Clinical Molecular Medicine: Principles and Practice

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Dhavendra Kumar


Academic Press




581 pages







Book Description

The PDF version of Kumar’s Clinical Molecular Medicine: Principles and Practice is incredibly readable while still managing to cover a vast amount of ground. This e-book is the ideal way to get started learning about the molecular underpinnings of disease as well as the innovative therapeutic alternatives that have recently become accessible.

This electronic book, entitled Clinical Molecular Medicine: Principles and Practice, details the most recent discoveries made by scientists in the fields of molecular and cellular biology. These discoveries include the creation of effective and innovative drug and biological therapies as well as diagnostic methods. This e-book offers researchers, as well as medical and biomedical students, a comprehensive and clinically relevant understanding of the molecular basis of human disease. This e-book is a valuable and much-needed resource that unites the fundamental principles of molecular biology with the most recent and most promising advances in genomics. With an increased focus on new practice concepts such as stratified, personalized, and precision medicine, this ebook brings together the fundamentals of molecular biology.



  • Molecular heterogeneity is discussed from a clinical perspective in this article.


  • Molecular and cellular biology’s fundamental principles, as well as their applications in therapeutics, are broken down and explained in this book.


  • Includes extensive coverage of a wide variety of disorders, such as those related to growth and development, metabolism, skin, cardiovascular disease, digestion, blood, neuropsychiatric disorders, inflammation, and many others.



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Table of contents

Table of contents :
Clinical Molecular Medicine: Principles and Practice
List of contributors
About the author
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
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
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
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 Patient history Physical examination Family history Genetic diagnosis
5.2.2 Case 2 Genetic diagnosis
5.2.3 Case 3 Genetic diagnosis 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 Melanocortin-4 receptor Proopiomelanocortin
5.4.8 Monogenic obesity syndromes with intellectual disability Prader–Willi syndrome Bardet–Biedl syndrome
5.5 Targeted molecular diagnosis and therapy
5.5.1 Targeted molecular diagnosis Leptin DNA diagnostics
5.5.2 Prader–Willi syndrome
5.5.3 Copy number variation
5.5.4 Therapy Lifestyle interventions Bariatric surgery Bariatric surgery in genetic obesity Monogenic nonsyndromic obesity Prader–Willi syndrome
5.5.5 Medication Nonpersonalized medication 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
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 The splitting
Split hand–foot malformation Syndromes with genetic connections: the lumping
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
Sickle cell disease
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
6.4 Conclusion/summary
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 Disorders of androgen synthesis associated with adrenal dysfunction 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 Exposure to androgens of nonfetal origin 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
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] 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
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 Increased automaticity Re-entry Triggered activity
9.4 Overview of molecular biology and pathophysiology
9.4.1 Mechanisms of channelopathy
9.4.2 Long QT syndrome Overview of long QT syndrome Long QT syndrome diagnosis Long QT syndrome type 1 Long QT syndrome type 2 Long QT syndrome type 3 Jervell and Lange-Nielsen syndrome Anderson–Tawil syndrome 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 Clinical risk assessment in long QT syndrome Targeted therapies in long QT syndrome
9.8.2 Short QT syndrome Clinical risk assessment and therapy in short QT syndrome
9.8.3 Catecholaminergic polymorphic ventricular tachycardia Clinical risk assessment and therapy in catecholaminergic polymorphic ventricular tachycardia
9.8.4 Brugada syndrome Clinical risk assessment in Brugada syndrome Targeted therapy in Brugada syndrome
9.9 Summary
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 Plasma natriuretic peptides Cardiomyopathy screen
10.4.5 Electrocardiography Resting electrocardiography Ambulatory electrocardiography
10.4.6 Imaging studies Plain chest radiography Echocardiography Cardiac magnetic resonance imaging 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 Diagnostic confirmation and prognostication in clinically suspected cases 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
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 Case report: a 52-year-old man with hypertension and hyperkalemia was presented Definition Genetics WNK genes KLHL3 gene CUL3 gene Pathophysiology WNK kinases KLHL3 and CUL3 proteins Diagnosis Management
11.4.2 Liddle’s syndrome Case report: a 22-year-old woman with hypertension and hypokalemia was presented Definition Genetics SCNN1B gene SCNN1G gene SCNN1A gene Pathophysiology Diagnosis Management
11.4.3 Congenital adrenal hyperplasia Case report (1): a 12-year-old boy with hypertension and breast development was presented Definition of 11 β-hydroxylase deficiency Genetics of 11 β-hydroxylase deficiency
CYP11B1 gene Pathophysiology of 11 β-hydroxylase deficiency Case report (2): a 20-year-old man with hypertension and ambiguous external genitalia was presented Definition of 17 α-hydroxylase deficiency Genetics of 17 α-hydroxylase deficiency 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
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 Phosphodiesterase 4D, cAMP-specific gene Arachidonate 5-lipoxygenase-activating protein gene CDKN2B antisense RNA 1 gene Ninjurin 2 gene 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 Apolipoprotein E gene 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 Elastin gene and LIM domain kinase 1 gene Tumor necrosis factor receptor superfamily, member 13B gene Five loci for intracranial aneurysm identified by genome-wide association studies
12.5 Clinical implication
12.6 Conclusion
Further reading
13 Clinical molecular endocrinology
13.1 Introduction
13.2 Congenital hypopituitarism, congenital hypogonadotropic hypogonadism, and pituitary adenoma
13.2.1 Congenital hypopituitarism Introduction Clinical case
Overview of the relevant molecular systems underpinning the clinical scenario
Management of congenital hypopituitarism
13.2.2 Congenital hypogonadotropic hypogonadism Introduction Clinical case 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 Introduction Clinical case Discussion with reflection on the molecular systems underpinning the clinical scenario Overview of the relevant molecular systems underpinning the clinical scenario Management of patients with primary hyperparathyroidism Surgical management Medical management
13.4 Chronic hypocalcemia and hypophosphatemia
13.4.1 Chronic hypocalcemia Introduction Clinical case Discussion with reflection on the molecular systems underpinning the clinical scenario Management of patients with pseudohyperparathyroidism
13.4.2 Chronic hypophosphatemia Introduction Clinical case Discussion with reflection on the molecular systems underpinning the clinical scenario Overview of the relevant molecular systems underpinning the clinical scenario Management of patients with X-linked hypophosphatemia
13.5 Primary hyperaldosteronism
13.5.1 Introduction
13.5.2 Clinical case Discussion with reflection on the molecular systems underpinning the clinical scenario 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 Introduction
13.6.2 Clinical case Discussion with reflection on the molecular systems underpinning the clinical scenario Management
13.6.3 Apparent mineralocorticoid excess and renal tubular defects Introduction Clinical case Discussion with reflection on the molecular systems underpinning the clinical scenario Management of apparent mineralocorticoid excess and renal tubular defects
13.7 Pheochromocytoma and paraganglioma
13.7.1 Introduction
13.7.2 Clinical case Discussion with reflection on the molecular systems underpinning the clinical scenario Overview of the relevant molecular systems underpinning the clinical scenario Management of pheochromocytomas and paraganglioma
13.8 Primary gonadal failure and androgen resistance/insensitivity syndrome
13.8.1 Primary gonadal failure Introduction Clinical case Discussion with reflection on the molecular systems underpinning the clinical scenario Management of Klinefelter syndrome Clinical case
Discussion with reflection on the molecular systems underpinning the clinical scenario
Androgen resistance/insensitivity syndrome
Clinical scenario
Discussion with reflection on the molecular systems underpinning the clinical scenario
Management of patients with androgen insensitivity syndrome
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
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 Epidemiology 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 Family history and heritability Rare monogenic diseases and syndromes of obesity Polygenic/multifactorial obesity—genome-wide association studies /copy number variants/single-nucleotide polymorphisms Environment and epigenetics/epigenomics Metagenomics and obesity
15.6 Vitamin D and diabetes mellitus
15.7 Inherited monogenic diabetes mellitus
15.7.1 Neonatal diabetes mellitus Transient neonatal diabetes mellitus (OMIM 601410) 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
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
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
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 Mutations that alter gene transcription, that is, mRNA synthesis Mutants that affect mRNA processing 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
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 Antithrombin deficiency Protein C and S deficiency and activated protein C (APC) resistance Prothrombin allele G20210A Factor V Leiden Hyperhomocysteinemia 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 von Willebrand disease Hemophilia B (factor IX deficiency) 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
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 Chromosome 5q Chromosome 6p Chromosome 11 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
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
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 Rheumatoid arthritis Genetic factors Molecular pathology Clinical subtypes Articular features Nonarticular manifestations Treatment Systemic lupus erythematosus
22.5.3 Targeted molecular therapy for acute or chronic inflammatory diseases
22.6 Summary
Acknowledgments and disclaimer
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 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 Hemoglobin alterations—hemoglobinopathies 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 Acquired immunity
23.14 Conclusion
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
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 Clinical heterogeneity in chronic kidney disease 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
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
27 Molecular basis of movement disorders
27.1 Introduction
27.2 Parkinson’s disease
27.2.1 Epidemiology and pathophysiology
27.2.2 Genetics Autosomal dominant inheritance SNCA/PARK1: alpha-synuclein gene LRRK2/PARK8: leucine-rich repeat kinase 2 VPS35/PARK17
27.2.3 Autosomal recessive inheritance Parkin/PARK2 PINK1/PARK6: PTEN-induced kinase 1 DJ1/PARK7: protein deglycase Glucocerebrosidase mutations 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 DYT1: TorsinA mutations DYT5: GCH1 mutations (dopa-responsive dystonia) DYT6: THAP1 mutations DYT10: paroxysmal kinesigenic dyskinesia DYT11: SGCE mutations
27.3.6 Therapy of dystonia Physiotherapy Oral medication Botulinum toxin Deep brain stimulation
27.3.7 Dystonia: key learning points
27.4 Ataxia
27.4.1 Genetics of ataxia Gene transcription and RNA Intranuclear inclusions Transmembrane channel abnormalities Neuronal calcium homeostasis Mitochondrial dysfunction
27.4.2 Cerebellar degeneration
27.4.3 Targeted molecular diagnosis and therapy Diagnostic testing Blood plasma tests 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 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 Treatment of Huntington’s disease
27.6.2 Wilson’s disease
27.6.3 Neurodegeneration with brain iron accumulation Pantothenate kinase-associated neurodegeneration Phospholipase A2-associated neurodegeneration Mitochondrial membrane protein-associated neurodegeneration Beta-propeller protein-associated neurodegeneration Fatty acid hydroxylase-associated neurodegeneration Coenzyme A synthetase protein-associated neurodegeneration Neuroferritinopathy Aceruloplasminaemia Kufor Rakeb
27.6.4 Niemann–Pick type C
27.6.5 Dentarubral–pallidoluysian atrophy
27.7 Conclusion
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
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
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 Human papilloma virus vaccine The Hepatitis B recombinant vaccine HIV vaccines 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
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 Abacavir use in human immunodeficiency virus (HIV) infection—preventing an adverse effect through preprescription … 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
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
Glossary—molecular medicine*
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