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Herausgeber: John Wiley & Sons
Kategorie: Fachliteratur
Serie: At a Glance
Sprache: Englisch

Beschreibung

Clinical Genetics and Genomics at a Glance The market-leading at a Glance series is popular among healthcare students and newly qualified practitioners, for its concise and simple approach and excellent illustrations. Each bite-sized chapter is covered in a double-page spread with clear, easy-to-follow diagrams, supported by succinct explanatory text. Covering a wide range of topics, books in the at a Glance series are ideal as introductory texts for teaching, learning and revision, and are useful throughout university and beyond. Everything you need to know about Clinical Genetics and Genomics ... at a Glance! Comprehensive and accessible overview of genetics in clinical practice with a unique systems-based approach Clinical Genetics and Genomics at a Glance combines the clinical and scientific facets of a complex subject in a way that is both accessible and succinct to facilitate the diagnosis, treatment, and management of common genetic conditions. Using the popular "at a Glance" format, this book enables the reader to gain a solid understanding of the practical applications of clinical genetics in different systems. Covering a wide range of topics, this book is perfect for an introduction on the subject texts or for revision purposes and are useful throughout medical school and beyond. Clinical Genetics and Genomics at a Glance uses a systemic approach following all the systems in the body: * General topics such as inheritance, cytogenetic and molecular genetic techniques, how to read a genetic test report, and genetic counselling * Chapters on key conditions with a genetic basis, organised by body systems, for example: * Cardiology topics such as congenital heart disease, ischaemic heart disease, cardiomyopathies, arrhythmias, and sudden cardiac death * Dermatology topics such as tuberous sclerosis, Gorlin syndrome, Darier disease, lamellar ichthyosis, mal de meleda, cutaneous porphyria, and epidermolysis bullosa * Endocrinology topics such as adrenal gland conditions, androgen insensitivity syndrome, ambiguous sex syndromes, anorchism, Klinefelter syndrome, Turner syndrome, and diabetes mellitus Clinical Genetics and Genomics at a Glance is a helpful learning aid that can be used at various stages of medical training to gain an understanding of the aspects of clinical genetics and the fundamentals behind the specialty. The text also functions as a useful on-ward reference tool for practitioners of all experience levels.

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Cover

Table of Contents

Title Page

Dedication

Contributors

Foreword

Preface

Part 1: Introduction

1 What is clinical genetics and genomic medicine?

What is clinical genetics?

How does clinical genetic testing help clinical care?

Pedigrees

Variant interpretation and the role of the clinical geneticist

What is the impact of genetics on insurance and migration?

What is genomic medicine?

What does genomic medicine encompass?

2 Inheritance

Autosomal dominant (AD)

Autosomal recessive (AR)

X‐linked recessive (XLR)

X‐linked dominant (XLD)

Y‐chromosome inheritance

Mitochondrial

Imprinting and uniparental disomy

3 Cytogenetics and molecular genetic techniques

Cytogenetics

Molecular genetics

DNA sequencing

4 How to read a genetic test report

Introduction

Explanation of report

How likely is it that a gene change is linked with a genetic condition?

Genetic terminology

List of Tables

Chapter 5

Table 5.1 AGNC Code of Ethics.

Chapter 6

Table 6.1 Overview of certain Mendelian disorders associated with congenita...

Table 6.2 Factors suggesting adult CHD patients may benefit from counselling...

Chapter 7

Table 7.1 Summary of some different cardiomyopathy subtypes and commonly in...

Table 7.2 Presentation and diagnosis.

Chapter 9

Table 9.1 Genes commonly involved in inherited arrhythmia syndromes (not an...

Table 9.2 Clinical features and diagnosis.

Chapter 10

Table 10.1 TSC clinical diagnostic criteria, International Tuberous Sclerosi...

Table 10.2 Surveillance and management recommendations for patients already ...

Chapter 11

Table 11.1 Diagnostic criteria.

Chapter 13

Table 13.1 Main ichthyosis types and syndromes

Chapter 14

Table 14.1 Summary of Palmoplantar keratodermas.

Chapter 15

Table 15.1 Acute vs cutaneous porphyrias.

Table 15.2 Different types of cutaneous porphyrias.

Table 15.3 Biochemical measurements of porphyrias and porphyrin precursors ...

Table 15.4 Management of porphyrias.

Chapter 16

Table 16.1 Clinical features.

Table 16.2 Major and minor criteria.

Table 16.3 NCCN surveillance guidelines.

Chapter 17

Table 17.1 Features of different types of epidermolysis bullosa.

Chapter 21

Table 21.1 Classification of DSDs, based on the 2005 Chicago Consensus.

Chapter 22

Table 22.1 Clinical features of congenital adrenal hyperplasia.

Chapter 24

Table 24.1 Clinical features of Klinefelter syndrome.

Chapter 26

Table 26.1 Subtypes of MODY.

Chapter 27

Table 27.1 Causes of diabetes insipidus.

Chapter 31

Table 31.1 Disorders of carbohydrate metabolism.

Chapter 32

Table 32.1 What are the different types of lipids and why are they important...

Chapter 35

Table 35.1 Genes implicated in the susceptibility to IBD.

Chapter 38

Table 38.1 Gene alterations contributing to the susceptibility to coeliac d...

Chapter 40

Table 40.1 Chromosomal translocations.

Table 40.2 Gene alterations.

Chapter 42

Table 42.1 T‐B‐ SCID (Markedly decreased numbers of both T cells and B cell...

Table 42.2 T‐B+ SCID (Markedly decreased numbers of T cells, with normal nu...

Chapter 43

Table 43.1 CVID ‐ inheritance and features.

Table 43.2 European Society of Immunodeficiency diagnostic criteria for CVID...

Chapter 44

Table 44.1 Genetic basis of conditions affecting thymus development.

Table 44.2 Clinical presentation.

Chapter 45

Table 45.1 Alterations in DNA repair defects.

Table 45.2 Clinical features of DNA repair defects.

Chapter 46

Table 46.1 Overview of the two main subtypes of agammaglobulinaemia.

Chapter 48

Table 48.1 Alterations causing hyper IgM syndromes.

Chapter 49

Table 49.1 Principals of management of HIES.

Chapter 51

Table 51.1 Disorders associated with immune dysregulation and/or autoimmunit...

Chapter 52

Table 52.1 Specific laboratory markers.

Chapter 53

Table 53.1 Inheritance and alterations associated with the various MSMDs.

Chapter 54

Table 54.1 Alterations causing CGD.

Chapter 56

Table 56.1 Genetic basis of TLR defects.

Chapter 57

Table 57.1 Genetic basis of autoinflammatory diseases.

Chapter 58

Table 58.1 Genetic basis of complement deficiencies.

Chapter 59

Table 59.1 Clinical classification of SMA subtypes.

Chapter 61

Table 61.1 Full, permutation, intermediate, and normal allele sizes.

Chapter 66

Table 66.1 Conditions screened in England between 18 weeks and 20 weeks and...

Chapter 67

Table 67.1 Mandatory criteria for couples seeking NHS funded PGD.

Chapter 73

Table 73.1 Diagnostic criteria for Neurofibromatosis type 1.

Table 73.2 Diagnostic criteria for neurofibromatosis type 2.

Chapter 74

Table 74.1 Syndromes associated with hereditary renal cell carcinoma.

Chapter 75

Table 75.1 Relative and absolute risk of Peutz‐Jeghers syndrome associated t...

Table 75.2 Recommended screening for malignancy in patients with Peutz‐Jeghe...

Chapter 76

Table 76.1 Common Von Hippel‐Lindau associated lesions and symptoms.

Chapter 77

Table 77.1 Risk of common cancers in Lynch syndrome compared to the general ...

Chapter 78

Table 78.1 Genetic screening criteria for hereditary diffuse gastric cancer....

Chapter 81

Table 81.1 Main features of the subtypes of multiple endocrine neoplasia and...

Chapter 82

Table 82.1 Syndromic forms of CC and associated systemic disorders.

Chapter 85

Table 85.1 Clinical features of the conditions causing secondary glaucoma....

Chapter 86

Table 86.1 Several conditions have similar clinical features and must be dif...

Chapter 93

Table 93.1 Revised Ghent Criteria (2010) and Loeys et al. (2010).

Chapter 94

Table 94.1 Subtypes of Ehlers‐Danlos syndrome.

Chapter 95

Table 95.1 Features of common underlying syndromes associated with limb abno...

Table 95.2 Features of upper limb abnormalities.

Table 95.3 Features of lower limb abnormalities.

Chapter 98

Table 98.1 Diagnostic criteria for AS: Modified New York classification.

Chapter 99

Table 99.1 Grouping of common skeletal dysplasias by genetic basis.

Table 99.2 Rubin’s classification (based upon anatomical site of abnormalit...

Table 99.3 Features of more common/well‐known dysplasias.

List of Illustrations

Chapter 2

Figure 2.1 Autosomal dominant inheritance.

Figure 2.2 Autosomal recessive inheritance.

Figure 2.3 X‐linked recessive inheritance.

Figure 2.4 X‐linked dominant inheritance.

Chapter 3

Figure 3.1 G‐banding

Figure 3.2 Karyotyping

Figure 3.3 FISH ‐ demonstrating the use of fluorescent probes to highlight s...

Figure 3.4 Comparative genomic hybridisation

Figure 3.5 PCR

Figure 3.6 Southern blot.

Figure 3.7 Northern blot.

Chapter 7

Figure 7.1 The cardiomyocyte – the sarcomere, sarcoplasmic reticulum, nucleu...

Chapter 8

Figure 8.1 Circular Manhattan plot showing loci associated with CAD.

Figure 8.2 Development of atherosclerosis.

Chapter 9

Figure 9.1 Typical ECG appearances of inherited arrhythmia conditions. The b...

Chapter 11

Figure 11.1 Palmar pits.Source: DermNet New Zealand Trust.

Figure 11.2 Multiple BCC.

Figure 11.3 Odontogenic keratocysts.

Figure 11.4 Relative macrocephaly, hypertelorism, ectusexcavatum, kyphoscoli...

Chapter 12

Figure 12.1 Keratotic papules with pigmentation on (a) the neck and (b) armp...

Figure 12.2 Verrucous lesions with keratotic crusts on the leg.

Figure 12.3 Papillomatous and macerated lesion in the groin.

Figure 12.4 Pits and keratotic plugs on the sole.

Figure 12.5 Example of suprabasal cleavage of the epidermis containing acant...

Figure 12.6 Keratotic plug and parakeratotic cells in the horny layer with a...

Chapter 13

Figure 13.1 Thickened brown scaling.

Chapter 15

Figure 15.1 A simplified illustration of enzyme defects and associated porph...

Chapter 16

Figure 16.1 Clinical features.

Chapter 17

Figure 17.1 Alterations affecting different skin layers.

Figure 17.2 Clinical features of different subtypes.

Figure 17.3 Diagnostic algorithm.

Chapter 18

Figure 18.1 Clinical features.

Chapter 19

Figure 19.1 Functional consequences of the Epidermal cholesterol sulphate cy...

Chapter 21

Figure 21.1 Embryology of gonadal development.

Figure 21.2 Overview of sexual/gonadal differentiation.

Chapter 22

Figure 22.1 Pathophysiology of the most common cause of congenital adrenal h...

Chapter 23

Figure 23.1 Pathophysiology of CAIS.

Figure 23.2 Ligand‐gated

activation.

Figure 23.3 Clinical features of CAIS.

Figure 23.4 Clinical features of AIS and subgroups.

Chapter 24

Figure 24.1 Clinical features of Klinefelter syndrome.

Figure 24.2 Chromosome pattern.

Figure 24.3 Karyotype showing an extra X chromosome.

Chapter 25

Figure 25.1 Non‐disjunction during meiosis II, causing Turner syndrome (mono...

Figure 25.2 Clinical features of Turner syndrome.

Figure 25.3 Karyotype of Turner syndrome (45,XO).

Chapter 26

Figure 26.1 β‐cell.

Figure 26.2 Transcription factor network in MODY.

Figure 26.3 Diagnostic algorithm.

Figure 26.4 Stratification between different subtypes of diabetes.

Chapter 27

Figure 27.1 Pathophysiology of diabetes insipidus.

Figure 27.2 Signalling pathway of AQP2 translocation.

Figure 27.3 Water deprivation test.

Chapter 30

Figure 30.1 Methionine metabolic pathway.

Chapter 33

Figure 33.1 Peroxisome biogenesis pathway.

Chapter 36

Figure 36.1 System involvement in Wilson’s disease.

Figure 36.2 Kayser Fleischer rings.

Chapter 37

Figure 37.1 Systemic involvement of HHE.

Chapter 41

Figure 41.1 Global distribution of haemoglobinopathies.

Figure 41.2 Genetics of α‐thalassaemias.

Chapter 42

Figure 42.1 Disorders affecting different components of the immune pathway....

Chapter 43

Figure 43.1 Clinical features.

Chapter 44

Figure 44.1 Disorders of thymic development.

Chapter 46

Figure 46.1 Abnormalities in B‐cell development.

Chapter 47

Figure 47.1 Clinical features of Wiskott‐Aldrich syndrome.

Chapter 48

Figure 48.1 Stages of B cell development.Key: CLP, Common Lymphoid Precursor...

Chapter 49

Figure 49.1 Molecular basis for the shared clinical and immunological phenot...

Chapter 50

Figure 50.1 Diagnosis of chronic mucocutaneous candidiasis.

Figure 50.2 Treatment of chronic mucocutaneous candidiasis.Source: Sampson, ...

Chapter 52

Figure 52.1 Cytotoxic lymphocyte granule‐mediated cytotoxicity pathway.

Chapter 53

Figure 53.1 Mycobacterium Tuberculosis structure.

Chapter 54

Figure 54.1 Phagosome formation and oxidative killing of microbes by phagocy...

Chapter 55

Figure 55.1 Leucocyte migration.

Chapter 56

Figure 56.1 Defects in TLR pathways.

Chapter 57

Figure 57.1 Erysipelas‐like erythema during an attack of FMF.Source: Lachman...

Figure 57.3 Typical rash accompanying an attack of TRAPS.Source: Lachmann (2...

Figure 57.2 Classical diffuse urticarial rash of CAPS.Source: Lachmann (2011...

Chapter 58

Figure 58.1 Complement pathways.

Chapter 59

Figure 59.1 Genetic and cellular defects underlying motor system dysfunction...

Chapter 60

Figure 60.1 Motor neurone degeneration in MND can be brought about by mutant...

Chapter 61

Figure 61.1 Clinical features of Fragile X Syndrome

Chapter 62

Figure 62.1 Gross neuropathological findings in HD. The most striking featur...

Chapter 64

Figure 64.1 Clinical features of Parkinson’s disease.

Chapter 65

Figure 65.1 Clinical features of Myotonic Dystrophy.

Chapter 68

Figure 68.1 Trisomy 18.

Figure 68.2 Physical features of an infant with trisomy 18.

Chapter 69

Figure 69.1 Trisomy 13 (Patau syndrome).

Figure 69.2 Clinical features of Patau syndrome.

Figure 69.3 Infant with Patau syndrome.

Chapter 70

Figure 70.1 Clinical features of Williams syndrome (include broad forehead, ...

Chapter 71

Figure 71.1 Facial features of DiGeorge syndrome (upslanting and narrow palp...

Chapter 72

Figure 72.1 Hallmarks of cancer: Biochemical factors and cell processes that...

Figure 72.2 Cancer is a result of multiple hits in multiple pathways. A sing...

Figure 72.3 Simplified diagram showing the actions of some of the proteins t...

Chapter 73

Figure 73.1 Comparison of features of neurofibromatosis type 1 and type 2.

Figure 73.2 Somatic mosaicism commonly seen in first generation for NF1 and ...

Figure 73.3 Clinical features of Neurofibromatosis type 1.

Figure 73.4 MRI of NF2 patient demonstrating large sellar meningioma.

Chapter 74

Figure 74.1 Risk factors for developing prostate cancer GWAS – Genome‐wide a...

Figure 74.2 Extra‐renal manifestations of heritable conditions associated wi...

Chapter 75

Figure 75.1 Example pedigree diagram showing family with Peutz‐Jeghers syndr...

Figure 75.2 Peri‐oral lentigines.

Figure 75.3 Large pedunculated polyps in patient with Peutz‐Jeghers syndrome...

Figure 75.4 Intussusception shown via barium enema.

Chapter 76

Figure 76.1 Rule of 3 in Von Hippel‐Lindau syndrome.

Chapter 77

Figure 77.1 Proportion of bowel cancer with familial inheritance pattern.

Figure 77.2 Lynch syndrome pedigree with three affected individuals across t...

Figure 77.3 Differences in presentation of left‐ and right‐sided bowel tumou...

Figure 77.4 Multiple polyps seen on endoscopy with FAP.

Figure 77.5 Features of Gardner syndrome.

Figure 77.6 Cancers associated with Lynch syndrome.

Chapter 78

Figure 78.1 Palmoplantar keratoderma (left) and oral leukoplakia (right) see...

Figure 78.2 Example pedigree with an inherited E‐cadherin alteration (

CDH1

)....

Figure 78.3 CT showing hepatocellular carcinoma.

Figure 78.4 Risk factors for hepatocellular carcinoma (HCC).

Figure 78.5 Progression of non‐alcoholic fatty liver disease.

Chapter 79

Figure 79.1 Proportion of breast cancer associated with familial traits.

Figure 79.2 Breast cancer and ovarian cancer risk associated with

BRCA

mutat...

Figure 79.3 Pedigree showing

high‐risk

breast cancer (Three diagnoses ...

Figure 79.4 Pedigree showing

moderate‐risk

family history of breast ca...

Figure 79.5

BRCA1

and

maintain the genomic stability by facilitating doubl...

Figure 79.6 Outcomes of double strand break.

Figure 79.7 Cancers most commonly associated with Li‐Fraumeni syndrome.

Figure 79.8 Approach to genetic diagnosis and management in breast cancer.

Chapter 80

Figure 80.1

Two hit hypothesis;

two mutations are required for loss of gene ...

Figure 80.2 Role of the retinoblastoma (Rb) protein in cell cycle; The Rb pr...

Figure 80.3 Fundoscopic images of retinoblastoma.

Figure 80.4 Signs of retinoblastoma.

Figure 80.5 Common cancers associated with

RB1

gene alteration.

Figure 80.6 Process of pre‐implantation genetic diagnosis (PGD).

Chapter 81

Figure 81.1 Endocrine glands commonly affected by MEN.

Figure 81.2 Example pedigree diagram showing various presentations of

multip

...

Figure 81.3 Genetic conditions associated with phaeochromocytoma.

Chapter 82

Figure 82.1 Paediatric cataract.

Chapter 83

Figure 83.1 Ishihara chart for colour blindness testing.

Figure 83.2 Colour range variations between different pathologies.

Chapter 84

Figure 84.1 Appearance of a normal eye and an eye affected by RP.

Chapter 86

Figure 86.1 Clinical features of Bardet-Biedl syndrome.

Chapter 87

Figure 87.1 Clinical features of (a) ARPKD and (b) ADPKD.

Chapter 88

Figure 88.1 Pathophysiology of NPHP.

Figure 88.2 Features and investigation of the different forms of NPHP.

Chapter 90

Figure 90.1 Pathophysiology of Alport syndrome.

Chapter 91

Figure 91.1 Clinical features of cystinosis.

Chapter 92

Figure 92.1 Pathophysiology of cystinuria.

Chapter 93

Figure 93.1 Clinical signs associated with Marfan syndrome.

Chapter 94

Figure 94.1 Beighton score (out of 9).

Chapter 95

Figure 95.1 Examples of congenital abnormalities.

Chapter 96

Figure 96.1 Inheritance pattern of DMD.

Figure 96.2 X‐chromosome and location of affected genes.

Figure 96.3 Function of dystrophin.

Figure 96.4 Gowers sign.

Chapter 97

Figure 97.1 Classic clinical features: inverted champagne bottle legs (a, b)...

Chapter 98

Figure 98.1 Possible contributions to spondyloarthritis (SpA) pathogenesis....

Figure 98.2 Clinical posture and spinal features of AS.

Guide

Cover Page

Title Page

Dedication

Contributors

Foreword

Preface

Table of Contents

Begin Reading

Glossary

Index

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Clinical Genetics and Genomics at a Glance

Edited by

Neeta Lakhani

MBChB, BSc, MSc, MSt (Genomic Medicine), PG Cert, MRCPCH, Certificate in Medical GeneticsSpecialty Registrar in Clinical GeneticsDepartment of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester, UK

Kunal Kulkarni

BMBCh, MA (Oxon), MSc, FRCS (Tr&Orth), FEBHS, Dip Hand Surg (Br)Consultant Trauma & Orthopaedic SurgeonDepartment of Trauma & Orthopaedics, University Hospitals of Leicester NHS Trust, Leicester, UK

Julian Barwell

BSc, MBBS, PhD, FRCP (UK), AFHEAConsultant in Clinical Genetics and Honorary Professor in Genomic MedicineDepartment of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester, UK

Pradeep Vasudevan

MBBS, FRCP, MRCPCH, DCH (London), MSc (Genomic Medicine)Consultant in Clinical Genetics and Honorary ProfessorDepartment of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester, UK

Huw Dorkins

MA, MSc, MSt, FRCP, FRCPath, FHEA, FAcadMEdFellow and Senior Tutor in MedicineSt Peter’s College, University of Oxford, Oxford, UK

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The right of Neeta Lakhani, Kunal Kulkarni, Julian Barwell, Pradeep Vasudevan, and Huw Dorkins to be identified as the authors of the editorial material in this work has been asserted in accordance with law.

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Library of Congress Cataloging‐in‐Publication DataNames: Lakhani, Neeta, editor. | Kulkarni, Kunal, editor. | Barwell, Julian, editor. | Vasudevan, Pradeep, editor. | Dorkins, Huw, editor.Title: Clinical genetics and genomics at a glance / edited by Neeta Lakhani, Kunal Kulkarni, Julian Barwell, Pradeep Vasudevan, Huw Dorkins.Other titles: At a glance series (Oxford, England)Description: First edition. | Hoboken, NJ : Wiley‐Blackwell, 2024. | Series: At a glance series | Includes bibliographical references and index.Identifiers: LCCN 2023012124 (print) | LCCN 2023012125 (ebook) | ISBN 9781119240952 (paperback) | ISBN 9781119241034 (adobe pdf) | ISBN 9781119241027 (epub)Subjects: MESH: Genetics, Medical–methods | Genomic Medicine–methods | HandbookClassification: LCC RB155 (print) | LCC RB155 (ebook) | NLM QZ 39 | DDC 616/.042–dc23/eng/20230505LC record available at https://lccn.loc.gov/2023012124LC ebook record available at https://lccn.loc.gov/2023012125

Dedication

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Contributors

Rebecca Allchin Department of Haematology, University Hospitals of Leicester NHS Trust, Leicester, UK

Aqua Asif Division of Surgery and Interventional Science, University College London, London, UK

Ashanti Sham Balakrishnan Department of Paediatrics & Neonatology, University Hospitals of Leicester NHS Trust, Leicester, UK

Micheal Browning Department of Immunology, University Hospitals of Leicester NHS Trust, Leicester, UK

Scott Castell Department of Emergency Medicine, Kettering General Hospital NHS Foundation Trust, Kettering, UK and Pre‐hospital Emergency Medicine, The Air Ambulance Service, Northamptonshire, UK

Gemma Chandratillake East Genomic Laboratory Hub, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK

Emily Craft Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester, UK

Maurice Dungey Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester, UKCollege of Life Sciences, University of Leicester, Leicester, UK

Meghana Kulkarni Department of Urology, St George’s University Hospitals NHS Foundation Trust, London, UK, Clinical Research Fellow ‐ King's College London, London, UK

Gail Maconachie Division of Ophthalmology & Orthoptics, Health Sciences School, The University of Sheffield, Sheffield, UK

Karthick Manoharan Department of Cardiology, University Hospitals of Sussex NHS Trust, Brighton, UK

Titiksha Masand Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester, UK

Jessica Myring Department of Clinical Genetics, University Hospitals of Leicester NHS Trust, Leicester, UK

Julian Omerod Oxford Heart Centre, John Radcliffe Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK

Manisha Panchal Department of Dermatology, University Hospitals of Leicester NHS Trust, Leicester, UK

Adithri Pradeep University of Sheffield Medical School, Sheffield, UK

Arthur Price Department of Immunology, University Hospitals of Leicester NHS Trust, Leicester, UK

Ataf Sabir Department of Clinical Genetics, Birmingham Women’s and Children’s NHS Foundation Trust and University of Birmingham, Birmingham, UK

Mervyn Thomas Ulverscroft Eye Unit, College of Life Sciences, University of Leicester, Leicester, UK

Zoe Venables Dermatology Department, Norfolk and Norwich University Hospital, Norwich, UK

Simon Wagner Department of Haematology, University Hospitals of Leicester NHS Trust, Leicester, UK

Foreword

Genetics is coming in from the cold!

40 years ago, geneticists were specialists in a minority discipline, mainly involved in genetic diagnosis, testing, and counselling for relatively rare single gene or chromosomal disorders. Over recent years, we have become increasingly aware that there is a genetic component to all diseases, varying from a minor susceptibility to a very major component. Many diseases are multifactorial, with a variable genetic component. Genetic factors are involved in many aspects of disease susceptibility, including our ability to resist infections, and our susceptibility to certain cancers, so an understanding of genetics has become a necessary part of all aspects of medicine. This means that clinicians of all specialities need to know about inheritance and have a good working knowledge of the conditions in their specialty with a strong genetic component to their aetiology. A knowledge of the genetic aetiology of diseases can no longer be considered the sole domain of the geneticist but should be understood by all clinicians.

This novel book addresses this, by providing easily understood information about single gene disorders with the aim of empowering clinicians from all disciplines to understand and manage genetic disease and appreciate the impact of genomic medicine on clinical practice. The range of this book is wide, encompassing both, the more general specialities, and numerous subspecialties. Each topic is illustrated with key facts alongside informative and helpful diagrams for quick reference. It is an important and accessible reference for clinicians at all levels.

Professor Shirley Hodgson

Preface

Welcome to Clinical Genetics and Genomics at a Glance!

This novel textbook provides concise and accessible information that will be useful to clinicians managing patients with potentially inherited disease with a Mendelian component, within a framework that incorporates the wider psychosocial experience of the individual and their concerns, and which may include reproductive advice or cascading of risk information to relatives.

This is particularly important as molecular testing through targeted tests, gene panels, or whole genome sequencing becomes more widely available through standardised care pathways. More extensive genetic testing increases the likelihood that gene variants of uncertain clinical significance or incidental genetic findings will be identified. For this reason, thorough pre‐test consent and careful variant interpretation processes are key.

Within these pages we aim to summarise a range of common presentations and challenges patients face, arranged by different body systems, providing a succinct and digestible introduction to clinical management. We have consciously employed language that is used with patients in everyday practice, for example the term gene or chromosome alteration, rather than mutation, given the potentially negative connotations of the latter.

This book has been a labour of love of many different healthcare professionals from clinical genetics and beyond. We are indebted to numerous other specialists – including (but not limited to!) the orthopaedic surgeons, ophthalmologists, paediatricians, obstetricians, immunologists, dermatologists, cardiologists, neurologists, nephrologists, urologists, endocrinologists, gastroenterologists, and haematologists – who have all kindly contributed. This demonstrates the breadth of the coalition of clinicians establishing a genomic medicine‐empowered service throughout the United Kingdom.

As genetics becomes increasingly embedded in the various clinical subspecialties, and as medical decision making becomes more dependent on integrated data science and computer‐generated risk calculations, we hope that this book will provide a useful introduction to genetic aspects of individualised patient care. We trust that you find this book of value, and we would welcome your feedback to help shape future editions.

Neeta Lakhani, Kunal Kulkarni, Julian Barwell, Pradeep Vasudevan, and Huw Dorkins

Part 1Introduction

Chapters

What is clinical genetics and genomic medicine?

Inheritance

Cytogenetics and molecular genetic techniques

How to read a genetic test report

Genetic and genomic counselling

1What is clinical genetics and genomic medicine?

What is clinical genetics?

Clinical Genetics involves the identification of individuals with, or at risk of, single gene inherited traits that could impact their health, alongside that of their relatives. Clinical geneticists are clinical doctors who diagnose and manage families with genetic disorders.

Their role encompasses coordinating the overall care of patients with rare disorders, diagnostics/genetic testing, and counselling regarding risk assessment (for example, with future pregnancies and for other potentially affected family members).

Geneticists work closely with their laboratory‐based colleagues and genetic counsellors to perform and interpret the wealth of evolving molecular diagnostic tests in the clinical context.

Examples of conditions managed by clinical geneticists include:

Chromosomal abnormalities

Congenital (birth) defects with an underlying genetic basis

Single gene disorders (for example, cystic fibrosis, muscular dystrophy, and Huntington's disease)

Familial cancer and cancer‐risk syndromes (for example, inherited breast or colorectal cancers; neurofibromatosis)

Other inherited conditions that cause morbidity/mortality (for example, cardiac conditions at risk of causing sudden cardiac death)

Developmental delay or learning difficulties in children (with other associated features suggestive of an underlying genetic aetiology)

How does clinical genetic testing help clinical care?

Clinical genetics is underpinned by making a correct clinical and molecular diagnosis. Rare diseases with Mendelian (single disease) traits affect 1 in 17 of the population, and 1/2 of the population are likely to develop cancer at some point in their lifetime caused by acquired pathogenic variants deregulating cell growth, differentiation, and cell death.

A highly suggestive medical diagnosis can be made by bringing together a series of symptoms and signs within either an individual patient, or by combining information from several relatives. For example, this could include linking bilateral vestibular schwannomas and a meningioma in a patient under 40 years of age with a diagnosis of neurofibromatosis type 2, or considering a pituitary adenoma with concurrent hyperparathyroidism in a proband with a story of her mother having had kidney stones and a pancreatic tumour being highly suggestive of Multiple Endocrine Neoplasia type 1. Genetic testing can then be used to either confirm this medical diagnosis or assist with family planning in the future. As testing costs fall and genetic and genomic testing becomes more readily accessible, molecular tests are increasingly being used to either make or further inform the suspected medical diagnosis. Improving the ability of clinicians to make a correct diagnosis leads to a better understanding of the natural history of the condition, thereby providing scope for potential interventions to reduce the burden of disease at an earlier stage.

Having the correct molecular diagnosis allows us to compare the patient to others in the medical literature to determine the inheritance pattern of the condition. When extensive case series have been studied, the penetrance of the condition can also be estimated. Note that this is not always assessed from probands (the first affected patient in the family that presents clinically), as sometimes these patients, by definition, tend to be more severely affected to be offered a test and hence may produce biased results when calculating future risk for relatives.

Pedigrees

Identifying familial risk is carried out by drawing a family tree (pedigree), which shows who is present in the family and their basic demographics in a pictorial form. Men are generally placed on the left and depicted as squares and women as circles. The consultant (the person seeking medical advice) has an arrow pointing towards the symbol and the symbol is shaded to represent if a patient is affected.

Apart from ascertaining who is at risk, the pedigree might indicate an inheritance pattern. As clinical geneticists work with family files, care must be taken in showing individuals the data collected from other relatives (such as including medical and molecular information on pedigrees) if consent has not been obtained to share.

Variant interpretation and the role of the clinical geneticist

Variant interpretation is an increasingly important component of a clinical geneticist’s role, particularly as genetic testing and genomic sequencing becomes more widespread and it becomes clear that we all have multiple subtle variants that may impact on risk. This requires significant resource due to the sheer size of the human genome. Molecular biology expertise and framing within a clinical context is crucial in being able to explain risk effectively to patients, and this is an area where general physicians often struggle.

Classically, clinical geneticists have been highly effective in bringing together cohorts of patients for either research, governance, or shared experience. This has helped our understanding of the natural history of disorders and improved our ability to improve outcomes through large clinical research networks and patient support groups. Improved digital connectivity is making this more straightforward and effective.

Developing and championing a molecular culture within the wider NHS and public health is a key leadership role for geneticists. There are several competing acute medical and social care strains on our economy, and genetics has a potential role in improving some of this burden through targeted screening and prevention strategies, personalised medicine, and links to digital health. This involves education and training around molecular biology, innovation, and being early adopters of initiatives such as gene panels, genomic testing, and precision medicine. As artificial intelligence leads to improved integrated molecular, clinical, and social data sets, our ability to predict, prevent, and treat disease will improve. Clinical genetics therefore has a major role in Public Health, assisting with variant data collection and integrating this with health outcomes, as we generate an equation for life and well‐being.

What is the impact of genetics on insurance and migration?

These are common areas of concern for patients undergoing diagnostic or predictive testing. Health insurance coverage can be a significant concern, particularly in countries with primarily private medical cover‐based systems. Patients are therefore advised to investigate any specific policy exclusions, especially if planning to live or spend considerable periods of time overseas. Fortunately in the United Kingdom, this issue does not impact receipt of NHS care.

Unselected population‐based genetic testing in the private sector for well individuals can create funding and capacity challenges, for example, when it comes to confirming any significant findings in a NHS accredited laboratory, which is required to act on any findings and arrange either screening or preventative measures.

Insurance companies in the United Kingdom are currently able to ask about family history or on‐going investigations and screening. They can also currently ask about large amounts of cover for patients at risk of Huntington's (an autosomal dominant inherited condition with high penetrance), but not regarding other conditions. This is regularly reviewed with government oversight. The results from the 100 000‐genome project are also exempt (but not any downstreamed medical investigations). It is currently unclear as to whether this advice is likely to change. Given the potential for genetics to target screening and healthcare to those most likely to benefit, it is hoped that policies would seek to maintain the current position with insurance companies to not impact the benefits of appropriate genetic screening on patient care.

What is genomic medicine?

There is no single agreed term that encompasses Genomic Medicine, but it can be broadly classified into three areas: personalised medicine, holistic and integrated care modelling, and integrated data science for the wider population. Each of these complement Clinical Genetics and whole genome sequencing to improve future health and disease modelling.

In personalised medicine, additional nucleic acid‐derived data from the closer analysis of a broader spectrum of genes, intronic coding regions, or single nucleotide polymorphisms are used in conjunction with tumour or microbial genetics and circulating biomarkers to try and personalise care. This includes tumour‐specific therapies, pharmacokinetics, detection of potential antimicrobial resistance, and identification and monitoring of infectious agent outbreaks.

In integrated and holistic care modelling, the aim is to work with patients and patient stakeholder groups to develop and design equitable access to patient‐centred healthcare, building on patient involvement and empowerment to make informed decisions about their screening, management, and treatment in partnership with their doctors. This may involve the use of electronic care plans with access to additional support and red flag escalation alert systems for potential predictable complications and educational resources for clinicians and patients.

The use of patient‐centred and controlled electronic records provides opportunities to link health records to outcomes for artificial intelligence‐based solutions. These models will be simple to start with, but in time, uploading data (such as our postcode, wearable technology‐derived data, social media entries, supermarket store card and online purchase history, mental health questionnaires, alongside pathology, radiology, and genomic results) could provide a more accurate assessment of our health and well‐being.

Genomic medicine involves integrating the results of nucleic acid‐derived testing from blood and other biologically derived tissues with clinical and potentially social data. This aims to help predict future health outcomes more accurately via either the development of personalised treatments (intervention type and preferred dose of therapeutic agent if required) or through the design of more individualised and cost‐effective screening programmes. These aim to treat disease for what it is rather than what it looks like, by planning screening based on calculated risk and not age, alongside smart prescribing to treat the right patient with the right drug at the right dose, first time, every time.

What does genomic medicine encompass?

Genomic medicine includes six areas beyond the analysis of the coding sequences of genes responsible for Mendelian traits (i.e. classical human genetics):

The role of single nucleotide polymorphisms (SNPs) in non‐coding regions and epigenetic traits. Large genome wide association studies (GWAS) have identified many variants that are commonly found in the general population that are associated with risk. It is sometimes unclear if these have a cumulative effect when coupled with other variants or how they alter risk (through either altering gene expression from a distance), particularly when common in a population and inherited in close proximity (linked) to a true disease‐causing variant that is yet to be identified (variant in linkage disequilibrium with the disease‐causing variant).

Pharmacogenetics involves predicting the way that drugs are metabolised (and therefore the risk of side effects or lack of effectiveness) by identifying key variants in genes coding the relevant enzymes involved in their breakdown.

Testing other microorganisms can be helpful in identifying pathogens and predicting antibiotic or antiviral treatment resistance, as well as providing information about bacteria in the gut flora (microbiome) that is important for digestion. This could, for example, help possibly link food intake with the risk of obesity.

Testing other tissues for somatic mutations in either DNA or RNA can be particularly useful to identify circulating free DNA (cfDNA) released from tumours and predict either response to treatment or likelihood of relapse.

The use of other data sets, such as electronic patient records with linked radiology and pathology results, biometric data from smart handheld devices (e.g. fitbits) and background social data such as occupation, educational background, post code, supermarket store card/online purchases, and even social media interests, has the potential to be integrated with genomic results. Linking these large applied data sets to long‐term health outcomes with machine learning algorithms will provide the opportunity to generate better predictors for disease and health and social well‐being, thereby improving future health predictions.

Studying how gene expression can be altered by non‐sequence variant changes, such as epigenetic changes in methylation patterns of promoters or DNA folding around modified histones, reducing planned transcription.

In a way, Clinical Genetics helps explain where – from an evolutionary perspective – we have come from and may possibly describe why we become unwell. Genomic Medicine tries to understand the more complex aspects of disease within an individual's broader genetic and environmental landscape, to make better future predictions about specific interventions.

2Inheritance

Inheritance of characteristics and disorders may be chromosomal (due to aneuploidies, for example in Down syndrome), single‐gene (also called Mendelian, named after Gregor Mendel), or multifactorial (multiple genes and environmental factors playing a role). In this chapter, we will consider the most common patterns of single‐gene inheritances, with some examples of disorders more commonly encountered in clinical practice.

A gene located on chromosomes 1–22 is termed an autosomal gene; one on a sex chromosome (X or Y) is termed a X‐ or Y‐linked gene, respectively. It is important to note that a particular condition is not dominant or recessive in itself, rather its inheritance is what may exhibit one of these Mendelian patterns.

Autosomal dominant (AD)

In autosomal dominant (AD) inheritance, only one copy of the pathogenic allele (alternate form of the same gene) needs to be inherited to cause the disorder (i.e. from a heterozygous parent).

The altered copy of the gene (‘pathogenic’ or ‘mutant’ allele) is dominant over the normal or ‘wild‐type’ allele, causing the condition. When an affected individual has children (assuming the other parent is not affected), there is a 1 in 2 (i.e. 50%) chance that each child (son or daughter equally at risk in each pregnancy) will inherit the pathogenic gene alteration and therefore be affected with the condition (or unaffected if the child inherits the normal or wild‐type allele) (Figure 2.1).

Examples of conditions with AD inheritance:

Achondroplasia

Autosomal dominant polycystic kidney disease

Hereditary breast and bowel cancer

Huntington’s disease

Hypertrophic cardiomyopathy

Marfan syndrome

Myotonic dystrophy

Neurofibromatosis type 1 and 2

Osteogenesis imperfecta

Retinoblastoma

Figure 2.1 Autosomal dominant inheritance.

Variable expression and penetrance

These are features of this pattern of inheritance. Expression refers to the degree of severity of the disease, which may vary from individual to individual within the same family (e.g. in Neurofibromatosis type 1, there is variable expressivity between and within families).

Penetrance refers to the proportion of individuals expressing the condition to any degree (for e.g. Huntington disease, where there is age‐dependent penetrance).

Anticipation

This refers to an increasing severity of the condition and earlier age of onset in successive generations. This occurs due to the expansion of tri‐nucleotide repeat alterations (like ‘CAG repeats’ in Huntington disease or ‘CTG repeats’ in Myotonic dystrophy). Anticipation may also occur in conditions that follow X‐linked inheritance, such as Fragile‐X‐syndrome (‘CGG repeats’).

Germline or gonadal mosaicism

This is when a new pathogenic gene alteration arises in some cells in the gonads (testis or ovary) and may not cause any phenotype in the parent, but can be passed on to their offspring.

Autosomal recessive (AR)

Autosomal recessive (AR) inheritance occurs when two copies of the defective gene are required for an individual to inherit a particular disease (i.e. the parent is homozygous or compound‐heterozygous). Individuals that only have one copy of this allele are known as carriers. If both the parents are carriers of this ‘abnormal’ gene, the probability of the child being affected is 25% or a 1 in 4 chance.

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