominant Lymphatic-Related Fetal Hydrops (LRFH)—EPHB4
		8.4.3 Late-Onset Primary Lymphedema
			8.4.3.1 Lymphedema-Distichiasis Syndrome—FOXC2
			8.4.3.2 Late-Onset Four-Limb Lymphedema—GJC2 (Cx47)
			8.4.3.3 Meige Disease—No Gene Associated
			8.4.3.4 Emberger Syndrome—GATA2
	8.5 Autosomal Recessive Inheritance
		8.5.1 Hennekam Lymphangiectasia-Lymphedema Syndrome, Type 1—CCBE1
			8.5.1.1 Hennekam Lymphangiectasia-Lymphedema Syndrome, Type 2—FAT4
		8.5.2 Hereditary Lymphedema Type 3/Generalized Lymphatic Dysplasia of Fotiou—PIEZO1
		8.5.3 Hypotrichosis-Lymphedema-Telangiectasia Syndrome—SOX18
	8.6 Mosaic Disorders with Lymphatic Phenotype
		8.6.1 PIK3CA Related Overgrowth Spectrum (PROS)—PIK3CA
		8.6.2 Proteus Syndrome—AKT1
	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
		9.3.1 Glomuvenous Malformation
		9.3.2 Inherited Venous Malformation
		9.3.3 Sporadic Unifocal Venous Malformation
		9.3.4 Multifocal Sporadic Forms of Venous Malformation
		9.3.5 Molecular Basis of VM Pathogenesis
		9.3.6 Hyperkeratotic Cutaneous Capillarovenous Malformation
		9.3.7 Verrucous Venous Malformation
		9.3.8 Other VM-Associated Syndromes
		9.3.9 Conclusion
10 - Capillary Malformation/Arteriovenous Malformation
	10.1 Introduction
	10.2 Capillary Malformation
	10.3 Sturge–Weber Syndrome
		10.3.1 Arteriovenous Malformations
	10.4 Capillary Malformation—Arteriovenous Malformation
11 - Cerebral Cavernous Malformations, Molecular Biology, and Genetics
	11.1 Introduction
	11.2 Clinical Genetics
		11.2.1 Prevalence and Natural Clinical History
		11.2.2 Pattern of Inheritance
		11.2.3 Genetic Counseling
			11.2.3.1 Sporadic Cases with a Unique Lesion on MRI
			11.2.3.2 Symptomatic Cases with Multiple CCM Lesions and One or More Affected Relatives
			11.2.3.3 Symptomatic Sporadic Cases with Multiple CCM Lesions
			11.2.3.4 Asymptomatic Individuals Having an Affected Relative
			11.2.3.5 Prenatal Screening
		11.2.4 Genotype–Phenotype Correlations
	11.3 CCM Molecular Genetics
		11.3.1 CCM1-3 Germline Mutations
		11.3.2 Are There Additional CCM Genes
		11.3.3 Biallelic, Somatic and Germline, Mutations in Endothelial Cells from CCM Lesions
	11.4 CCM Protein Partners and Signaling Pathways
		11.4.1 CCMs and Endothelial Cell-Adhesion Processes
		11.4.2 CCMs Negatively Regulate Angiogenesis
		11.4.3 MEKK3-ERK5-Klf2/4 Pathway Upregulation Leads to CCM Lesion Development
		11.4.4 Specific CCM3 Interactors and Activities
	11.5 Modeling Human CCM Disease in Mouse Models for the Development of Pre-clinical Trials
		11.5.1 CCM Mouse Models
		11.5.2 Therapeutic Strategies Developed in CCM Mouse Models to Identify Repurposed Drugs
Section 2: Respiratory Disorders
12 - Cystic Fibrosis
	Summary
	12.1 Incidence of Cystic Fibrosis
	12.2 Clinical Features
		12.2.1 Classic Cystic Fibrosis
		12.2.2 Nonclassic Cystic Fibrosis and CFTR-Related Disorders
	12.3 Genetics
		12.3.1 Identification of the Gene Responsible for Cystic Fibrosis
		12.3.2 Properties of CFTR
		12.3.3 Variants in the CFTR Gene
		12.3.4 Effects of CF Variants on CFTR Function
		12.3.5 Relationship Between CFTR Genotype and Phenotype
	12.4 Diagnosis and Differential Diagnosis
	12.5 Management
13 - Genetic Underpinnings of Asthma and Related Traits
	Glossary
	Nomenclature
	13.1 Introduction
		13.1.1 Definition
		13.1.2 Asthma Diagnosis
		13.1.3 Asthma Prevalence and Severity
	13.2 The Genetics of Asthma and Allergic Diseases
		13.2.1 An Overview of the Analysis of the Genetic Contributions in Asthma
			13.2.1.1 Candidate Gene Studies
			13.2.1.2 Linkage Studies
			13.2.1.3 Genome-Wide Association Studies
		13.2.2 Themes Revealed by Genetic Analysis of Asthma Susceptibility
			13.2.2.1 TH2-Mediated Cell Response
			13.2.2.2 Environmental Sensing and Immune Detection
			13.2.2.3 Tissue Response
			13.2.2.4 Epithelial Barrier Function
		13.3.3 The Future of Asthma Genetics
			13.3.3.1 Gene–Environment Interactions
			13.3.3.2 Gene–Gene Interactions
			13.3.3.3 Replication
			13.3.3.4 Pharmacogenetics
	13.4 Conclusion
	Support
	Conflict of Interest
14 - Hereditary Pulmonary Emphysema*
	Abbreviations
	14.1 Introduction
	14.2 Diseases With Airflow Limitation: Definitions
		14.2.1 Pulmonary Emphysema
		14.2.2 Chronic Bronchitis
		14.2.3 Small Airway Disease
	14.3 Phenotypic Evaluation in COPD
		14.3.1 Pulmonary Function Tests
		14.3.2 Chest CT
		14.3.3 Questionnaire Phenotypes
		14.3.4 Biochemical Markers
	14.4 Cigarette Smoking and COPD
		14.4.1 Causal but Variable Relationship of Smoking and COPD
		14.4.2 Effects of Smoking at Different Life Stages
	14.5 Severe AAT Deficiency
		14.5.1 Description of the Protease Inhibitor Locus and Protease Inhibitor Alleles
		14.5.2 Diagnosis of AAT Deficiency
		14.5.3 Pathogenesis of COPD in Severe AAT Deficiency
		14.5.4 Prevalence of Severe AAT Deficiency
		14.5.5 Natural History of PI Z
		14.5.6 Other Familial Factors Influencing the Expression of AAT Deficiency
		14.5.7 Treatment of Severe AAT Deficiency
		14.5.8 Who Should Be Tested for AAT Deficiency
		14.5.9 Lessons from Severe AAT Deficiency
	14.6 Risk of COPD in Z Allele Heterozygotes
		14.6.1 PI MZ
		14.6.2 PI SZ
	14.7 COPD and COPD-Related Phenotypes in Other Genetic Syndromes
	14.8 Risk to Relatives for Non-AAT COPD*
		14.8.1 Familial Aggregation of Spirometry and COPD
		14.8.2 Familial Aggregation of Severe, Early-Onset COPD
	14.9 Linkage Analysis
		14.9.1 Linkage Analysis in COPD Families
		14.9.2 Linkage Analysis of Pulmonary Function in the General Population
	14.10 Genetic Association Studies
	14.11 Animal Models of COPD
	14.12 Conclusions
	Further Reading
15 - Genetic Determinants of Interstitial Lung Diseases*
	15.1 Introduction
	15.2 Idiopathic Interstitial Pneumonias
		15.2.1 Clinical Characteristics of IIPs
			15.2.1.1 Idiopathic Interstitial Pneumonias
			15.2.1.2 Familial Interstitial Pneumonia
	15.3 Genetic Basis of IIP
		15.3.1 Familial Studies
			15.3.1.1 Surfactant Proteins
			15.3.1.2 Telomere Pathway Genes and Telomere Length in FIP
			15.3.1.3 ELMOD2 in Finnish FIP Cases
		15.3.2 Idiopathic Pulmonary Fibrosis
			15.3.2.1 MUC5B
			15.3.2.2 Other Common Genetic Variants and IPF
		15.3.3 Rare Variants and Common Variants
		15.3.4 Clinical Outcomes
			15.3.4.1 Disease Severity
			15.3.4.2 Response to Medical Therapy
			15.3.4.3 Lung Transplant Outcomes
			15.3.4.4 Utilization in Clinical Care
		15.3.5 Early Fibrosis
	15.4 Systemic Diseases that can Cause ILD
		15.4.1 Systemic Sclerosis and ILD
		15.4.2 Sarcoidosis
		15.4.3 Hypersensitivity Pneumonitis
		15.4.4 Chronic Beryllium Disease
	15.5 Other Genetic Diseases that Can Cause ILD
		15.5.1 Dyskeratosis Congenita
		15.5.2 Hermansky–Pudlak Syndrome
	15.6 Other Restrictive Lung Diseases
		15.6.1 Lymphangioleiomyomatosis and Tuberous Sclerosis
		15.6.2 Pulmonary Langerhans Cell Histiocytosis
		15.6.3 Pulmonary Alveolar Proteinosis
		15.6.4 Lysinuric Protein Intolerance
		15.6.5 Birt–Hogg–Dube
		15.6.6 Neurofibromatosis
		15.6.7 Pulmonary Alveolar Microlithiasis
		15.6.8 Lipoid Proteinosis
		15.6.9 Gaucher Disease
		15.6.10 Niemann–Pick Disease
		15.6.11 Fabry Disease
		15.6.12 Marfan Syndrome
	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
		16.5.1 Reduced Penetrance
		16.5.2 Gender Dimorphism
		16.5.3 Variable Expressivity
		16.5.4 Genetic Anticipation
	16.6 Connecting BMPR2 to PAH
		16.6.1 Identification of Mutations in BMPR2 in PAH that Occur in Families
		16.6.2 Range of BMPR2 Mutations
		16.6.3 BMPR2 Mutations in PAH that Occur Sporadically
		16.6.4 BMPR2 Mutations in Other Disorders
		16.6.5 Additional Genetic Modifiers of IPAH and HPAH
	16.7 Molecular and Cellular Pathogenesis
		16.7.1 BMPR2-Mediated Pathogenesis
			16.7.1.1 Smad-Dependent BMP Signaling
			16.7.1.2 MAPK-Dependent BMP Signaling
			16.7.1.3 ACVRL1 and Endoglin
			16.7.1.4 Serotonin
			16.7.1.5 Transforming Growth Factor β1
			16.7.1.6 Other Contributors to Pathogenesis
	16.8 Diagnosis
	16.9 Management
		16.9.1 Approved Therapies in the United States
			16.9.1.1 Adjunctive Therapies
			16.9.1.2 Calcium Channel Blockers
			16.9.1.3 Prostaglandin Analogs
			16.9.1.4 ET Receptor Antagonists
			16.9.1.5 Phosphodiesterase-5 Inhibitors
			16.9.1.6 Surgical Therapy: Lung Transplantation
	16.10 Counseling
		16.10.1 Clinical Screening and Surveillance for PAH
		16.10.2 Agents and Circumstances for At-Risk Subjects to Avoid
		16.10.3 Genetic Counseling
		16.10.4 Mutation Testing of Relatives at Risk
	Acknowledgments
Section 3: Gastrointestinal Disorders
17 - Gastrointestinal Tract and Hepatobiliary Duct System
	17.1 Introduction
	17.2 Embryological Background
	17.3 Classification of Gastrointestinal Disorders
		17.3.1 Gross Defects of the Intestinal Anatomical Structures
			17.3.1.1 Gastrointestinal Atresias
			17.3.1.2 Defects of the Abdominal Wall
			17.3.1.3 Malrotation
			17.3.1.4 Duplication
			17.3.1.5 Meckel Diverticulum
			17.3.1.6 Partial Agenesis of the Pancreas
			17.3.1.7 Congenital Defects of the Diaphragm
		17.3.2 Disorders of the GI Enteric Nervous System (Congenital Intestinal Aganglionosis; Hirschsprung Disease)
			17.3.2.1 Definition and Clinical Aspects
			17.3.2.2 Types of Aganglionosis
			17.3.2.3 Diagnosis
				17.3.2.3.1  Clinical signs. Failure to pass meconium within the first 48h is the first and sometimes only manifestation in the ne...
				17.3.2.3.2 X-ray. Regular abdominal X-rays show a distended proximal colon and small intestines above an empty rectum (Fig. 17.3...
				17.3.2.3.3 Rectal biopsy. The absence of ganglion cells in the myenteric plexus (Auerbach) and the submucosal plexus (Meissner) ...
			17.3.2.4 Formal Genetics
				17.3.2.4.1 Inheritance pattern. Systematic genetic studies of the familial occurrence of nonsyndromic Hirschsprung disease prece...
				17.3.2.4.2 Genetic counseling. If the index patient is female, the proportion of affected first-degree relatives is about 6%–18%...
			17.3.2.5 Molecular Genetics
				17.3.2.5.1 Loci, genes, and noncoding variants involved. The underlying genetic components of this complex disorder include codi...
				17.3.2.5.2  Role of the RET gene. The RET gene (MIM 164761), located on the long arm of chromosome 10, region 1, band 1.2, encode...
			17.3.2.6 Syndromic Forms of Hirschsprung Disease
			17.3.2.7 Hirschsprung Disease in Mutant Mice
		17.3.3 Genetic Defects of the Hepatobiliary Duct System
			17.3.3.1 Biliary Atresia
			17.3.3.2 Arteriohepatic Dysplasia Syndrome (Alagille Syndrome)
				17.3.3.2.1 Clinical manifestations. ALGS (OMIM 118450/601920) is an autosomal dominant multisystem developmental disorder with i...
				17.3.3.2.2 Formal genetics. The first descriptions of ALGS were based on familial occurrence consistent with autosomal dominant ...
				17.3.3.2.3 Molecular genetics. In about 94% of patients, ALGS is caused by mutations in the gene, Jagged-1 (JAG1, OMIM 601920). ...
				17.3.3.2.4 Diagnosis and genetic counseling. In a typical constellation the diagnosis can be made easily on the basis of the mai...
		17.3.4 Functional GI Disorders
			17.3.4.1 Irritable Bowel Syndrome
			17.3.4.2 Hereditary Pancreatitis
			17.3.4.3 Infantile Hypertrophic Pyloric Stenosis
			17.3.4.4 Achalasia
			17.3.4.5 Intestinal Pseudo-obstruction
			17.3.4.6 Intussusception
	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
		18.6.1 Simple Mendelian Model
		18.6.2 Multifactorial/Polygenic Model [31c]
		18.6.3 Multilocus (Oligogenic) Model
		18.6.4 Genetic Heterogeneity Model
	18.7 Association of Inflammatory Bowel Disease with Rare Genetic Syndromes
		18.7.1 Turner Syndrome
		18.7.2 Hermansky–Pudlak Syndrome
		18.7.3 Glycogen Storage Disease Type Ib
		18.7.4 Immunodeficiency Syndromes
	18.8 Associations With Other Diseases
	18.9 Gene and Environmental Interactions
		18.9.1 Smoking
		18.9.2 Westernization
		18.9.3 Appendectomy
		18.9.4 Intestinal Bacteria
		18.9.5 An Evolutionary Perspective
	18.10 Gene Identification
		18.10.1 Genome-wide Linkage Studies
		18.10.2 Chromosome 16 (IBD1, OMIM #266600)
	18.11 Meta-Analysis Across all Genome Scans
	18.12 Candidate Gene Studies (Table 18.10)
		18.12.1 The Major Histocompatibility Complex (MHC; IBD3)
			18.12.1.1 The MHC Class II Region
	18.13 Clinical Application of Genetic Information
	Further Reading
19 - Bile Pigment Metabolism and Its Disorders
	19.1 Introduction
	19.2 Formation of Bilirubin
		19.2.1 Enzyme-Mediated Opening of the Heme Ring
			19.2.1.1 Heme Oxygenase Inhibitors
		19.2.2 Reduction of Biliverdin to Bilirubin
		19.2.3 Measurement of Bilirubin Production
	19.3 Structure of Bilirubin
		19.3.1 Photoisomerization of Bilirubin
	19.4 Possible Physiologic Benefits of Biliverdin and Bilirubin
	19.5 Bilirubin-Induced Neurological Dysfunctions
		19.5.1 Clinical Features of Bilirubin Neurotoxicity
		19.5.2 Pathophysiology of Kernicterus
		19.5.3 Biochemical Mechanism of Bilirubin Toxicity
		19.5.4 Bilirubin Nephrotoxicity
	19.6 Disposition of Bilirubin
		19.6.1 The Role of Albumin
		19.6.2 Bilirubin Uptake by Hepatocytes
		19.6.3 Storage of Bilirubin Within the Hepatocyte
		19.6.4 Bilirubin Conjugation
			19.6.4.1 Conversion of Bilirubin to Polar Derivatives
			19.6.4.2 Enzyme-Catalyzed Glucuronidation of Bilirubin
			19.6.4.3 Families and Subfamilies of UGT
		19.6.5 Excretion of Conjugated Bilirubin Across the Bile Canaliculus
		19.6.6 Nuclear Receptors
		19.6.7 Degradation of Bilirubin in the Gastrointestinal Tract
		19.6.8 Extrahepatic Disposition of Bilirubin
		19.6.9 Alternative Pathways of Bilirubin Disposition
			19.6.9.1 Bilirubin Measurement
		19.6.10 Bilirubin Measurement Following Reaction With Diazo Reagents
		19.6.11 Chromatographic Analysis of Bilirubin as Intact Tetrapyrrole
		19.6.12 Slide Test
		19.6.13 Transcutaneous Bilirubinometry
		19.6.14 Measurement of Bilirubin Unbound to Protein (Free Bilirubin, Bf)
	19.7 Bilirubin in Body Fluids
		19.7.1 Bilirubin in Plasma
		19.7.2 Bilirubin in Bile
	19.8 Disorders of Bilirubin Metabolism
		19.8.1 Metabolic Disorders Causing Unconjugated Hyperbilirubinemia
			19.8.1.1 Neonatal Hyperbilirubinemia
				19.8.1.1.1 Increased bilirubin load. Bilirubin production, as measured by carbon monoxide production, is increased in the newbor...
				19.8.1.1.2 Low hepatic bilirubin uptake. During the first few days of life, the rate of hepatic uptake of bilirubin is lower tha...
				19.8.1.1.3 Reduced bilirubin glucuronidation. Only 1% of the normal adult level of hepatic UGT1A1 activity is present at birth [...
				19.8.1.1.4  Maternal milk jaundice. Serum bilirubin levels in breast-fed infants are, in general, higher than in formula-fed babi...
				19.8.1.1.5  Maternal serum jaundice. This syndrome, associated with moderate to severe unconjugated hyperbilirubinemia (8.9–65mg/...
				19.8.1.1.6 Decreased canalicular bilirubin excretory capacity. Maturation of canalicular excretion processes may take longer tha...
				19.8.1.1.7 Increased intestinal reabsorption. Intestinal β-glucuronidase–mediated deconjugation releases unconjugated bilirubin ...
			19.8.1.2 Hyperbilirubinemia due to Bilirubin Overproduction
			19.8.1.3 Inherited Disorders of Bilirubin Glucuronidation
				19.8.1.3.1 Crigler–Najjar syndrome type 1. Crigler and Najjar [186] described this rare, recessively inherited syndrome in 1952 ...
					19.8.1.3.1.1  Laboratory tests. Serum bilirubin levels usually range from 20 to 25mg/dL, but may reach 50mg/dL [186–188]. Serum b...
					19.8.1.3.1.2 Liver histology. Historically, liver histology has been reported as normal, except that, in several patients, bilir...
					19.8.1.3.1.3 Abnormalities of hepatic UGTs. Hepatic UGT activity toward bilirubin is virtually absent in all patients with CN1. ...
					19.8.1.3.1.4 Animal models of CN1. Gunn rats are a mutant strain of Wistar rats that exhibit lifelong nonhemolytic unconjugated ...
					19.8.1.3.1.5 UGT1A1-knockout mice. A mouse model of CN1 has been generated by disrupting the exon 4 of the UGT1 locus [41]. Thes...
					19.8.1.3.1.6 Treatment of CN1. Temporizing measures are directed at reducing serum bilirubin levels. Definitive treatment consis...
					19.8.1.3.1.7  Phototherapy. Phototherapy is the most commonly used medical therapy for severe unconjugated hyperbilirubinemia [19...
					19.8.1.3.1.8  Plasmapheresis. During neurologic emergencies, serum bilirubin concentration can be acutely reduced by plasmapheres...
					19.8.1.3.1.9 Orthotopic liver transplantation. Presently, the transplantation of whole liver or a segment of the liver is the on...
				19.8.1.3.2 Experimental methods for reduction of serum bilirubin levels
					19.8.1.3.2.1  Inhibition of heme oxygenase activity. Non-iron metalloporphyrins are strong inhibitors of microsomal heme oxygenas...
					19.8.1.3.2.2  Oxidative degradation of bilirubin. Bilirubin oxidase from Myrothecium verrucaria [231] catalyzes the oxidation of ...
					19.8.1.3.2.3 Induction of P-450c. Induction of cytochrome P-450c activity results in increased oxidative degradation of bilirubi...
					19.8.1.3.2.4 Replacement of UGT1A1 activity. UGT1A1 activity is present in excess in normal liver. Therefore, partial replacemen...
					19.8.1.3.2.5 Gene therapy. Supplementation with a normal UGT1A1 gene is an attractive potential therapeutic modality. Methods fo...
					19.8.1.3.2.6 Targeted DNA integration. Recently, the possibility of inserting a DNA of interest at a specific genomic site by ho...
					19.8.1.3.2.7 Genetic lesions. Molecular genetic studies that have performed so far support an autosomal recessive mode of inheri...
					19.8.1.3.2.8  Clinical features. Gilbert syndrome is usually diagnosed in young adults who are incidentally found to have mild, p...
					19.8.1.3.2.9 Incidence. Gilbert syndrome is perhaps the most common inherited disorder in man, the reported incidence ranging fr...
					19.8.1.3.2.10 Bilirubin glucuronidation. Hepatic UGT1A1 activity, as determined by in vitro assays, is present at a consistently...
					19.8.1.3.2.11 Diagnosis. Gilbert syndrome is diagnosed in individuals with mild unconjugated hyperbilirubinemia without evidence...
					19.8.1.3.2.12  Effect of fasting. Reduction of daily caloric intake to 400kcal for 48h results in elevation of serum bilirubin le...
					19.8.1.3.2.13 Nicotinic acid tests. Intravenous administration of nicotinic acid increases unconjugated hyperbilirubinemia, prob...
					19.8.1.3.2.14 Bilirubin Conjugates in Bile. As in CN2, bile in Gilbert syndrome contains an increased proportion of bilirubin mo...
					19.8.1.3.2.15 Genetic basis of Gilbert syndrome. Gilbert syndrome is associated with a variant TATAA box in the promoter upstrea...
					19.8.1.3.2.16 Health implications of Gilbert syndrome. Gilbert syndrome is generally considered innocuous, and its recognition i...
					19.8.1.3.2.17 Animal Model. Bolivian squirrel monkeys have higher serum unconjugated bilirubin concentrations and a greater hype...
		19.8.2 Disorders Associated With Predominantly Conjugated Hyperbilirubinemia
			19.8.2.1 Dubin–Johnson Syndrome
				19.8.2.1.1  Laboratory tests. Liver function tests, including serum bile acid levels, are normal [323]. Serum bilirubin levels fl...
				19.8.2.1.2  Organic anion transport. The hepatic secretion of bilirubin glucuronides, the leukotriene LTC4, reduced and oxidized ...
				19.8.2.1.3 Urinary Coproporphyrin Excretion. In normal subjects, approximately 75% of the urinary coproporphyrin is isomer III, ...
				19.8.2.1.4 Genetic basis and inheritance. Dubin–Johnson syndrome has been reported in all races and both sexes. There is a high ...
		19.8.3 Animal Models
			19.8.3.1 Mutant Corriedale Sheep
			19.8.3.2 TR− rats
			19.8.3.3 A Nonhuman Primate Model
			19.8.3.4 Rotor Syndrome
				19.8.3.4.1  Organic anion excretion. After intravenous injection of 5mg/kg BSP, over 25% of injected BSP is retained in serum at ...
				19.8.3.4.2 Hepatic storage. Transport maximum and hepatic storage of BSP has been determined by a constant infusion technique [3...
				19.8.3.4.3 Urinary Coproporphyrin Excretion. In Rotors’ syndrome, total urinary coproporphyrin is increased two- to fivefold ove...
			19.8.3.5 Hyperbilirubinemia Resulting from Inherited Cholestasis Syndromes
				19.8.3.5.1 Progressive familial intrahepatic cholestasis (PFIC). These inherited disorders do not specifically affect bilirubin ...
				19.8.3.5.2 Progressive familial intrahepatic cholestasis type I. PFIC I was originally described in a family in the Amish-Mennon...
				19.8.3.5.3 Benign recurrent intrahepatic cholestasis. This disorder was first described in 1959 [375]. It presents in adolescenc...
				19.8.3.5.4 Progressive familial intrahepatic cholestasis type II. This disorder resembles Byler disease clinically, but occurs i...
				19.8.3.5.5 Progressive familial intrahepatic cholestasis type III. PFIC III involves mutations in the multidrug resistance prote...
					19.8.3.5.6 Progressive familial intrahepatic cholestasis type IV. In 2014, 33 children from 29 families were reported to have se...
					19.8.3.5.7 Treatment. The treatment options currently available for PFICs are limited. Experimental transplantation of normal he...
					19.8.3.5.8 Other inherited cholestatic disorders. The cholangiopathy of North American Indian childhood cirrhosis is caused by t...
	Further Reading
INDEX
	A
	B
	C
	D
	E
	F
	G
	H
	I
	K
	L
	M
	N
	O
	P
	Q
	R
	S
	T
	U
	V
	W
	X
	Y
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