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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Serie: At a Glance
- Sprache: Englisch
Medical Genetics at a Glance covers the core scientific principles necessary for an understanding of medical genetics and its clinical applications, while also considering the social implications of genetic disorders.
This third edition has been fully updated to include the latest developments in the field, covering the most common genetic anomalies, their diagnosis and management, in clear, concise and revision-friendly sections to complement any health science course.
Medical Genetics at a Glance now has a completely revised structure, to make its content even more accessible. Other features include:
- Three new chapters on Gene Identification, The Biology of Cancer, and Genomic Approaches to Cancer
- A much extended treatment of Biochemical Genetics
- A completely revised chapter on The Cell Cycle, explaining principles of biochemistry and genetics which are fundamental to understanding cancer causation
- Two new chapters on Cardiac Developmental Pathology
- An extended Case Studies section
Providing a broad understanding of one of the most rapidly progressing topics in medicine, Medical Genetics at a Glance is perfect for students of medicine, molecular biology, genetics and genetic counselling, and is a previous winner of a BMA Award.
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Seitenzahl: 595
Veröffentlichungsjahr: 2013
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Table of Contents
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Title page
Copyright page
Preface to the first edition
Preface to the third edition
Acknowledgements
List of abbreviations
Part 1: Overview
1: The place of genetics in medicine
The case for genetics
Genes in development
Genotype and phenotype
Genetics in medicine
The application of genetics
Part 2: The Mendelian approach
2: Pedigree drawing
Overview
The medical history
Rules for pedigree diagrams
The practical approach
Use of pedigrees
3: Mendel's laws
Overview
The principle of unit inheritance
The principle of dominance
The principle of segregation
The principle of independent assortment
The test-mating
Matings between double heterozygotes
Biological support for Mendel's laws
Exceptions to Mendel's laws
Conclusion
4: Principles of autosomal dominant inheritance and pharmacogenetics
Overview
Rules for autosomal dominant inheritance
Estimation of risk
Estimation of mutation rate
Pharmacogenetics
5: Autosomal dominant inheritance, clinical examples
Overview
Disorders of the fibroblast growth factor receptors
Achondroplasia
Marfan syndrome (MFS)
Familial hypercholesterolaemia (FH)
Dentinogenesis imperfecta 1 (DGI)
Otosclerosis 1 (OTSC1)
Adult polycystic kidney disease (APKD, PKD)
Multiple hereditary exostoses (EXT)
6: Autosomal recessive inheritance, principles
Overview
Rules for autosomal recessive inheritance
Estimation of risk
7: Consanguinity and major disabling autosomal recessive conditions
Overview
Consanguineous matings
Incestuous matings
First cousin marriages
Mental handicap
Oculocutaneous albinism
Recessive blindness
Retinitis pigmentosa (RP)
Severe congenital deafness
Connexin 26 defects (CX26)
Pendred syndrome (PDS)
8: Autosomal recessive inheritance, life-threatening conditions
Overview
Cystic fibrosis (CF)
Tay–Sachs disease, GM2 gangliosidosis
Phenylketonuria (PKU)
Spinal muscular atrophy (SMA)
9: Aspects of dominance
Overview
Codominance (Co-D), the ABO blood groups
Incomplete dominance, overdominance and heterosis
Incomplete penetrance
Delayed onset
Variable expressivity
Neurofibromatosis type 1 (NF1), Von Recklinghausen disease
10: X-linked and Y-linked inheritance
Overview
Rules of X-linked recessive inheritance
Estimation of risk for offspring
X-linked dominant disorders
Y-linked or holandric inheritance
Pseudoautosomal inheritance or ‘partial sex linkage’
Sex limitation and sex influence
11: X-linked inheritance, clinical examples
Introduction
Haemophilia A (HbA), classic haemophilia
Red and green colour blindness
Duchenne muscular dystrophy (DMD)
Becker muscular dystrophy (BMD)
Fragile X syndrome (FRAX-A [and FRAX-E])
Vitamin D-resistant rickets, hypophosphataemic rickets
Hereditary motor and sensory neuropathy (HMSN), Charcot–Marie–Tooth disease
Incontinentia pigmenti (IP)
Barth syndrome, X-linked cardioskeletal myopathy, endocardial fibroelastosis
Rett syndrome
12: Mitochondrial inheritance
Overview
Mitochondrial disorders
Rules of mitochondrial inheritance
Examples
Maternally transmitted ototoxic deafness
13: Risk assessment in Mendelian conditions
Overview
Risk assessment
Bayes' theorem
Application of Bayes' theorem
Isolated cases
Empiric risks
Part 3: Basic cell biology
14: The cell
Overview
The plasma membrane
The nucleus
The cytoplasm
The secretion pathway
Endocytosis
Cell junctions
Medical issues
15: The chromosomes
Overview
Chromatin structure
Chromosome banding
The centromere
The telomeres
Euchromatin and heterochromatin
16: The cell cycle
Overview
G1-phase
S-phase
Mitosis or M-phase
The centrosome cycle
Medical issues
17: Biochemistry of the cell cycle
Overview
The G1/S checkpoint
The G2/M checkpoint
The M-phase checkpoint
18: Gametogenesis
Overview
Meiosis I
Prophase I
Metaphase I, anaphase I, telophase I, cytokinesis I
Meiosis II
Male meiosis
Female meiosis
The significance of meiosis
Part 4: Basic molecular biology
19: DNA structure
Overview
The structure of DNA
The centromeres
The telomeres
Structural classes of human DNA
Medical and legal issues
20: DNA replication
Overview
Replication
Replication of the telomeres
Repair systems
Medical issues
21: The structure of genes
Overview
The structure of a typical gene
Gene length
Genes that share a promoter
Overlapping genes
Chromatin conformation
Medical issues
22: Production of messenger RNA
Overview
Transcription factors
Transcription
RNA processing
Medical issues
23: Non-coding RNA
Overview
Heterogeneous nuclear and messenger RNA
Long non-coding RNA
Transfer RNA
Ribosomal RNA
Small nuclear RNA
Signal recognition particle RNA
MicroRNAs
Medical issues
24: Protein synthesis
Overview
The genetic code
Translation
Protein structure
Post-translational modification
Medical issues
Part 5: Genetic variation
25: Types of genetic alterations
Overview
Substitutions, deletions, insertions, frameshifts and duplications
Copy number variation
Transcriptional control
RNA processing
Mobile elements
Haemoglobinopathies
Haemophilia A
Nomenclature of mutations
26: Mutagenesis and DNA repair
Overview
Chemical mutagenesis
Electromagnetic radiation
Ultraviolet light
Atomic radiation
Biological effects of radiation
Safety measures when using X-rays
DNA repair
27: Genomic imprinting
Overview
Prader–Willi and Angelman syndromes (P-WS and AS)
Beckwith–Wiedemann syndrome (B-WS)
Maintenance methylase
28: Dynamic mutation
Overview
The triplet repeat disorders
Huntington disease (HD); Huntington's chorea
Fragile X disease A (FRAX-A)
Myotonic dystrophy type 1 (MD1)
29: Normal polymorphism
Overview
Environment-related polymorphism
Selection by malaria
Resistance to Human Immunodeficiency Virus, HIV
Transfusion and transplantation
Drug metabolism
30: Allele frequency
Overview
The Hardy–Weinberg law
Necessary conditions
Applications of the Hardy–Weinberg law
Examples
Consequence of medical intervention
Measures of disease frequency
Part 6: Organization of the human genome
31: Genetic linkage and genetic association
Overview
Genetic linkage
Genetic mapping
The Human Genome Project (HGP)
Genetic association
32: Physical gene mapping
Overview
Chromosome assignment
Regional mapping
High-resolution mapping
33: Gene identification
Overview
Identification of genes with known gene products
Positional cloning
Gene identification by whole exome/whole genome sequencing
34: Clinical application of linkage and association
Overview
Linkage analysis
Association analysis
Part 7: Cytogenetics
35: Chromosome analysis
Overview
Preparation of a karyotype
Use of unique sequence probes
Chromosome painting
Primed in situ hybridization
Comparative genome hybridization (CGH)
Multiplex PCR screening for aneuploidy
Indications for chromosome analysis
36: Autosomal aneuploidies
Overview
Aetiology
Down syndrome (DS)
37: Sex chromosome aneuploidies
Overview
Klinefelter syndrome
Turner syndrome, X chromosome monosomy
47,XYY syndrome
Triple-X syndrome
38: Chromosome structural abnormalities
Overview
Somatic mosaicism
Translocations
Deletions (code: ‘del’)
Ring chromosomes (code: ‘r’)
Duplications (code: ‘dup’)
Inversions (code: ‘inv’)
Isochromes (code: ‘iso’)
Fragile sites (code: ‘fra’)
39: Chromosome structural abnormalities, clinical examples
Overview
Deletions and segmental aneuploidies
Autosomal translocations
X-autosome translocations
40: Contiguous-gene and single-gene syndromes
Overview
Contiguous gene deletion syndromes
Contiguous gene duplication syndrome
Single-gene syndromes
Part 8: Embryology and congenital abnormalities
41: Human embryology in outline
Overview
The pre-embryo (weeks 0–2)
The embryo (weeks 2–8)
The fetus (weeks 8–38)
Expected date of delivery (EDD)
42: Body patterning
Overview
The main body
The limbs
43: Sexual differentiation
Overview
X chromosome inactivation
Early development
The ovary
The testis
Genital ducts
External genitalia
Descent of the testis
Puberty
Medical issues
44: Abnormalities of sex determination
Overview
Problems in genetic females
Problems in genetic males
45: Congenital abnormalities, pre-embryonic, embryonic and of intrinsic causation
Overview
Classification of defects
Timing and aetiology
Defects of the CNS
Congenital heart defects
Gastro-intestinal (GI) tract defects
46: Congenital abnormalities arising at the fetal stage
Overview
Pathogenic mechanisms
Maternal illness
Maternal infection
Congenital deformations
Limb malformations
The role of chemicals
Physical agents
47: Development of the heart
Overview
Initial development
Formation of cardiac septa
Septum formation in the atrium
Septum formation in the ventricles
Septum formation in the atrioventricular canal
Septum formation in the truncus arteriosus and conus cordis
Circulatory changes at birth
48: Cardiac abnormalities
Overview
Circulatory changes at birth
Clinically significant defects
49: Facial development and dysmorphology
Overview
Fetal alcohol syndrome
Development of the face
Facial clefts
Classification of abnormal developmental features
Assessment of development
Clinically important growth parameters
Diagnosis in dysmorphology
Part 9: Multifactorial inheritance and twin studies
50: Principles of multifactorial disease
Overview
Continuous variation
Heritability (h2)
Estimation of risk
Discontinuous variation, multifactorial threshold traits
Rules for identification of a multifactorial threshold trait
51: Multifactorial disease in children
Overview
Methodology
Examples
52: Common disorders of adult life
Overview
Odds ratios
Coronary artery disease (CAD)
Cardiomyopathy (see Chapters and )
Hypertension
Stroke
Type 2 diabetes mellitus and MODY
Low intelligence
Schizophrenia
Affective disorder
Alzheimer disease
Obesity
Alcoholism
53: Twin studies
Overview
Frequency of multiple births
Analysis of discontinuous multifactorial traits
Analysis of continuously variable multifactorial traits
Health risks in twins
Copy number variation (CNV)
Weaknesses of the twin study approach
Part 10: Cancer
54: The signal transduction cascade
Overview
Environmental triggers
Viruses
Tumour suppressor proteins
The signal transduction cascade
Conversion of proto-oncogenes to oncogenes
Enabling characteristics
55: The eight hallmarks of cancer
Overview
1 Self-sufficiency in mitotic stimulation
2 Evasion of growth suppressors
3 Resistance to apoptosis
4 Limitless replicative potential
5 Sustained angiogenesis
6 Tissue invasion and metastasis
7 Reprogramming of cellular energy metabolism
8 Evasion of immune destruction
Cancer stem cells
56: Familial cancers
Overview
Indicators of inherited cancer
The two-hit hypothesis
The multi-hit hypothesis
Oncogenes
57: Genomic approaches to cancer management
Overview
Analysis of tumour gene expression
Analysis of cancer genomes
Genetic testing in cancer diagnosis
Genetic testing and treatment of cancer
Part 11: Biochemical genetics
58: Disorders of amino acid metabolism
Inborn errors of metabolism
Enzyme deficiencies and disease
Errors in amino acid metabolism
59: Disorders of carbohydrate metabolism
Overview
Lactose intolerance
Galactosaemia
Fructose intolerance
Diabetes mellitus
Glycogen storage disorders (GSDs)
60: Metal transport, lipid metabolism and amino acid catabolism defects
Metal transport defects
Lipid metabolism
Acidaemia and aciduria due to defective amino acid catabolism
61: Disorders of porphyrin and purine metabolism and the urea/ornithine cycle
Overview
Biosynthesis of haem
Porphyria
Errors of purine metabolism
Disorders of the urea/ornithine cycle
62: Lysosomal, glycogen storage and peroxisomal diseases
Overview
Sphingolipidoses, lipid storage disorders (LSDs)
Mucopolysaccharidoses (MPSs)
Peroxisomal disease
Glycogen storage disorders
63: Biochemical diagnosis
Overview
Inborn errors of metabolism
Approaches to diagnosis
Part 12: Immunogenetics
64: Immunogenetics, cellular and molecular aspects
Overview
The innate immune system
The adaptive immune system
Memory cells
The major histocompatibility complex (MHC)
The immunoglobulins
The T-cell receptor (TCR)
The immune system in pregnancy
65: Genetic disorders of the immune system
Overview
Hypersensitivity
Disorders of innate humoral immunity
Disorders of innate cell-mediated immunity
Disorders of adaptive humoral immunity
Disorders of adaptive cell-mediated immunity
Associated and secondary immunodeficiency
Immune system subversion
66: Autoimmunity, HLA and transplantation
Overview
Acquisition of tolerance
Autoimmune disease
Causes of autoimmunity
Explanations for HLA-disease association
Tissue incompatibility in transfusion and transplantation
Part 13: Molecular diagnosis
67: DNA hybridization-based analysis systems
Overview
DNA probes
Restriction endonucleases and DNA polymorphism
Gel electrophoresis
DNA hybridization in Southern blotting
Methodological variants
Diagnostic applications
68: DNA sequencing
Overview
The dideoxy-DNA sequencing method
Iterative pyrosequencing
Massively parallel, or next-generation, DNA sequencing
69: The polymerase chain reaction
Overview
The polymerase chain reaction
70: DNA profiling
Overview
Application of Southern blotting
Application of the polymerase chain reaction (PCR)
The modern approach to proof of identification
Part 14: Genetic counselling, disease management, ethical and social issues
71: Reproductive genetic counselling
Overview
Communication
Comprehension
Care
Reproductive options
X-linked disease
72: Prenatal sampling
Overview
Non-invasive procedures
Invasive procedures
Preimplantation genetic diagnosis
Problems of prenatal sampling
73: Avoidance and prevention of disease
Overview
Preimplantation diagnosis
Prenatal screening
Neonatal screening
Screening for adult-onset disease
Occupational screening
Limitations of genetic testing
Genetic registers
Prophylactic surgery
Therapeutic cloning
74: Management of genetic disease
Overview
Pharmacogenomics
Gene therapy
Modification of the properties of proteins
Correction of metabolic dysfunction
Modification of gross phenotype
75: Ethical and social issues in clinical genetics
Overview
The Darwinian perspective
An historical perspective
The religious perspective
Application of ethical principles
Non-directiveness in genetic counselling
Confidentiality
Conflicts of interest between family members
Genetic testing of children
Genetic screening
Additional problems in genetic counselling
Areas of ethical challenge arising from new reproductive technologies
Self-assessment case studies: questions
Case 1: Unbalanced translocation
Case 2: A metabolic problem
Case 3: A child with skin spots
Case 4: Muscle weakness
Case 5: Cancer in the family
Case 6: Targeted treatment
Case 7: Worries about senility
Case 8: A sleepy infant
Case 9: Advance warning
Case 10: Enzyme replacement
Case 11: Autism spectrum disorder
Case 12: Exome sequencing
Case 13: Direct-to-consumer genomic testing
Case 14: Treatment of genetic disorders
Case 15: Pharmacogenetics
Self-assessment case studies: answers
Glossary
Appendix 1: the human karyotype
Appendix 2: information sources and resources
Index
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This edition first published 2013 © 2013 by John Wiley & Sons, Ltd
Previous editions 2003, 2008 © Dorian J. Pritchard, Bruce R. Korf.
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Library of Congress Cataloging-in-Publication Data
Pritchard, D. J. (Dorian J.)
Medical genetics at a glance / Dorian J. Pritchard, Bruce R. Korf. – 3rd ed.
p. ; cm. – (At a glance series)
Includes bibliographical references and index.
ISBN 978-0-470-65654-9 (softback : alk. paper) – ISBN 978-1-118-68900-4 (mobi) – ISBN 978-1-118-68901-1 (pub) – ISBN 978-1-118-68902-8 (pdf)
I. Korf, Bruce R. II. Title. III. Series: At a glance series (Oxford, England)
[DNLM: 1. Genetic Diseases, Inborn. 2. Chromosome Aberrations. 3. Genetics, Medical. QZ 50]
RB155
616'.042–dc23
2013007103
A catalogue record for this book is available from the British Library.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.
Cover image: Tim Vernon, LTH NHS Trust/Science Photo Library
Cover design by Meaden Creative
Preface to the first edition
This book is written primarily for medical students seeking a summary of genetics and its medical applications, but it should be of value also to advanced students in the biosciences, paramedical scientists, established medical doctors and health professionals who need to extend or update their knowledge. It should be of especial value to those preparing for examinations.
Medical genetics is unusual in that, whereas its fundamentals usually form part of first-year medical teaching within basic biology, those aspects that relate to inheritance may be presented as an aspect of reproductive biology. Clinical issues usually form a part of later instruction, extending into the postgraduate years. This book is therefore presented in three sections, which can be taken together as a single course, or separately as components of several courses. Chapters are however intended to be read in essentially the order of presentation, as concepts and specialised vocabulary are developed progressively.
There are many excellent introductory textbooks in our subject, but none, so far as we know, is at the same time so comprehensive and so succinct. We believe the relative depth of treatment of topics appropriately reflects the importance of these matters in current thinking.
Dorian Pritchard
Bruce Korf
Preface to the third edition
The first two editions have been quite successful, having been translated into Chinese, Japanese, Greek, Serbo-Croat, Korean, Italian and Russian. In keeping with this international readership, we stress clinical issues of particular relevance to the major ethnic groups, with information on relative disease allele frequencies in diverse populations. The second edition was awarded First Prize in the Medicine category of the 2008 British Medical Association Medical Book Competition Awards. In this third edition we aim to exceed previous standards.
Editions one and two presented information across all subject areas in order of the developing complexity of the whole field, so that a reader's vocabulary, knowledge and understanding could progress on a broad front. That approach was popular with student reviewers, but their teachers commented on difficulty in accessing specific subject areas. The structure of this third edition has therefore been completely revised into subject-based sections, of which there are fourteen.
Three former introductory chapters have been combined and all other chapters revised and updated. In addition we have written seventeen new chapters and five new case studies, with illustrations to accompany the latter. New features include a comprehensively illustrated treatment of cardiac developmental pathology, a radically revised outline of cancer, a much extended review of biochemical genetics and outline descriptions of some of the most recent genomic diagnostic techniques.
Dorian Pritchard
Bruce Korf
Acknowledgements
We thank thousands of students, for the motivation they provided by their enthusiastic reception of the lectures on which these chapters are based. We appreciate also the interest and support of many colleagues, but special mention should be made of constructive contributions to the first edition by Dr Paul Brennan of the Department of Human Genetics, University of Newcastle. We are most grateful also to Professor Angus Clarke of the Department of Medical Genetics, Cardiff University for his valuable comments on Chapter 61 of Edition 2 and to Dr J. Daniel Sharer, Assistant Professor of Genetics, University of Alabama at Birmingham for constructive advice on our diagram of the tandem mass spectrometer. DP wishes to pay tribute to the memory of Ian Cross for his friendship and professional support over many years and for his advice on the chapters dealing with cytogenetics.
We thank the staff of Wiley for their encouragement and tactful guidance throughout the production of the series and Jane Fallows and Graeme Chambers for their tasteful presentation of the artwork.
Dorian Pritchard
Bruce Korf
List of abbreviations
1
The place of genetics in medicine
The case for genetics
In recent years medicine has been in a state of transformation, created by the convergence of two major aspects of technological advance. The first is the explosion in information technology and the second, the rapidly expanding science of genetics. The likely outcome is that within the foreseeable future we will see the establishment of a new kind of medicine, individualized medicine, tailored uniquely to the personal needs of each patient. Some diseases, such as hypertension, have many causes for which a variety of treatments may be possible. Identification of a specific cause allows clinicians to give personal guidance on the avoidance of adverse stimuli and enable precise targeting of the disease with personally appropriate medications.
One survey of over a million consecutive births showed that at least one in 20 people under the age of 25 develops a serious disease with a major genetic component. Studies of the causes of death of more than 1200 British children suggest that about 40% died as a result of a genetic condition, while genetic factors are important in 50% of the admissions to paediatric hospitals in North America. Through variation in immune responsiveness and other host defences, genetic factors even play a role in infectious diseases.
Genetics underpins and potentially overlaps all other clinical topics, but is especially relevant to reproduction, paediatrics, epidemiology, therapeutics, internal medicine and nursing. It offers unprecedented opportunities for prevention and avoidance of disease because genetic disorders can often be predicted long before the onset of symptoms. This is known as predictive or presymptomatic genetics. Currently healthy families can be screened for persons with a particular genotype that might cause later trouble for them or their children.
‘Gene therapy’ is the ambitious goal of correcting errors associated with inherited deficiencies by introduction of ‘normal’ versions of genes into their cells. Progress along those lines has been slower than anticipated, but has now moved powerfully into related areas. Some individuals are hypersensitive to standard doses of commonly prescribed drugs, while others respond poorly. Pharmacogenetics is the study of differential responses to unusual biochemicals and the insights it provides guide physicians in the correct prescription of doses.
Genes in development
Genes do not just cause disease, they define normality and every feature of our bodies receives input from them. Typically every one of our cells contains a pair of each of our 20 000–25 000 genes and these are controlled and expressed in molecular terms at the level of the cell. During embryonic development the cells in different parts of the body become exposed to different influences and acquire divergent properties as they begin to express different combinations of the genes they each contain. Some of these genes define structural components, but most define the amino acid sequences of enzymes that catalyse biochemical processes.
Genes are in fact coded messages written within enormously long molecules of DNA distributed between 23 pairs of chromosomes. The means by which the information contained in the DNA is interpreted is so central to our understanding that the phrase: ‘DNA makes RNA makes protein’; or more correctly: ‘DNA makes heterogeneous nuclear RNA, which makes messenger RNA, which makes polypeptide, which makes protein’; has become accepted as the ‘central dogma’ of molecular biology.
During the production of the gametes the 23 pairs of chromosomes are divided into 23 single sets per ovum or sperm, the normal number being restored in the zygote by fertilization. The zygote proliferates to become a hollow ball that implants in the maternal uterus. Prenatal development then ensues until birth, normally at around 38 weeks, but all the body organs are present in miniature by 6–8 weeks. Thereafter embryogenesis mainly involves growth and differentiation of cell types. At puberty development of the organs of reproduction is re-stimulated and the individual attains physical maturity. The period of 38 weeks is popularly considered to be 9 months, traditionally interpreted as three ‘trimesters’. The term ‘mid-trimester’ refers to the period covering the 4th, 5th and 6th months of gestation.
Genotype and phenotype
Genotype is the word geneticists use for the genetic endowment a person has inherited. Phenotype is our word for the anatomical, physiological and psychological complex we recognize as an individual. People have diverse phenotypes partly because they inherited different genotypes, but an equally important factor is what we can loosely describe as ‘environment’. A valuable concept is summarized in the equation:
It is very important to remember that practically every aspect of phenotype has both genetic and environmental components. Diagnosis of high liability toward ‘genetic disease’ is therefore not necessarily an irrevocable condemnation to ill health. In some cases optimal health can be maintained by avoidance of genotype-specific environmental hazards.
Genetics in medicine
The foundation of the science of genetics is a set of principles of heredity, discovered in the mid-19th century by an Augustinian monk called Gregor Mendel. These give rise to characteristic patterns of inheritance of variant versions of genes, called alleles, depending on whether the unusual allele is dominant or recessive to the common, or ‘wild type’ one. Any one gene may be represented in the population by many different alleles, only some of which may cause disease. Recognition of the pattern of inheritance of a disease allele is central to prediction of the risk of a couple producing an affected child. Their initial contact with the clinician therefore usually involves construction of a ‘family tree’ or pedigree diagram.
For many reasons genes are expressed differently in the sexes, but from the genetic point of view the most important relates to possession by males of only a single X-chromosome. Most sex-related inherited disease involves expression in males of recessive alleles carried on the X-chromosome.
Genetic diseases can be classed in three major categories: monogenic, chromosomal and multifactorial. Most monogenic defects reveal their presence after birth and are responsible for 6–9% of early morbidity and mortality. At the beginning of the 20th century, Sir Archibald Garrod coined the term ‘inborn errors of metabolism’ to describe inherited disorders of physiology. Although individually most are rare, the 350 known inborn errors of metabolism account for 10% of all known single-gene disorders.
Because chromosomes on average carry about 1000 genes, too many or too few chromosomes cause gross abnormalities, most of which are incompatible with survival. Chromosomal defects can create major physiological disruption and most are incompatible with even prenatal survival. These are responsible for more than 50% of deaths in the first trimester of pregnancy and about 2.5% of childhood deaths.
‘Multifactorial traits’ are due to the combined action of several genes as well as environmental factors. These are of immense importance as they include most of the common disorders of adult life. They account for about 30% of childhood illness and in middle-to-late adult life play a major role in the common illnesses from which most of us will die.
The application of genetics
If genes reside side-by-side on the same chromosome they are ‘genetically linked’. If one is a disease gene, but cannot easily be detected, whereas its neighbour can, then alleles of the latter can be used as markers for the disease allele. This allows prenatal assessment, informing decisions about pregnancy, selection of embryos fertilized in vitro and presymptomatic diagnosis.
Genetically based disease varies between ethnic groups, but the term ‘polymorphism’ refers to genetic variants like blood groups that occur commonly in the population, with no major health connotations. The concept of polymorphism is especially important in blood transfusion and organ transplantation.
Mutation of DNA involves a variety of changes which can be caused for example by exposure to X-rays. Repair mechanisms correct some kinds of change, but new alleles are sometimes created in the germ cells, which can be passed on to offspring. Damage that occurs to the DNA of somatic cells can result in cancer, when a cell starts to proliferate out of control. Some families have an inherited tendency toward cancer and must be given special care.
A healthy immune system eliminates possibly many thousands of potential cancer cells every day, in addition to disposing of infectious organisms. Maturation of the immune system is associated with unique rearrangements of genetic material, the study of which comes under the heading of immunogenetics.
The study of chromosomes is known as cytogenetics. This provides a broad overview of a patient's genome and depends on microscopic examination of cells. By contrast molecular genetic tests are each specifically for just one or a few disease alleles. The molecular approach received an enormous boost around the turn of the millennium by the detailed mapping of the human genome.
The modern application of genetics to human health is therefore complex. Because it focuses on reproduction it can impinge on deeply held ethical, religious and social convictions, which are often culture variant. At all times therefore, clinicians dealing with genetic matters must be acutely aware of the real possibility of causing personal offence and take steps to avoid that outcome.
2
Pedigree drawing
Overview
The collection of information about a family is the first and most important step taken by doctors, nurses or genetic counsellors when providing genetic counselling. A clear and unambiguous pedigree diagram, or ‘family tree’, provides a permanent record of the most pertinent information and is the best aid to clear thinking about family relationships.
Information is usually collected initially from the consultand, that is the person requesting genetic advice. If other family members need to be approached it is wise to advise them in advance of the information required. Information should be collected from both sides of the family.
The affected individual who caused the consultand(s) to seek advice is called the propositus (male), proposita (female), proband or index case. This is frequently a child or more distant relative, or the consultand may also be the proband. A standard medical history is required for the proband and all other affected family members.
The medical history
In compiling a medical history it is normal practice to carry out a systems review broadly along the following lines:
cardiovascular system: enquire about congenital heart disease, hypertension, hyperlipidaemia, blood vessel disease, arrhythmia, heart attacks and strokes;respiratory system: asthma, bronchitis, emphysema, recurrent lung infection;gastrointestinal tract: diarrhoea, chronic constipation, polyps, atresia, fistulas and cancer;genitourinary system: ambiguous genitalia and kidney function;musculoskeletal system: muscle wasting, physical weakness;neurological conditions: developmental milestones, hearing, vision, motor coordination, fits.Rules for pedigree diagrams
Some sample pedigrees are shown (see also Chapters 4–12). Females are symbolized by circles, males by squares, persons of unknown sex by diamonds. Affected individuals are represented by solid symbols, those unaffected, by open symbols. Marriages or matings are indicated by horizontal lines linking male and female symbols, with the male partner preferably to the left. Offspring are shown beneath the parental symbols, in birth order from left to right, linked to the mating line by a vertical, and numbered (1, 2, 3, etc.), from left to right in Arabic numerals. The generations are indicated in Roman numerals (I, II, III, etc.), from top to bottom on the left, with the earliest generation labelled I.
The proband is indicated by an arrow with the letter P, the consultand by an arrow alone. (N.B. earlier practice was to indicate the proband by an arrow without the P).
Only conventional symbols should be used, but it is admissible (and recommended) to annotate diagrams with more complex information. If there are details that could cause embarrassment (e.g. illegitimacy or extramarital paternity) these should be recorded as supplementary notes.
Include the contact address and telephone number of the consultand on supplementary notes. Add the same details for each additional individual that needs to be contacted.
The compiler of the family tree should record the date it was compiled and append his/her name or initials.
The practical approach
The details below should be inserted beside each symbol, whether that individual is alive or dead. Personal details of normal individuals should also be specified. The ethnic background of the family should be recorded if different from that of the main population.
Details for each individual:
Use of pedigrees
A good family pedigree reveals the mode of inheritance of the disease and can be used to predict the genetic risk in several instances (see Chapter 13). These include:
3
Mendel's laws
Overview
Gregor Mendel's laws of inheritance were derived from experiments with plants, but they form the cornerstone of the whole science of genetics. Previously, heredity was considered in terms of the transmission and mixing of ‘essences’, as suggested by Hippocrates over 2000 years before. But, unlike fluid essences that should blend in the offspring in all proportions, Mendel showed that the instructions for contrasting characters segregate and recombine in simple mathematical proportions. He therefore suggested that the hereditary factors are particulate.
Mendel postulated four new principles concerning unit inheritance, dominance, segregation and independent assortment that apply to most genes of all diploid organisms.
The principle of unit inheritance
Hereditary characters are determined by indivisible units of information (which we now call genes). An allele is one version of a gene.
The principle of dominance
Alleles occur in pairs in each individual, but the effects of one allele may be masked by those of a dominant partner allele.
The principle of segregation
During formation of the gametes the members of each pair of alleles separate, so that each gamete carries only one allele of each pair. Allele pairs are restored at fertilization.
Example
The earlobes of some people have an elongated attachment to the neck while others are free, a distinction we can consider for the purposes of this explanation to be determined by two alleles of the same gene, f for attached, F for free. (Note: In reality some individuals have earlobes of intermediate form and in some families the genetic basis is more complex.)
Consider a man carrying two copies of F (i.e. FF), with free earlobes, married to a woman with attached earlobes and two copies of f (i.e. ff). Both can produce only one kind of gamete, F for the man, f for the woman. All their children will have one copy of each allele, i.e. are Ff, and it is found that all such children have free earlobes because Fis dominant tof. The children constitute the first filial generation or F1 generation (irrespective of the symbol for the gene under consideration). Individuals with identical alleles are homozygotes; those with different alleles are heterozygotes.
The second filial, or F2, generation is composed of the grandchildren of the original couple, resulting from mating of their offspring with partners of the same genotype in this respect. In each case both parents are heterozygotes, so both produce F and f gametes in equal numbers. This creates three genotypes in the F2: FF, Ff (identical to fF) and ff,in the ratio: 1 : 2 : 1.
Due to the dominance of F over f, dominant homozygotes are phenotypically the same as heterozygotes, so there are three offspring with free earlobes to each one with attached. The phenotypic ratio 3 : 1 is characteristic of the offspring of two heterozygotes.
The principle of independent assortment
Different genes control different phenotypic characters and the alleles of different genes re-assort independently of one another.
Example
Auburn and ‘red’ hair occur naturally only in individuals who are homozygous for a recessive allele r. Non-red is dominant, with the symbol R. All red-haired people are therefore rr, while non-red are either RR or Rr.
Consider the mating between an individual with red hair and attached earlobes (rrff) and a partner who is heterozygous at both genetic loci (RrFf). The recessive homozygote can produce only one kind of gamete, of genotype rf, but the double heterozygote can produce gametes of four genotypes: RF, Rf, rF and rf. Offspring of four genotypes are produced: RrFf, Rrff, rrFf and rrff and these are in the ratio 1 : 1 : 1 : 1.
These offspring also have phenotypes that are all different: non-red with free earlobes, non-red with attached, red with free, and red with attached, respectively.
The test-mating
The mating described above, in which one partner is a double recessive homozygote (rrff), constitutes a test-mating, as his or her recessive alleles allow expression of all the alleles of their partner.
The value of such a test is revealed by comparison with matings in which the recessive partner is replaced by a double dominant homozygote (RRFF). The new partner can produce only one kind of gamete, of genotype RF, and four genotypically different offspring are produced, again in equal proportions: RRFF, RRFf, RrFF and RrFf. However, due to dominance all have non-red hair and free earlobes, so the genotype of the heterozygous parent remains obscure.
Matings between double heterozygotes
The triumphant mathematical proof of Mendel laws was provided by matings between pairs of double heterozygotes. Each can produce four kinds of gametes: RF, Rf, rF and rf, which combined at random produce nine different genotypic combinations. Due to dominance there are four phenotypes,in the ratio 9 : 3 : 3 : 1 (total = 16). This allows us to predict the odds of producing:
Biological support for Mendel's laws
When published in 1866 Mendel's deductions were ignored, but in 1900 they were re-discovered and rapidly found acceptance. This was in part because the chromosomes had by then been described and the postulated behaviour of Mendel's factors coincided with the observed properties and behaviour of the chromosomes: (i) both occur in homologous pairs; (ii) at meiosis both separate, but reunite at fertilization; and (iii) the homologues of both segregate and recombine independently of one another. This coincidence is because the genes are components of the chromosomes.
Exceptions to Mendel's laws
Several patterns of inheritance deviate from those described by Gregor Mendel for which a variety of explanations has been suggested.
1. Sex-related effects
The genetic specification of sexual differentiation is described in Chapter 43. In brief, male embryos carry one short chromosome designated Y and a much longer chromosome designated X, so the male karyotype can be summarized as XY. The Y carries a small number of genes concerned with development and maturation of masculine features and also sections homologous with parts of the X. The normal female karyotype is XX, females having two X chromosomes and no Y.
A copy of the father's Y chromosome is transmitted to every son, while a copy of his X chromosome is passed to every daughter. Y-linked traits (of which there are very few) are therefore confined to males, but X-linked can show a criss-cross pattern from fathers to daughters, mothers to sons down the generations.
The most significant aspect of sex-related inheritance concerns X-linked recessive alleles, of which there are many. Those which have no counterpart on the Y are more commonly expressed in hemizygous males than in homozygous females.
2. Mitochondrial inheritance
The units of inheritance such as Mendel described are carried on the autosomes (non-sex chromosomes), which exist in homologous pairs. These exchange genetic material by ‘crossing over’ with their partners and segregate at meiosis (see Chapter 18). In addition there are multiple copies of a much smaller genome in virtually every cell of the human body, which resides in the tiny subcellular organelles called mitochondria (see Chapter 12).
The mode of inheritance of mitochondria derives from the mechanism of fertilization. Sperm are very small, light in weight and fast moving. They carry little else but a nucleus, a structure that assists penetration of the ovum and a tail powered by a battery of mitochondria. The latter are however shed before the sperm nucleus enters the ovum and so make no contribution to the mitochondrial population of the zygote. By contrast the ovum is massive and loaded with nutrients and many copies of the subcellular organelles of somatic body cells (see Chapter 14). All the genes carried in the mitochondrial genome are therefore passed on only by females, and equally to offspring of both sexes. Mitochondrial inheritance is therefore entirely from mothers, to offspring of both sexes.
3. Genetic linkage
Mendel did not know where the hereditary information resides. He was certainly unaware of the importance of chromosomes in that regard and the traits he described showed independent assortment with one another. ‘Genetic linkage’ refers to the observed tendency for combinations of alleles of different genes to be inherited as a group, because they reside close together on the same chromosome (see Chapter 31).
4. Polygenic conditions
Many aspects of phenotype cannot be segregated simply into positive and negative categories, but instead show a continuous range of variation. Examples are height and intelligence. The conventional explanation is that they are controlled by the joint action of many genes. In addition, environmental factors modify phenotypes, further blurring genetically based distinctions (see Chapters 50 and 51).
5. Overdominance, codominance, variable expressivity and incomplete penetrance
Mendel's concept of dominance is that expression of a dominant allele obliterates that of a recessive and that heterozygotes are phenotypically indistinguishable from dominant homozygotes, but this is not always the case. In achondroplasia, a form of short-limbed dwarfism, homozygotes for the dominant achondroplasia allele are so severely affected that they die in utero. This phenomenon is called overdominance. The consequence is that the live offspring of heterozygous achondroplastic partners occur in the ratio of two affected not three, to each unaffected recessive homozygote (see Chapter 5).
Codominance refers to the expression of both antigens in a heterozygote. A familiar example is the presence of both A and B antigenic determinants on the surfaces of red blood cells of AB blood group heterozygotes (see Chapter 29).
The expression of many genes is modified by alleles of other genes as well as by environmental factors. Many genetic conditions therefore show variable expressivity, confusing the concept of simple dominance.
In some cases an apparently dominant allele may appear to skip a generation because its expression in one carrier has been negated by other factors. Such alleles are said to show incomplete penetrance (see Chapter 9).
6. Genomic imprinting
A striking exception to Mendel's description is mutant alleles that confer markedly different phenotypes in relation to the parental origin of the mutant gene. For example, when a site on the long arm of the maternally derived chromosome 15 has been deleted it gives rise to Angelman syndrome in the offspring. Children with this condition show jerky movements and are severely mentally handicapped. When the equivalent site is deleted from the paternally derived chromosome 15, the child is affected in a very different way. These children have Prader–Willi syndrome, characterized by features that include compulsive consumption of food, obesity and a lesser degree of mental handicap. The explanation is in terms of differential ‘imprinting’ of the part of chromosome 15 concerned (see Chapter 27). Several hundred human genes receive ‘imprinting’.
7. Dynamic mutation
Around 20 human genetic diseases develop with increasing severity in consecutive generations, or make their appearance in progressively younger patients. A term that relates to both features is ‘dynamic mutation’, which involves progressive expansion of three-base repeats in the DNA associated with certain genes (see Chapter 28).
8. Meiotic drive
Heterozygotes produce two kinds of gametes, carrying alternative alleles at that locus and the proportions of the offspring described by Mendel indicate equal transmission of those alternatives. Rarely one allele is transmitted at greater frequency than the other, a phenomenon called meiotic drive. There is some evidence this may occur with myotonic dystrophy (see Chapter 28).
Conclusion
Despite being derived from simple experiments with garden plants and the existence of numerous exceptions, Mendel's laws remain the central concept in our understanding of familial patterns of inheritance in our own species, and in those of most other ‘higher’ organisms. Examples of simple dominant and recessive conditions of great medical significance are familial hypercholesterolaemia (Chapters 5 and 6) and cystic fibrosis (Chapter 6).
4
Principles of autosomal dominant inheritance and pharmacogenetics
Overview
In principle, dominant alleles are expressed when present as single copies (c.f. recessive, Chapter 6), but ‘incompletely penetrant’ alleles can remain unexpressed in some circumstances (see Chapter 9). Some alleles that are especially important in medicine are revealed only when people are exposed to unusual chemicals. Some such ‘pharmacogenetic traits’ are inherited as dominants, others in other ways (see below).
Rules for autosomal dominant inheritance
The following are the basic rules for simple autosomal dominant (AD) inheritance. These rules apply only to conditions of complete penetrance and where no novel mutation has arisen.
Example
The first condition in humans for which the mode of inheritance was elucidated was brachydactyly, characterized by abnormally short phalanges.
In Mendelian symbols, dominant allele B causes brachydactyly and every affected individual is either a homozygote (BB) or a heterozygote (Bb). In practice most are heterozygotes, because brachydactyly is a rare trait (i.e. <1/5000 births), as are almost all dominant disease alleles. Unrelated marriage partners are therefore usually recessive homozygotes (bb) and the mating can be represented:
Bb × bb
↓
Bb,bb
1 : 1
Dominant disease alleles are kept at low frequency since their carriers are less fit than normal homozygotes.
Matings between heterozygotes are the only kind that can produce homozygous offspring:
Bb × Bb
↓
BB, Bb, bb
1 : 2 : 1; i.e. 3 affected : 1 unaffected.
Dominant disease allele homozygotes are extremely rare and with many disease alleles homozygosity is lethal or causes a more pronounced or severe phenotype.
Matings between heterozygotes may involve inbreeding (see Chapter 5), or occur when patients have met as a consequence of their disability (e.g. at a clinic for the disorder).
All offspring of affected homozygotes are affected:
BB × bb
↓
Bb
Unaffected members of affected families are normal homozygotes, so do not transmit the condition: bb × bb → bb.
Estimation of risk
In simply inherited AD conditions where the diagnosis is secure, estimation of risk for the offspring of a family member can be based simply on the predictions of Mendel's laws. For example:
Calculations involving dominant conditions can, however, be problematical as we usually do not know whether an affected offspring is homozygous or heterozygous (see Chapter 13).
Estimation of mutation rate
The frequency of dominant diseases in families with no prior cases can be used to estimate the natural frequency of new point mutations (see Chapter 26). This varies widely between genes, but averages about one mutational event in any specific gene per 500 000 zygotes. Almost all point mutations arise in sperm, each containing, at the latest estimates, 20–25 000 genes (see Chapter 19). There are therefore perhaps 25 000 mutations per 500 000 sperm, so we can expect around 5% of viable sperm (and babies) to carry a new genetic mutation. However, only a minority of these occurs within genes that produce clinically significant effects, or would behave as dominant traits.
Pharmacogenetics
Pharmacogenetic traits are inherited in a variety of ways (AD, AR, X-linked R, ACo-D, etc., see Abbreviations and Chapter 29).
Debrisoquine hydroxylase deficiency (AR)
Genes of the cytochrome P450 group are of particular importance in drug deactivation (see Chapter 29). One such is debrisoquine hydroxylase, involved in the metabolism of the antihypertensive debrisoquine and other drugs. Five to 10% of Europeans show serious adverse reactions to debrisoquine.
