Clinical Molecular Medicine: Principles and Practice

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Clinical Molecular Medicine: Principles and Practice
Copyright
Dedication
Dedication
Contents
List of contributors
About the author
Foreword
Preface
Acknowledgement and Disclaimer
Section 1: Fundamentals of molecular medicine
1 The human genome and molecular medicine
	1.1 Introduction
	1.2 Hereditary factors: genes, genetics, and genomics
		1.2.1 Structure and organization of nucleic acids
	1.3 Human genome variation and human disease
		1.3.1 Measuring genetic and genomic variation
		1.3.2 Genome variation and human disease
	1.4 The mitochondrial genome
	1.5 Functional genomics, transcriptomics, and proteomics
	1.6 Translational human genomics
	1.7 Human genomics for socioeconomic development
	1.8 Conclusions
	References
2 Cellular structure and molecular cell biology
	2.1 Plasma membrane
		2.1.1 Cell signaling
		2.1.2 Cell junctions
	2.2 Cytoskeleton
	2.3 Cell nucleus and gene expression
		2.3.1 Chromosome territories, gene transcription and the nuclear lamina
		2.3.2 Cajal bodies, speckles and pre-mRNA processing
		2.3.3 Nucleolus
		2.3.4 Nuclear envelope and mRNA quality control
	2.4 Protein synthesis
		2.4.1 Ribosomes and mRNA translation
	2.5 Vesicular trafficking: the secretory and endocytic pathways
	2.6 Protein turnover and cell size control
	2.7 Microtubule-organizing centers and the cell cycle
		2.7.1 The cell cycle
		2.7.2 Primary cilium
	2.8 Energy production and oxidative stress
		2.8.1 Mitochondria
		2.8.2 Peroxisomes
	2.9 Summary
	Bibliography
3 Molecular basis of clinical metabolomics
	3.1 Introduction
	3.2 Clinical applications of metabolomics
		3.2.1 Inborn errors of metabolism
		3.2.2 Metabolomics in cancer and other human diseases
		3.2.3 Other applications of clinical metabolomics
	3.3 Techniques used in metabolomics and databases
	3.4 Conclusions
	Acknowledgments
	References
4 Clinical applications of next-generation sequencing
	4.1 Introduction
	4.2 Next-generation sequencing technologies
		4.2.1 First generation—Sanger sequencing
		4.2.2 Second- (next-) generation sequencing
		4.2.3 The third-generation sequencing
	4.3 Choice of test
		4.3.1 Small gene panels
		4.3.2 Whole-exome sequencing and large curated panels
	4.4 Whole-genome sequencing
	4.5 Summary
	4.6 Ethical considerations
	4.7 Bioinformatics
	4.8 Clinical interpretation of variants
		4.8.1 Population data
		4.8.2 Computational and predictive data
		4.8.3 Functional data
		4.8.4 De novo status and segregation data
		4.8.5 Allelic data
		4.8.6 Other databases
		4.8.7 Other data
		4.8.8 Criticism of American College of Medical Genetics and Genomics guidelines
		4.8.9 Summary: potential future developments in clinical genomics
Section II: Molecular medicine in clinical practice
5 Molecular basis of obesity disorders
	5.1 Introduction
		5.1.1 Consequences of obesity
		5.1.2 Obesity: nature or nurture
		5.1.3 Genetic obesity
	5.2 Clinical cases
		5.2.1 Case 1
			5.2.1.1 Patient history
			5.2.1.2 Physical examination
			5.2.1.3 Family history
			5.2.1.4 Genetic diagnosis
		5.2.2 Case 2
			5.2.2.1 Genetic diagnosis
		5.2.3 Case 3
			5.2.3.1 Genetic diagnosis
			5.2.3.2 Follow-up
	5.3 Molecular systems underpinning the clinical scenario
		5.3.1 Case 1. Melanocortin-4-receptor gene mutations
		5.3.2 Case 2. Leptin receptor deficiency
		5.3.3 Case 3. 16p11.2 deletion
	5.4 Molecular biology and pathophysiology of obesity
		5.4.1 Fat storage
		5.4.2 The big two
		5.4.3 Nongenetic causes of obesity
		5.4.4 The energy balance
		5.4.5 Leptin resistance
		5.4.6 Not just the leptin–melanocortin pathway
		5.4.7 Genetic obesity: leptin–melanocortin pathway
			5.4.7.1 Melanocortin-4 receptor
			5.4.7.2 Proopiomelanocortin
		5.4.8 Monogenic obesity syndromes with intellectual disability
			5.4.8.1 Prader–Willi syndrome
			5.4.8.2 Bardet–Biedl syndrome
	5.5 Targeted molecular diagnosis and therapy
		5.5.1 Targeted molecular diagnosis
			5.5.1.1 Leptin
			5.5.1.2 DNA diagnostics
		5.5.2 Prader–Willi syndrome
		5.5.3 Copy number variation
		5.5.4 Therapy
			5.5.4.1 Lifestyle interventions
			5.5.4.2 Bariatric surgery
			5.5.4.3 Bariatric surgery in genetic obesity
				5.5.4.3.1 Monogenic nonsyndromic obesity
				5.5.4.3.2 Prader–Willi syndrome
		5.5.5 Medication
			5.5.5.1 Nonpersonalized medication
			5.5.5.2 Personalized treatment
		5.5.6 Obesity does not run in your family, the problem is that nobody runs in your family—obesity stigma and genetic counseling
	5.6 Summary
	References
	Guide to further reading: articles
		Online material
6 Molecular dysmorphology
	6.1 Introduction
		6.1.1 Limitations of “clinical” dysmorphology and the newer dysmorphology tools
		6.1.2 Molecular dysmorphology
		6.1.3 Molecular diagnosis and molecular medicine
	6.2 Clinical cases and molecular basis
		6.2.1 Genetic heterogeneity
			6.2.1.1 The splitting
				Holoprosencephaly
				Split hand–foot malformation
			6.2.1.2 Syndromes with genetic connections: the lumping
				RASopathies
				Laminopathies
				Ciliopathies
				Filaminopathies
		6.2.2 Epigenetic mechanisms and transcriptomopathies
		6.2.3 Spliceopathies
	6.3 Molecular diagnosis and therapy
		6.3.1 Gene therapy
			Primary immunodeficiencies
			Duchenne muscular dystrophy
			Hemophilia B
			Leber congenital amaurosis
			Achondroplasia
			Sickle cell disease
			Laminopathies
		6.3.2 The histone deacetylase inhibitors
			Kabuki syndrome
			Autosomal dominant polycystic kidney disease
		6.3.3 Protein modulation
		6.3.4 Novel uses of known pharmacological agents
			Joubert syndrome
			Farber/Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME)
			Thanatophoric dysplasia and achondroplasia
			Dystrophic epidermolysis bullosa
			Laminopathies
	6.4 Conclusion/summary
	References
7 Disorders of sex development
	7.1 Introduction
	7.2 Sex chromosome disorder of sex development
	7.3 46, XY disorders of sexual differentiation
		7.3.1 Disorders of testicular (gonadal) development
		7.3.2 Disorders of androgen synthesis
			7.3.2.1 Disorders of androgen synthesis associated with adrenal dysfunction
			7.3.2.2 Disorders of androgen synthesis associated without adrenal dysfunction
		7.3.3 Disorders of androgen response
	7.4 46, XX disorders of sex development
		7.4.1 Ovarian development
		7.4.2 Exposure or overproduction of androgens
			7.4.2.1 Exposure to androgens of nonfetal origin
			7.4.2.2 Steroid synthesis defects—overproduction of androgens
	7.5 Investigations
	7.6 Gender assignment
	7.7 Gonadal cancer risk
	7.8 Conclusion
	7.9 Resources Web-based resources
		7.9.1 Support groups
	References
8 Molecular systems in cardiovascular developmental disorders
	8.1 Introduction
	8.2 Historical overview
	8.3 Normal development of the heart
	8.4 Advances in technology
		8.4.1 Genome-wide association studies
		8.4.2 Whole genome and exome sequencing
	8.5 Chromosomal aneuploidy and structural heart disease
		8.5.1 Congenital heart disease and copy-number variations
	8.6 Single-gene (Mendelian) disorders
		8.6.1 RASopathies
		8.6.2 Transcription factor–related disorders [34]
			8.6.2.1 CHARGE association
		8.6.3 Isolated congenital heart disease caused by single gene
	8.7 The noncoding regulatory genome in congenital heart disease: microRNAs and circular RNAs
		8.7.1 Congenital heart disease and single-nucleotide polymorphisms
	8.8 Noncardiac congenital anomalies in congenital heart disease
	8.9 The epigenome and congenital heart disease
		8.9.1 DNA methylation
		8.9.2 Histone modification
	8.10 Future considerations
	References
9 Channelopathies in clinical medicine—cardiac arrhythmias
	9.1 Introduction
	9.2 Clinical cases
		9.2.1 Case 1
		9.2.2 Case 2
		9.2.3 Case 3
	9.3 Molecular systems underpinning the clinical scenario
		9.3.1 Overview of the cardiac action potential
		9.3.2 Relation of the action potential to the surface electrocardiogram
		9.3.3 The sarcoplasmic reticulum and excitation–contraction coupling
		9.3.4 Generation and propagation of clinical arrhythmias
			9.3.4.1 Increased automaticity
			9.3.4.2 Re-entry
			9.3.4.3 Triggered activity
	9.4 Overview of molecular biology and pathophysiology
		9.4.1 Mechanisms of channelopathy
		9.4.2 Long QT syndrome
			9.4.2.1 Overview of long QT syndrome
			9.4.2.2 Long QT syndrome diagnosis
				9.4.2.2.1 Long QT syndrome type 1
				9.4.2.2.2 Long QT syndrome type 2
				9.4.2.2.3 Long QT syndrome type 3
				9.4.2.2.4 Jervell and Lange-Nielsen syndrome
				9.4.2.2.5 Anderson–Tawil syndrome
				9.4.2.2.6 Timothy syndrome
		9.4.3 Molecular risk stratification in long QT syndrome
		9.4.4 Drug-induced long QT
		9.4.5 Generation and propagation of arrhythmia in long QT syndrome
	9.5 Short QT syndrome
		9.5.1 Generation and propagation of arrhythmia
	9.6 Catecholaminergic polymorphic ventricular tachycardia
		9.6.1 Generation and propagation of arrhythmia in catecholaminergic polymorphic ventricular tachycardia
		9.6.2 Molecular risk stratification in catecholaminergic polymorphic ventricular tachycardia
	9.7 Brugada syndrome
		9.7.1 Generation and propagation of arrhythmia in Brugada syndrome
	9.8 Targeted molecular diagnosis and therapy
		9.8.1 Long QT syndrome
			9.8.1.1 Clinical risk assessment in long QT syndrome
			9.8.1.2 Targeted therapies in long QT syndrome
		9.8.2 Short QT syndrome
			9.8.2.1 Clinical risk assessment and therapy in short QT syndrome
		9.8.3 Catecholaminergic polymorphic ventricular tachycardia
			9.8.3.1 Clinical risk assessment and therapy in catecholaminergic polymorphic ventricular tachycardia
		9.8.4 Brugada syndrome
			9.8.4.1 Clinical risk assessment in Brugada syndrome
			9.8.4.2 Targeted therapy in Brugada syndrome
	9.9 Summary
	References
10 Chronic heart failure
	10.1 Introduction
	10.2 Epidemiology
	10.3 Etiology of heart failure
	10.4 Clinical assessment
		10.4.1 Personal history
		10.4.2 Family history
		10.4.3 Physical examination
		10.4.4 Laboratory studies
			10.4.4.1 Plasma natriuretic peptides
			10.4.4.2 Cardiomyopathy screen
		10.4.5 Electrocardiography
			10.4.5.1 Resting electrocardiography
			10.4.5.2 Ambulatory electrocardiography
		10.4.6 Imaging studies
			10.4.6.1 Plain chest radiography
			10.4.6.2 Echocardiography
			10.4.6.3 Cardiac magnetic resonance imaging
			10.4.6.4 Other imaging modalities
		10.4.7 Exercise testing
		10.4.8 Cardiac biopsy
	10.5 Genetic testing
		10.5.1 Limitations of clinical assessment
		10.5.2 The genetics of acquired heart failure
		10.5.3 The genetic basis of the inheritable cardiomyopathies
		10.5.4 Indications for genetic testing in cardiomyopathies
			10.5.4.1 Diagnostic confirmation and prognostication in clinically suspected cases
			10.5.4.2 Predictive testing of family members
		10.5.5 Genetic testing techniques in heart failure
		10.5.6 The cardiac genetics multidisciplinary team
		10.5.7 Limitations of genetic testing in heart failure
	10.6 Management
		10.6.1 Pharmacological therapies
		10.6.2 Nonsurgical device therapies and risk stratification for sudden death
		10.6.3 Exercise
	References
11 Molecular pathophysiology of systemic hypertension
	11.1 Introduction
	11.2 Blood pressure regulation—key systems
		11.2.1 Endothelium
		11.2.2 Renin–angiotensin aldosterone system
		11.2.3 Natriuretic peptides
		11.2.4 Sympathetic nervous system
		11.2.5 Immune system
	11.3 Genetics of hypertension
	11.4 Monogenic forms of systemic hypertension
		11.4.1 Gordon’s syndrome
			11.4.1.1 Case report: a 52-year-old man with hypertension and hyperkalemia was presented
			11.4.1.2 Definition
			11.4.1.3 Genetics
				11.4.1.3.1 WNK genes
				11.4.1.3.2 KLHL3 gene
				11.4.1.3.3 CUL3 gene
			11.4.1.4 Pathophysiology
				11.4.1.4.1 WNK kinases
				11.4.1.4.2 KLHL3 and CUL3 proteins
			11.4.1.5 Diagnosis
			11.4.1.6 Management
		11.4.2 Liddle’s syndrome
			11.4.2.1 Case report: a 22-year-old woman with hypertension and hypokalemia was presented
			11.4.2.2 Definition
			11.4.2.3 Genetics
				11.4.2.3.1 SCNN1B gene
				11.4.2.3.2 SCNN1G gene
				11.4.2.3.3 SCNN1A gene
			11.4.2.4 Pathophysiology
			11.4.2.5 Diagnosis
			11.4.2.6 Management
		11.4.3 Congenital adrenal hyperplasia
			11.4.3.1 Case report (1): a 12-year-old boy with hypertension and breast development was presented
			11.4.3.2 Definition of 11 β-hydroxylase deficiency
				11.4.3.2.1 Genetics of 11 β-hydroxylase deficiency
					CYP11B1 gene
				11.4.3.2.2 Pathophysiology of 11 β-hydroxylase deficiency
			11.4.3.3 Case report (2): a 20-year-old man with hypertension and ambiguous external genitalia was presented
			11.4.3.4 Definition of 17 α-hydroxylase deficiency
			11.4.3.5 Genetics of 17 α-hydroxylase deficiency
			11.4.3.6 Pathophysiology of 17 α-hydroxylase deficiency
		11.4.4 Diagnosis of congenital adrenal hyperplasia
		11.4.5 Management of congenital adrenal hyperplasia
	11.5 Familial hyperaldosteronism; type 1—glucocorticoid remediable aldosteronism
		11.5.1 Case report: a 18-year-old male student with hypertension and hyperaldosteronemia was presented
		11.5.2 Definition
		11.5.3 Genetics
		11.5.4 Pathophysiology
		11.5.5 Diagnosis
		11.5.6 Management
	11.6 Genetic overlap of monogenic and essential hypertension
	11.7 Clinical implications from genetic studies of hypertension
	11.8 Future perspectives
	Acknowledgments
	References
12 Molecular basis of stroke
	12.1 Introduction
	12.2 Genetics of stroke
	12.3 Single-gene disorders associated with stroke
	12.4 Genetics of common forms of stroke
		12.4.1 Strategies for genetic analysis of stroke
		12.4.2 Molecular pathophysiology of ischemic stroke
		12.4.3 Molecular genetics of ischemic stroke
			12.4.3.1 Phosphodiesterase 4D, cAMP-specific gene
			12.4.3.2 Arachidonate 5-lipoxygenase-activating protein gene
			12.4.3.3 CDKN2B antisense RNA 1 gene
			12.4.3.4 Ninjurin 2 gene
			12.4.3.5 Paired-like homeodomain 2 gene and zinc finger homeobox 3 gene
		12.4.4 Molecular pathophysiology of intracerebral hemorrhage
		12.4.5 Molecular genetics of intracerebral hemorrhage
			12.4.5.1 Apolipoprotein E gene
			12.4.5.2 Collagen, type IV, alpha 1 gene
		12.4.6 Molecular pathophysiology of intracranial aneurysm and subarachnoid hemorrhage
		12.4.7 Molecular genetics of intracranial aneurysm and subarachnoid hemorrhage
			12.4.7.1 Elastin gene and LIM domain kinase 1 gene
			12.4.7.2 Tumor necrosis factor receptor superfamily, member 13B gene
			12.4.7.3 Five loci for intracranial aneurysm identified by genome-wide association studies
	12.5 Clinical implication
	12.6 Conclusion
	References
	Further reading
13 Clinical molecular endocrinology
	13.1 Introduction
	13.2 Congenital hypopituitarism, congenital hypogonadotropic hypogonadism, and pituitary adenoma
		13.2.1 Congenital hypopituitarism
			13.2.1.1 Introduction
				13.2.1.1.1 Clinical case
					Overview of the relevant molecular systems underpinning the clinical scenario
					Management of congenital hypopituitarism
		13.2.2 Congenital hypogonadotropic hypogonadism
			13.2.2.1 Introduction
			13.2.2.2 Clinical case
				13.2.2.2.1 Discussion with reflection on the molecular systems underpinning the clinical scenario
					Overview of the relevant molecular systems underpinning the clinical scenario
					Targeted molecular diagnosis and therapy
					Management of congenital hypogonadotropic hypogonadism
		13.2.3 Genetics of pituitary adenoma
	13.3 Primary hyperparathyroidism and multiple endocrine neoplasia syndromes
		13.3.1 Primary hyperparathyroidism
			13.3.1.1 Introduction
				13.3.1.1.1 Clinical case
				13.3.1.1.2 Discussion with reflection on the molecular systems underpinning the clinical scenario
				13.3.1.1.3 Overview of the relevant molecular systems underpinning the clinical scenario
			13.3.1.2 Management of patients with primary hyperparathyroidism
				13.3.1.2.1 Surgical management
				13.3.1.2.2 Medical management
	13.4 Chronic hypocalcemia and hypophosphatemia
		13.4.1 Chronic hypocalcemia
			13.4.1.1 Introduction
			13.4.1.2 Clinical case
				13.4.1.2.1 Discussion with reflection on the molecular systems underpinning the clinical scenario
				13.4.1.2.2 Management of patients with pseudohyperparathyroidism
		13.4.2 Chronic hypophosphatemia
			13.4.2.1 Introduction
			13.4.2.2 Clinical case
				13.4.2.2.1 Discussion with reflection on the molecular systems underpinning the clinical scenario
				13.4.2.2.2 Overview of the relevant molecular systems underpinning the clinical scenario
				13.4.2.2.3 Management of patients with X-linked hypophosphatemia
	13.5 Primary hyperaldosteronism
		13.5.1 Introduction
		13.5.2 Clinical case
			13.5.2.1 Discussion with reflection on the molecular systems underpinning the clinical scenario
			13.5.2.2 Overview of the relevant molecular systems underpinning the clinical scenario
		13.5.3 Management of patients with primary hyperaldosteronism
	13.6 Congenital adrenal hyperplasia, apparent mineralocorticoid excess, and renal tubular defects
		13.6.1 Congenital adrenal hyperplasia
			13.6.1.1 Introduction
		13.6.2 Clinical case
			13.6.2.1 Discussion with reflection on the molecular systems underpinning the clinical scenario
			13.6.2.2 Management
		13.6.3 Apparent mineralocorticoid excess and renal tubular defects
			13.6.3.1 Introduction
			13.6.3.2 Clinical case
				13.6.3.2.1 Discussion with reflection on the molecular systems underpinning the clinical scenario
				13.6.3.2.2 Management of apparent mineralocorticoid excess and renal tubular defects
	13.7 Pheochromocytoma and paraganglioma
		13.7.1 Introduction
		13.7.2 Clinical case
			13.7.2.1 Discussion with reflection on the molecular systems underpinning the clinical scenario
			13.7.2.2 Overview of the relevant molecular systems underpinning the clinical scenario
			13.7.2.3 Management of pheochromocytomas and paraganglioma
	13.8 Primary gonadal failure and androgen resistance/insensitivity syndrome
		13.8.1 Primary gonadal failure
			13.8.1.1 Introduction
			13.8.1.2 Clinical case
				13.8.1.2.1 Discussion with reflection on the molecular systems underpinning the clinical scenario
				13.8.1.2.2 Management of Klinefelter syndrome
				13.8.1.2.3 Clinical case
					Discussion with reflection on the molecular systems underpinning the clinical scenario
					Androgen resistance/insensitivity syndrome
						Introduction
						Clinical scenario
						Discussion with reflection on the molecular systems underpinning the clinical scenario
						Management of patients with androgen insensitivity syndrome
	References
14 Genetic disorders of lipoprotein metabolism
	14.1 Introduction
	14.2 An outline of lipoprotein metabolism
	14.3 The environmental and genetic factors affecting lipid metabolism
	14.4 Screening for lipoprotein disorders
	14.5 Diagnosing genetic disorders of lipoprotein metabolism
	14.6 Common (polygenic) hypercholesterolemia
	14.7 Familial hypercholesterolemia
	14.8 Characteristic clinical features of familial hypercholesterolemia
	14.9 Screening strategies for familial hypercholesterolemia
	14.10 Genetic disorders resulting in hypertriglyceridemia
	14.11 Type 3 hyperlipoproteinemia
	14.12 Treatment of primary lipoprotein disorders
	14.13 Management of hypercholesterolemia
	14.14 Agents in development
	14.15 Management of hypertriglyceridemia
	References
	Further reading
15 Molecular medicine of diabetes mellitus
	15.1 Introduction
	15.2 Molecular basis of glycemic homeostasis
		15.2.1 Glucose utilization
		15.2.2 Cellular glucose transport
		15.2.3 Role of insulin and insulin receptor
	15.3 Disorders of the glycemic regulation
		15.3.1 Molecular mechanisms in type 1 diabetes mellitus
		15.3.2 Human leucocyte antigens and T1DM
		15.3.3 Other genes or gene regions
		15.3.4 Autoimmunity and type 1 diabetes mellitus
		15.3.5 Environmental factors
		15.3.6 Type 2 diabetes mellitus
			15.3.6.1 Epidemiology
			15.3.6.2 Genetic factors in T2DM
	15.4 Diagnosis of diabetes mellitus
		15.4.1 Clinical manifestations
		15.4.2 Blood glucose parameters—World Health Organization criteria
		15.4.3 HbA1C correlation
		15.4.4 Genetic testing
	15.5 Overweight, obesity, and diabetes mellitus
		15.5.1 Neurobiological factors
		15.5.2 Nutritional factors—high glycemic foods
		15.5.3 Constitutional and medical obesity
		15.5.4 Genetic/genomic factors
			15.5.4.1 Family history and heritability
			15.5.4.2 Rare monogenic diseases and syndromes of obesity
			15.5.4.3 Polygenic/multifactorial obesity—genome-wide association studies /copy number variants/single-nucleotide polymorphisms
			15.5.4.4 Environment and epigenetics/epigenomics
			15.5.4.5 Metagenomics and obesity
	15.6 Vitamin D and diabetes mellitus
	15.7 Inherited monogenic diabetes mellitus
		15.7.1 Neonatal diabetes mellitus
			15.7.1.1 Transient neonatal diabetes mellitus (OMIM 601410)
			15.7.1.2 Permanent neonatal diabetes mellitus (OMIM 606176)
		15.7.2 Maturity onset diabetes of the young (OMIM 125850)
		15.7.3 Mitochondrial diabetes mellitus
		15.7.4 Syndromes of inherited insulin resistance
		15.7.5 Malformation syndromes with diabetes mellitus
	15.8 Management of diabetes mellitus
		15.8.1 Diet/nutritional supplements
		15.8.2 Insulin
		15.8.3 Oral antidiabetic drugs
	15.9 Summary
	References
	Further reading
16 Molecular genetic management of epilepsy
	16.1 Introduction
	16.2 What are seizures?
	16.3 What is epilepsy?
	16.4 Evidence for the genetic basis of epilepsies
	16.5 The genetic architecture of epilepsies
		16.5.1 Linkage studies in families
		16.5.2 Genome-wide association studies
		16.5.3 Rare variants in epileptic encephalopathies
		16.5.4 Rare coding sequence variants in common epilepsies
		16.5.5 Noncoding variants
		16.5.6 Karyotypic abnormalities
		16.5.7 Copy number variation
	16.6 Mitochondrial epilepsies
		16.6.1 Heteroplasmy
		16.6.2 Clinical phenotypes
		16.6.3 Recognized mitochondrial epilepsy syndromes
	16.7 Progressive myoclonic epilepsies
	16.8 Pharmacogenetics of epilepsy
		16.8.1 Human leukocyte antigens and adverse antiepileptic drug reactions
		16.8.2 Cytochrome enzymes and antiepileptic medication
		16.8.3 Sodium channel genes and drug response
		16.8.4 Hyponatremia and sodium channel blocking antiepileptic drugs
	16.9 Molecular genetic testing strategies for epilepsy
		16.9.1 Genetic testing methods
		16.9.2 Limitations to current genetic testing strategies
	16.10 Summary
	References
17 The human leukocyte antigen system in human disease and transplantation medicine
	17.1 Introduction
	17.2 Human leukocyte antigen system
	17.3 Human leukocyte antigen and disease
		17.3.1 Human leukocyte antigen and drug-induced hypersensitivities
		17.3.2 Epistatic interaction of major histocompatibility complex genes
	17.4 Human leukocyte antigen expression: an explanation for disease development
		17.4.1 Human leukocyte antigen-C expression and disease development
		17.4.2 Human leukocyte antigen-DP expression and increased risk of chronic HBV infection
		17.4.3 Human leukocyte antigen expression correlates in autoimmune diseases
		17.4.4 Low versus high expression mismatches in transplantation
		17.4.5 Human leukocyte antigen class I expression loss/downregulation in tumor immune escape
		17.4.6 Mechanisms underlying allele-specific human leukocyte antigen expression
	17.5 Human leukocyte antigen and organ transplantation
		17.5.1 Allorecognition
		17.5.2 Classification of rejection
		17.5.3 Antibody-mediated rejection
		17.5.4 Complement activation
		17.5.5 Antibody-dependent cell-mediated cytotoxicity
		17.5.6 Direct activation of endothelium
		17.5.7 Cellular rejection
	17.6 Human leukocyte antigen–antibody-detection techniques
		17.6.1 Relevance of anti–human leukocyte antigen antibodies
		17.6.2 Role of non–human leukocyte antigen antibodies
		17.6.3 Preventive measures
	17.7 Human leukocyte antigen and blood transfusion
	17.8 Conclusions
	References
	Further reading
18 Disorders of abnormal hemoglobin
	18.1 Introduction
	18.2 The hemoglobin molecule: normal structure and function
		18.2.1 Globin gene clusters: structure and its regulation
		18.2.2 Characteristics of the α-globin and β-globin gene loci
		18.2.3 Globin gene switch during the fetal to adult transition
		18.2.4 β-Globin gene expression and its control
	18.3 The classification and genetics of the thalassemias
		18.3.1 β Thalassemia
		18.3.2 Molecular pathogenesis of β thalassemia
		18.3.3 Molecular basis of nondeletional β thalassemia
			18.3.3.1 Mutations that alter gene transcription, that is, mRNA synthesis
			18.3.3.2 Mutants that affect mRNA processing
			18.3.3.3 Mutations resulting in abnormal posttranscriptional modification of mRNA
		18.3.4 Mutants that affect β-globin mRNA translation
	18.4 Gene deletions in β thalassemia
		18.4.1 Deletions restricted to the β-globin gene
		18.4.2 Upstream deletions and (εγδβ)0 thalassemia
	18.5 Other less common, specific molecular causes of β thalassemia
		18.5.1 Dominant β thalassemia
		18.5.2 Silent and almost silent β-thalassemia trait
		18.5.3 Trans acting mutations associated with β thalassemia
		18.5.4 Uniparental isodisomy/somatic deletion of β-globin gene
	18.6 Laboratory diagnosis of β thalassemia
	18.7 Prevention of β thalassemia
		18.7.1 Screening for β-thalassemia trait
		18.7.2 Prenatal diagnosis
		18.7.3 Preimplantation genetic diagnosis
		18.7.4 Noninvasive prenatal diagnosis by analyzing cell-free circulating fetal DNA in the maternal blood
	18.8 α Thalassemia
		18.8.1 Classification and clinical phenotypes of α thalassemia
		18.8.2 Molecular pathology of deletional and nondeletional α thalassemias
		18.8.3 Laboratory diagnosis of α-deletions, point mutations and triplications
		18.8.4 Thalassemia intermedia: Molecular genetics and genotype–phenotype correlation
	18.9 Qualitative defects (structural hemoglobin variants and other abnormalities)
		18.9.1 Sickle-cell hemoglobin
		18.9.2 Hemoglobin E
		18.9.3 Hemoglobin C
		18.9.4 Hemoglobin M or methemoglobinemic hemoglobin variants
		18.9.5 Unstable hemoglobins
		18.9.6 High-oxygen affinity hemoglobins
		18.9.7 Low-oxygen affinity hemoglobins
		18.9.8 Defects of erythroid heme biosynthesis
	18.10 Summary
	References
	Further reading
19 Coagulation and bleeding disorders
	19.1 Introduction
	19.2 Genetic basis of thrombosis
		19.2.1 Case 1
		19.2.2 Molecular genetics of APLS
		19.2.3 Molecular basis of other causes of thrombosis
			19.2.3.1 Antithrombin deficiency
			19.2.3.2 Protein C and S deficiency and activated protein C (APC) resistance
				19.2.3.2.1 Prothrombin allele G20210A
			19.2.3.3 Factor V Leiden
			19.2.3.4 Hyperhomocysteinemia
			19.2.3.5 Inherited deficiency of fibrinolysis
	19.3 Genetic basis of the bleeding disorders
		19.3.1 Case 2
		19.3.2 Hemophilia A (factor VIII deficiency)
		19.3.3 Molecular basis of other inherited coagulopathies
			19.3.3.1 von Willebrand disease
			19.3.3.2 Hemophilia B (factor IX deficiency)
			19.3.3.3 Afibrinogenemia and dysfibrinogenemia
	19.4 Structural defects of the vascular system
		19.4.1 Hereditary hemorrhagic telangiectasia
		19.4.2 Ehlers–Danlos syndrome
	19.5 Inherited defects of platelets
		19.5.1 Inherited macrothrombocytopenia
		19.5.2 Bernard–Soulier syndrome
		19.5.3 Glanzmann’s thrombasthenia
		19.5.4 Storage pool disease
		19.5.5 May–Hegglin anomaly
		19.5.6 Wiscott–Aldrich syndrome
	19.6 Conclusion
	Conflict of interest
	Author’s roles
	References
20 Molecular and genomic basis of bronchial asthma
	20.1 Introduction
	20.2 Genomics of bronchial asthma
	20.3 Genetic and genomic studies in bronchial asthma
		20.3.1 Segregation analysis
		20.3.2 Twin genetic studies
		20.3.3 Genetic linkage
			20.3.3.1 Chromosome 5q
			20.3.3.2 Chromosome 6p
			20.3.3.3 Chromosome 11
			20.3.3.4 Chromosome 12q
		20.3.4 Candidate gene studies
		20.3.5 Genome-wide association studies
		20.3.6 Next-generation sequencing
	20.4 Management and treatment of bronchial asthma
		20.4.1 Symptomatic control
		20.4.2 Inflammation control
		20.4.3 Commonly used drugs in bronchial asthma
	20.5 Conclusion
	References
21 Molecular systems in inflammatory bowel disease
	21.1 Introduction
	21.2 Complex clinical predisposition with complex complications
		21.2.1 Epidemiology
		21.2.2 Genome versus environome
		21.2.3 Genetics and genomics
		21.2.4 Epigenome
		21.2.5 Transcriptome
		21.2.6 Proteomics and metabolomics
	21.3 The identification of the NOD2 gene
	21.4 NOD2 and innate immunity
		21.4.1 Epidemiology of NOD2 in Crohn’s disease
		21.4.2 NOD2 mutations and phenotype
		21.4.3 The Ancestor’s tale of mutations that predispose to inflammatory bowel disease
	21.5 Major histocompatibility complex (6p21)
	21.6 The causative genome variants and functional implications
	21.7 Autophagy
	21.8 Adaptive immune system
	21.9 Mucosal barrier function
	21.10 The parallels and paradoxes with other diseases
	21.11 Clinical implications and translation
	21.12 Conclusion
	References
	Further reading
22 Molecular biology of acute and chronic inflammation
	22.1 Introduction
	22.2 Molecular pathology of acute inflammation (sepsis and trauma)
	22.3 Molecular pathology of chronic inflammation
	22.4 Age-associated chronic inflammation
	22.5 Molecular diagnosis and treatment of chronic inflammatory diseases
		22.5.1 Genomic and molecular diagnosis
		22.5.2 Chronic inflammatory connective tissue diseases
			22.5.2.1 Rheumatoid arthritis
				22.5.2.1.1 Genetic factors
				22.5.2.1.2 Molecular pathology
				22.5.2.1.3 Clinical subtypes
				22.5.2.1.4 Articular features
				22.5.2.1.5 Nonarticular manifestations
				22.5.2.1.6 Treatment
			22.5.2.2 Systemic lupus erythematosus
		22.5.3 Targeted molecular therapy for acute or chronic inflammatory diseases
	22.6 Summary
	Acknowledgments and disclaimer
	References
23 Molecular basis of susceptibility and protection from microbial infections
	23.1 Introduction
	23.2 Understanding host genetic variation of susceptibility to infectious disease
		23.2.1 Host genetic determinants of human immunodeficiency virus infection
		23.2.2 Coreceptor and their ligand variants in human immunodeficiency virus disease progression
		23.2.3 Chemokine receptor genetic variants affecting HIV-1 mother-to-child transmission in absence of antiretrovirals
		23.2.4 Chemokine receptor genetic variants affecting HIV-1 mother-to-child transmission in absence of antiretrovirals
		23.2.5 Innate immunity genetic associations with human immunodeficiency virus type 1 disease
		23.2.6 Human leukocyte antigen genotypes alter mother-to-child transmission and rate of disease progression
		23.2.7 Intracellular antiviral host factor affecting human immunodeficiency virus disease
	23.3 Clinical relevance of human leukocyte antigen gene variants in HBV infection
	23.4 Human leukocyte antigen gene variants and susceptibility and persistence of HBV infection
		23.4.1 Human leukocyte antigen gene variants and spontaneous HBsAg clearance
		23.4.2 Human leukocyte antigen gene variants and early HBeAg seroconversion
		23.4.3 Human leukocyte antigen gene variants and risk of developing liver cirrhosis and HBV-related hepatocellular carcinoma
		23.4.4 Human leukocyte antigen gene variant and response to hepatitis B virus vaccine
		23.4.5 Human leukocyte antigen gene variants and efficacy of interferon alfa and NAs treatment
		23.4.6 Host genetic determinants in hepatitis C virus infection
	23.5 Immunogenetics and microbial infection
		23.5.1 Genes involved in innate immunity
		23.5.2 Genes involved in adaptive immunity
		23.5.3 Genes involved in T-cell regulation and function
	23.6 Host genetic susceptibility to human papillomavirus infection and development of cervical cancer
	23.7 Host genetics of Epstein–Barr infection
	23.8 Dengue viral infection
		23.8.1 Dengue and major histocompatibility complex antigens
		23.8.2 Cytokine polymorphism and dengue
	23.9 Genetic susceptibility of humans to hantavirus infection
		23.9.1 Immunity-related gene polymorphisms and severity of hantavirus infections
		23.9.2 Immune-related gene expression variability and severity of hantavirus infection
		23.9.3 Genetic susceptibility to severe influenza
		23.9.4 Influenza-associated encephalopathy
	23.10 Host factors and genetic susceptibility to intracellular bacteria
		23.10.1 Mycobacterium tuberculosis
		23.10.2 Mycobacterium leprae
		23.10.3 Chlamydia trachomatis
		23.10.4 Chlamydia pneumoniae
		23.10.5 Mycoplasma pneumoniae
		23.10.6 Coxiella burnetii
		23.10.7 Trophyrema whipplei
	23.11 Host genetic susceptibility and protection from fungal infections
		23.11.1 Candida
		23.11.2 Aspergillosis
			23.11.2.1 Genetic variability of host and susceptibility to invasive aspergillosis
		23.11.3 Cryptococcus neoformans and Cryptococcus gattii
	23.12 Malaria
		23.12.1 Membrane and enzymatic disorders of red blood cells
			23.12.1.1 Hemoglobin alterations—hemoglobinopathies
			23.12.1.2 Systemic regulation of heme
		23.12.2 Immune response
		23.12.3 Malaria vaccine
	23.13 Genetics of susceptibility to enteral pathogens
		23.13.1 Host receptors used by enteral pathogens and their role in susceptibility
		23.13.2 Innate immune genes associated with increased susceptibility to enteral pathogens
		23.13.3 Innate immune response and cellular injury
			23.13.3.1 Acquired immunity
	23.14 Conclusion
	References
24 Molecular mechanisms in cancer susceptibility—lessons from inherited cancers
	24.1 Introduction
	24.2 Inherited and familial cancer
	24.3 Oncogenes and tumor suppressor genes
	24.4 DNA repair genes
		24.4.1 The breast and ovarian cancer
		24.4.2 Colorectal cancer
	24.5 Cancer family syndromes
		24.5.1 Multiple endocrine neoplasia
		24.5.2 RAS–MAPK syndromes
		24.5.3 Von Hippel–Lindau disease and related syndromes
		24.5.4 Immunogenetics and cancer
		24.5.5 RNA interference and cancer
	24.6 Genetic imprinting and cancer
	24.7 Complex cancer genomics
	24.8 Inherited susceptibility to leukemia
	24.9 Tumor markers in circulating blood
	24.10 Genetic counseling for inherited cancer susceptibility
	24.11 Diagnostic and predictive genetic testing for cancer
	References
	Further reading
25 Clinical molecular nephrology—acute kidney injury and chronic kidney disease
	25.1 Introduction
	25.2 Acute kidney injury
		25.2.1 Candidate gene association studies
		25.2.2 Genome-wide association studies
	25.3 Chronic kidney disease
		25.3.1 Causes of chronic kidney disease
		25.3.2 Establishing a molecular genetic diagnosis of chronic kidney disease
			25.3.2.1 Clinical heterogeneity in chronic kidney disease
			25.3.2.2 Genetic heterogeneity in chronic kidney disease
		25.3.3 Understanding pathogenesis of chronic kidney disease
		25.3.4 Genetic variants and chronic kidney disease
	25.4 Clinical renal genomic medicine
		25.4.1 Targeted gene panel analysis in chronic kidney disease
		25.4.2 Targeted clinical management
		25.4.3 Personalized pharmacotherapy in chronic kidney disease—pharmacogenomics
		25.4.4 Targeted clinical surveillance
		25.4.5 Genetic counseling
	25.5 Molecular basis of kidney transplantation
		25.5.1 Human leukocyte antigen typing for renal transplantation
		25.5.2 Selection of donors
		25.5.3 Predicting the long-term kidney allograft function
	25.6 Conclusion
	References
26 Molecular basis of chronic neurodegeneration
	26.1 Introduction
	26.2 Neurodegenerative disease clinical case studies and molecular systems underpinning the clinical scenario
		26.2.1 Alzheimer’s disease
		26.2.2 Parkinson’s disease
		26.2.3 Frontotemporal dementia
	26.3 Molecular pathology of neurodegenerative diseases
	26.4 Application of molecular diagnostics in neurodegeneration
	26.5 Summary
	References
27 Molecular basis of movement disorders
	27.1 Introduction
	27.2 Parkinson’s disease
		27.2.1 Epidemiology and pathophysiology
		27.2.2 Genetics
			27.2.2.1 Autosomal dominant inheritance
				27.2.2.1.1 SNCA/PARK1: alpha-synuclein gene
				27.2.2.1.2 LRRK2/PARK8: leucine-rich repeat kinase 2
				27.2.2.1.3 VPS35/PARK17
		27.2.3 Autosomal recessive inheritance
			27.2.3.1 Parkin/PARK2
			27.2.3.2 PINK1/PARK6: PTEN-induced kinase 1
			27.2.3.3 DJ1/PARK7: protein deglycase
			27.2.3.4 Glucocerebrosidase mutations
			27.2.3.5 Other genes implicated in Parkinson’s
		27.2.4 Treatment of Parkinson’s disease
		27.2.5 Parkinson’s disease: key learning points
	27.3 Dystonia
		27.3.1 Clinical characteristics
		27.3.2 Genetics of dystonia
		27.3.3 Pathophysiology of dystonia
		27.3.4 Targeted molecular diagnosis and therapy of dystonia
		27.3.5 Diagnosis of dystonia
			27.3.5.1 DYT1: TorsinA mutations
			27.3.5.2 DYT5: GCH1 mutations (dopa-responsive dystonia)
			27.3.5.3 DYT6: THAP1 mutations
			27.3.5.4 DYT10: paroxysmal kinesigenic dyskinesia
			27.3.5.5 DYT11: SGCE mutations
		27.3.6 Therapy of dystonia
			27.3.6.1 Physiotherapy
			27.3.6.2 Oral medication
			27.3.6.3 Botulinum toxin
			27.3.6.4 Deep brain stimulation
		27.3.7 Dystonia: key learning points
	27.4 Ataxia
		27.4.1 Genetics of ataxia
			27.4.1.1 Gene transcription and RNA
			27.4.1.2 Intranuclear inclusions
			27.4.1.3 Transmembrane channel abnormalities
			27.4.1.4 Neuronal calcium homeostasis
			27.4.1.5 Mitochondrial dysfunction
		27.4.2 Cerebellar degeneration
		27.4.3 Targeted molecular diagnosis and therapy
			27.4.3.1 Diagnostic testing
				27.4.3.1.1 Blood plasma tests
				27.4.3.1.2 Genetic testing
		27.4.4 Freidreich’s ataxia
		27.4.5 Spinocerebellar ataxia 2
		27.4.6 Spinocerebellar ataxia type 3: Machado–Joseph disease
		27.4.7 Spinocerebellar ataxia type 7
		27.4.8 Ataxia-telangiectasia
			27.4.8.1 Therapy of ataxia telangiectasia (AT)
		27.4.9 Potential future targets for molecular therapy
	27.5 Ataxia: key learning points
	27.6 Other movement disorders
		27.6.1 Huntington’s disease
			27.6.1.1 Treatment of Huntington’s disease
		27.6.2 Wilson’s disease
		27.6.3 Neurodegeneration with brain iron accumulation
			27.6.3.1 Pantothenate kinase-associated neurodegeneration
			27.6.3.2 Phospholipase A2-associated neurodegeneration
			27.6.3.3 Mitochondrial membrane protein-associated neurodegeneration
			27.6.3.4 Beta-propeller protein-associated neurodegeneration
			27.6.3.5 Fatty acid hydroxylase-associated neurodegeneration
			27.6.3.6 Coenzyme A synthetase protein-associated neurodegeneration
			27.6.3.7 Neuroferritinopathy
			27.6.3.8 Aceruloplasminaemia
			27.6.3.9 Kufor Rakeb
		27.6.4 Niemann–Pick type C
		27.6.5 Dentarubral–pallidoluysian atrophy
	27.7 Conclusion
	References
28 Molecular pathology in neuropsychiatric disorders
	28.1 Introduction
	28.2 Copy number variation in psychiatric disorders
	28.3 Cognitive function among copy number variation carriers
	28.4 Penetrance of copy number variations
	28.5 Results from genome-wide association studies
	28.6 High-throughput sequencing studies
	28.7 Pathway analysis
	28.8 Conclusions
	References
29 “Targeted molecular therapy: the cancer paradigm
	29.1 Introduction
	29.2 Oncogene addiction
	29.3 Synthetic lethality
	29.4 Histology agnostic treatment
	29.5 Limitations of molecularly targeted therapy in cancer
	29.6 Making common cancer rare
	29.7 Conclusion
	References
30 Gene, genome, and molecular therapeutics
	30.1 Introduction
	30.2 Recombinant protein drugs and vaccines
		30.2.1 Recombinant pharmacotherapy
		30.2.2 Recombinant vaccines
			30.2.2.1 Human papilloma virus vaccine
			30.2.2.2 The Hepatitis B recombinant vaccine
			30.2.2.3 HIV vaccines
			30.2.2.4 DNA vaccines
		30.2.3 Recombinant therapeutic enzymes
	30.3 Stem-cell therapy
	30.4 Gene therapy
	30.5 Antisense oligonucleotides
	30.6 Ribozymes
	30.7 RNA interference
	30.8 Aptamers
	30.9 Gene and genome editing
	30.10 Summary
	Disclaimer and acknowledgments
	References
31 Personalizing medicine with pharmacogenetics and pharmacogenomics
	31.1 Introduction and historical perspective
	31.2 The Human Genome Project
	31.3 The introduction of the field of personalized medicine/precision medicine
	31.4 Genetic and molecular basis of the individual drug-response variation
		31.4.1 Genetic factors in pharmacokinetics
		31.4.2 Genetic factors in pharmacodynamics
	31.5 Tailoring or individualizing drug therapy—select examples of application of pharmacogenomics in clinical practice
		31.5.1 Trastuzumab and ERBB2 (HER2) genotype—tailoring treatment based on genomic testing
		31.5.2 Warfarin use as an anticoagulant—tailoring an individual’s dose using preprescription genetic information—testing fo...
		31.5.3 Human leukocyte antigen testing in clinical practice
			31.5.3.1 Abacavir use in human immunodeficiency virus (HIV) infection—preventing an adverse effect through preprescription ...
			31.5.3.2 HLA testing for prediction Stevens–Johnson syndrome with the use of the antiepileptic carbamazepine
		31.5.4 Testing for the activity of CYP2C19 prior to the use of clopidogrel
	31.6 Validation of genetic/genomic information for drug response
	31.7 Clinical implementation of pharmacogenetics and pharmacogenomic information
		31.7.1 Cost of testing and turnaround time
		31.7.2 Limitations of single-nucleotide polymorphism testing in isolation
		31.7.3 Physician barriers
		31.7.4 The need for specific protocols to guide decision-making post–pharmacogenetic testing
		31.7.5 Lack of strong evidence/weak evidence base
		31.7.6 Stakeholder engagement including the regulator
	31.8 Clinical pharmacogenetics implementation consortium—helping clinicians understand and apply pharmacogenetic informatio...
	31.9 Pharmacogenomics and drug development—novel study designs in precision medicine
	31.10 Ethical issues in genomic medicine
	31.11 Resources to collect and curate pharmacogenetic variants
	31.12 The future of pharmacogenetics, pharmacogenomics, and personalized medicine
	References
	Further reading
32 Integrated genomic and molecular medicine
	32.1 Introduction
	32.2 Genetic, genomic, and molecular revolutions in medicine
	32.3 Evidence-based, precision, and personalized medicine
	32.4 The stratified medicine
	32.5 Integrated genomic and molecular medicine
	32.6 Summary
	References
Glossary—molecular medicine*
Index
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