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C H A P T E R 1 Introduction

THE BIRTH AND DEVELOPMENT OFGENETICS AND GENOMICS

Few areas of science and medicine are seeing advancesat the pace we are experiencing in the related elds ofgenetics and genomics. It may appear surprising tomany students today, then, to learn that an appreciationof the role of genetics in medicine dates back well overa century, to the recognition by the British physician

Archibald Garrod and others that Mendel’s laws ofinheritance could explain the recurrence of certain clini-cal disorders in families. During the ensuing years, withdevelopments in cellular and molecular biology, the eldof medical genetics grew from a small clinical subspe-cialty concerned with a few rare hereditary disorders toa recognized medical specialty whose concepts andapproaches are important components of the diagnosisand management of many disorders, both common andrare.

At the beginning of the 21st century, the HumanGenome Project provided a virtually complete sequenceof human DNA—our genome (the sufx -ome coming

from the Greek for “all” or “complete”)—which nowserves as the foundation of efforts to catalogue allhuman genes, understand their structure and regulation,determine the extent of variation in these genes in dif-ferent populations, and uncover how genetic variationcontributes to disease. The human genome of any indi-vidual can now be studied in its entirety, rather than onegene at a time. These developments are making possiblethe eld of genomic medicine , which seeks to apply alarge-scale analysis of the human genome and its prod-ucts, including the control of gene expression, humangene variation, and interactions between genes and theenvironment, to medical care.

GENETICS AND GENOMICS IN MEDICINE

The Practice of Genetics

The medical geneticist is usually a physician who worksas part of a team of health care providers, includingmany other physicians, nurses, and genetic counselors,to evaluate patients for possible hereditary diseases.They characterize the patient’s illness through carefulhistory taking and physical examination, assess possiblemodes of inheritance, arrange for diagnostic testing,

develop treatment and surveillance plans, and partici-pate in outreach to other family members at risk for thedisorder.

However, genetic principles and approaches are notrestricted to any one medical specialty or subspecialty;they permeate many, and perhaps all, areas of medicine.Here are just a few examples of how genetics andgenomics are applied to medicine today:• A pediatrician evaluates a child with multiple con-

genital malformations and orders a high-resolutiongenomic test for submicroscopic chromosomal dele-tions or duplications that are below the level of reso-lution of routine chromosome analysis (Case 32) .

• A genetic counselor specializing in hereditary breastcancer offers education, testing, interpretation, andsupport to a young woman with a family history ofhereditary breast and ovarian cancer (Case 7) .

• An obstetrician sends a chorionic villus sample takenfrom a 38-year-old pregnant woman to a cytogenet-ics laboratory for conrmation of abnormalities inthe number or structure of the fetal chromosomes,following a positive screening result from a non-

invasive prenatal blood test (see Chapter 17).• A hematologist combines family and medical history

with gene testing of a young adult with deep venousthrombosis to assess the benets and risks of initiat-ing and maintaining anticoagulant therapy (Case 46) .

• A surgeon uses gene expression array analysis of alung tumor sample to determine prognosis and toguide therapeutic decision making (see Chapter 15).

• A pediatric oncologist tests her patients for genetic varia-tions that can predict a good response or an adversereaction to a chemotherapeutic agent (Case 45) .

• A neurologist and genetic counselor provide APOE gene testing for Alzheimer disease susceptibility for awoman with a strong family history of the diseaseso she can make appropriate long-term nancialplans (Case 4) .

• A forensic pathologist uses databases of genetic poly-morphisms in his analysis of DNA samples obtainedfrom victims’ personal items and surviving relativesto identify remains from an airline crash.

• A gastroenterologist orders genome sequence analysisfor a child with a multiyear history of life-threateningand intractable inammatory bowel disease. Sequenc-ing reveals a mutation in a previously unsuspected

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2 THOMPSON & THOMPSON GENETICS IN MEDICINE

1000 individuals but is usually much less. Althoughindividually rare, single-gene disorders as a group areresponsible for a signicant proportion of disease anddeath. Overall, the incidence of serious single-gene dis-orders in the pediatric population has been estimated tobe approximately 1 per 300 liveborn infants; over anentire lifetime, the prevalence of single-gene disorders is1 in 50. These disorders are discussed in Chapter 7.

Multifactorial disease with complex inheritance describes the majority of diseases in which there is agenetic contribution, as evidenced by increased risk fordisease (compared to the general public) in identicaltwins or close relatives of affected individuals, and yetthe family history does not t the inheritance patternsseen typically in single-gene defects. Multifactorial dis-eases include congenital malformations such asHirschsprung disease (Case 22) , cleft lip and palate, andcongenital heart defects, as well as many common dis-orders of adult life, such as Alzheimer disease (Case 4) ,diabetes, and coronary artery disease. There appears to

be no single error in the genetic information in many ofthese conditions. Rather, the disease is the result of thecombined impact of variant forms of many differentgenes; each variant may cause, protect from, or predis-pose to a serious defect, often in concert with or trig-gered by environmental factors. Estimates of the impactof multifactorial disease range from 5% in the pediatricpopulation to more than 60% in the entire population.These disorders are the subject of Chapter 8.

ONWARDDuring the 50-year professional life of today’s profes-

sional and graduate students, extensive changes arelikely to take place in the discovery, development, anduse of genetic and genomic knowledge and tools inmedicine. Judging from the quickening pace of discov-ery within only the past decade, it is virtually certainthat we are just at the beginning of a revolution in inte-grating knowledge of genetics and the genome intopublic health and the practice of medicine. An introduc-tion to the language and concepts of human and medicalgenetics and an appreciation of the genetic and genomicperspective on health and disease will form a frameworkfor lifelong learning that is part of every health profes-sional’s career.

GENERAL REFERENCES

Feero WG, Guttmacher AE, Collins FS: Genomic medicine—anupdated primer, N Engl J Med 362:2001–2011, 2010.

Ginsburg G, Willard HF, editors: Genomic and personalized medicine (vols 1 & 2), ed 2, New York, 2012, Elsevier.

gene, clarifying the clinical diagnosis and alteringtreatment for the patient (see Chapter 16).

• Scientists in the pharmaceutical industry sequencecancer cell DNA to identify specic changes in onco-genic signaling pathways inappropriately activatedby a somatic mutation, leading to the developmentof specic inhibitors that reliably induce remissionsof the cancers in patients (Case 10) .

Categories of Genetic DiseaseVirtually any disease is the result of the combined actionof genes and environment, but the relative role of thegenetic component may be large or small. Among dis-orders caused wholly or partly by genetic factors, threemain types are recognized: chromosome disorders,single-gene disorders, and multifactorial disorders.

In chromosome disorders, the defect is due not to asingle mistake in the genetic blueprint but to an excessor a deciency of the genes located on entire chromo-

somes or chromosome segments. For example, the pres-ence of an extra copy of one chromosome, chromosome21, underlies a specic disorder, Down syndrome, eventhough no individual gene on that chromosome isabnormal. Duplication or deletion of smaller segmentsof chromosomes, ranging in size from only a singlegene up to a few percent of a chromosome’s length, cancause complex birth defects like DiGeorge syndrome oreven isolated autism without any obvious physicalabnormalities. As a group, chromosome disorders arecommon, affecting approximately 7 per 1000 liveborninfants and accounting for approximately half of allspontaneous abortions occurring in the rst trimester of

pregnancy. These types of disorders are discussed inChapter 6.

Single-gene defects are caused by pathogenic muta-tions in individual genes. The mutation may be presenton both chromosomes of a pair (one of paternal originand one of maternal origin) or on only one chromosomeof a pair (matched with a normal copy of that geneon the other copy of that chromosome). Single-genedefects often cause diseases that follow one of the classicinheritance patterns in families (autosomal recessive,autosomal dominant, or X-linked). In a few cases, themutation is in the mitochondrial rather than in thenuclear genome. In any case, the cause is a critical errorin the genetic information carried by a single gene.Single-gene disorders such as cystic brosis (Case 12) ,sickle cell anemia (Case 42) , and Marfan syn-drome (Case 30) usually exhibit obvious and charac-teristic pedigree patterns. Most such defects are rare,with a frequency that may be as high as 1 in 500 to