New Clinical Genetics: A Guide to Genomic Medicine

Citation

Read, A., & Donnai, D. (2020). New Clinical Genetics: A Guide to Genomic Medicine (4th ed.). Scion Publishing.

Chapter Summary

The fourth edition has 468 pages and fourteen printed chapters, plus a fifteenth chapter that is available free online. Each chapter is framed as a question a student might ask, and all but the last follow the same pattern, set out in the book's "How to use this book" section: learning points; case studies of fictional families (based, the authors say, on their long experience of real ones); a "Science toolkit" with the methods and concepts needed; "Investigations of patients", in which the cases are taken forward; "Going deeper", which extends the science; a disease box; references and useful websites; and self-assessment questions, for which the book gives hints rather than answers. Twenty-six family cases run through the book, and the margin of each case gives the pages on which its story continues: the Ashton family, for example, reappears in Chapters 3, 4, 6 and 14.

Chapter 1: What can we learn from a family history?

Six families open the book. The science sections show how to take a family history and draw a pedigree, summarise the modes of monogenic inheritance and explain penetrance, expressivity, rarer modes of inheritance and mosaicism. The disease box is type 1 neurofibromatosis.

Chapter 2: How can a patient's chromosomes be studied?

How chromosomes are studied, the nomenclature of abnormalities, numerical syndromes, recurrent microdeletions and chromosome behaviour in cell division. Going deeper covers copy number variants, balanced and unbalanced, constitutional and mosaic abnormalities; the disease box is Williams–Beuren syndrome.

Chapter 3: How do genes work?

The molecular basics: nucleic acids, exons and introns, splicing, translation and the genetic code, with collagen biosynthesis as a worked example. The deeper section covers transcriptional control, the human genome, non-coding DNA and how to use the Ensembl genome browser; the disease box is the RASopathies.

Chapter 4: How can a patient's DNA be studied?

Hybridization-based testing (Southern blotting, restriction enzymes, gel electrophoresis) and the polymerase chain reaction, each applied to cases. Quantitative PCR, chromosome painting and RNA and protein testing follow, with a disease box on expanding nucleotide repeats.

Chapter 5: How can we check a patient's DNA for gene mutations?

Methods for detecting a specific change and for scanning a gene, Sanger sequencing and next-generation sequencing, and the nomenclature of variants. The learning points include reading a straightforward Sanger trace and knowing when to test for a single change, a gene, a panel, an exome or a genome. The disease box is sudden arrhythmic death syndrome.

Chapter 6: What do mutations do?

Types of variants, from whole-gene deletions to splicing and translation errors, then loss and gain of function, dominance and recessiveness, genotype–phenotype correlations (with the FGFR genes as an example) and how mutations arise. Mosaicism is the disease box.

Chapter 7: Is cancer genetic?

Moved forward in this edition, the preface explains, so that it directly follows the introduction of loss and gain of function. It covers cancer as somatic evolution, oncogenes and tumour suppressor genes, mismatch repair and the multistage development of cancer, then BRCA1/2 risk assessment, liquid biopsies, multi-omics and genomics-based tumour classification. The disease box is chronic myeloid leukaemia.

Chapter 8: How do researchers identify genes for mendelian diseases?

Routes to a disease gene, from gene products and chromosomal abnormalities to positional cloning, autozygosity mapping and exome or genome sequencing, and how to show that a variant causes a phenotype. The disease box describes the Deciphering Developmental Disorders study.

Chapter 9: Why are some conditions common and others rare?

Population genetics for the clinic: Hardy–Weinberg and carrier risks, heterozygote advantage and founder effects, consanguinity, and whether genetic disease can be abolished.

Chapter 10: How do our genes affect our metabolism, drug responses and immune system?

Inborn errors of metabolism, pharmacogenetics and immunogenetics side by side; the disease box covers disorders of the spliceosome.

Chapter 11: How are genes regulated?

Epigenetics: X-inactivation, imprinting, DNA methylation, histone modifications and chromatin conformation, ending with how far epigenetic effects explain individual differences and a disease box on chromatin diseases.

Chapter 12: When is screening useful?

Screening versus diagnostic tests, when, whom and how to screen, antenatal screening for trisomies, the criteria of the UK National Screening Committee, incidental findings, "lifestyle" genetic testing and non-invasive prenatal testing.

Chapter 13: Should we be testing for genetic susceptibility to common diseases?

Heritability, linkage versus association, genome-wide association studies, effect sizes and ROC curves, then why GWAS have yielded little clinically useful information, missing heritability and polygenic risk scores. Autism spectrum disorders form the disease box.

Chapter 14: What clinical services are available for families with genetic disorders?

The only chapter without opening cases, and much expanded in this edition. It covers reasons for referral, diagnosis and dysmorphology, predictive and prenatal testing, preimplantation diagnosis, counselling and Bayesian risk estimation, management and treatment (gene therapy, spinal muscular atrophy, cancer immunotherapy), the outcomes for all twenty-six cases, and the changing role of genetics services.

Chapter 15: How to use linkage to map a disease gene

An online-only chapter: the preface explains that linkage analysis, now largely replaced by sequencing, was moved online to keep the printed book the same length.

Key Concepts

Chapters 1–3: Inheritance, chromosomes and genes

• Penetrance and expressivity: whether, and how strongly, a genotype shows itself, two of the main pitfalls in reading pedigrees.
• Copy number variants: deletions and duplications of DNA segments, behind recurrent microdeletion syndromes.

Chapters 4–6: Testing DNA and interpreting variants

• PCR and hybridization: the two basic ways of examining a chosen stretch of a patient's DNA.
• Next-generation sequencing: massively parallel sequencing that makes panel, exome and genome tests routine.
• Loss versus gain of function: the distinction that explains dominant and recessive effects of mutations.

Chapters 7–11: Cancer, gene discovery, populations, metabolism and regulation

• Oncogenes and tumour suppressor genes: genes whose activation or loss drives the multistage development of cancer.
• Hardy–Weinberg distribution: the link between allele frequencies and carrier risks.
• Pharmacogenetics: inherited differences in drug response.
• Imprinting: parent-of-origin-specific gene expression.

Chapters 12–15: Screening, common disease and services

• Screening versus diagnosis: tests that identify people at higher risk, as distinct from tests that establish a diagnosis.
• Polygenic risk scores: combined effects of many common variants, now starting to become clinical tools.
• Bayesian risk calculation: revising genetic risk in the light of additional information.

Critical Analysis

Strengths

• Cases that run through the book. The same families reappear as new methods are introduced, so a student follows each diagnosis from family history to chromosomes, DNA tests and management in Chapter 14.
• Two routes through each chapter. The authors suggest a problem-based route (cases and investigations, with the science as reference) or a more didactic route (Science toolkit and Going deeper).
• Learning points tied to curricula. The learning points are chosen to cover the American Society of Human Genetics curriculum and the competencies of the UK NHS Genetics Education Centre.
• Updated for genomic medicine. The fourth edition adds polygenic risk scores, non-invasive prenatal testing, companion diagnostics, liquid biopsies, preimplantation diagnosis and routine next-generation and exome sequencing, and greatly expands the chapter on services.
• Questions that require thinking. The self-assessment questions come with hints, not answers, by design.

Limitations

• Not a catalogue of disorders. The authors state that the book is not a diagnostic manual and does not attempt to describe all the major mendelian and chromosomal disorders; readers are directed to OMIM for specific conditions.
• Hints, not answers. Students who study alone may find the lack of worked answers frustrating; a reader review quoted by the publisher makes the same point.
• Linkage moved online. Readers who need linkage analysis for a course must use the online chapter.
• UK framing in places. Screening criteria follow the UK National Screening Committee and services are described from British practice, so readers elsewhere should check local arrangements.

Where It Fits in the Course

This is one of two short entry points to the medical genetics course, and the one that teaches principles. Clinical Genetics and Genomics at a Glance is the other: a system-by-system reference of short illustrated chapters on individual conditions, with a brief introduction to inheritance, testing and counselling. Read and Donnai is the better first book, since it builds understanding through cases; the At a Glance volume is a lookup aid for conditions met on placements.

Emery's Elements of Medical Genetics and Genomics and Thompson & Thompson Genetics and Genomics in Medicine are fuller textbooks covering similar principles at greater length. Harper's Practical Genetic Counselling extends Chapter 14's material on risk estimation and counselling, and Strachan and Read's Human Molecular Genetics is the advanced treatment of the molecular science in Chapters 3–8 and 11.

How to Use This Book

Scion presents the book as a textbook for medical students and a guide for genetic counsellors, physician assistants, clinical and nurse geneticists and students on allied health courses. Basic cell biology helps, but Chapter 3 covers how genes work from the beginning.

A practical plan:

• Read Chapters 1–6 in order. They build the toolkit on which the rest depends: pedigrees, chromosomes, gene structure, DNA testing, sequencing and the effects of mutations.
• Choose a route. For problem-based learning, follow a case through its margin page references; for a lecture course, read the Science toolkit and Going deeper sections and use the cases as examples.
• Then select by topic. Chapter 7 for cancer genetics, Chapters 9 and 12 for population genetics and screening, Chapter 10 for pharmacogenetics, Chapters 11 and 13 for epigenetics and common disease. Chapter 8 and the online Chapter 15 suit students interested in research.
• Finish with Chapter 14, which draws all twenty-six cases together.
• Use the questions and OMIM. Attempt the self-assessment questions before reading the hints, and look up the OMIM numbers given for each condition.