Chapter 062. Principles of Human Genetics (Part 1)

Harrisons Internal Medicine Chapter 62. Principles of Human GeneticsImpact of Genetics on Medical PracticeImpact of Genetics on Medical Practice: IntroductionThe beginning of the new millennium was marked by the announcement that the vast majority of the human genome had been sequenced. This milestone in the exploration of the human genome was preceded by numerous conceptual and technological advances. They include, among others, the elucidation of the DNA double-helix structure, the discovery of restriction enzymes and the polymerase chain reaction (PCR), the development and automatization of DNA sequencing,and the generation of genetic and physical maps by the Human Genome...
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Chapter 062. Principles of Human Genetics (Part 1) Chapter 062. Principles of Human Genetics (Part 1) Harrisons Internal Medicine > Chapter 62. Principles of HumanGenetics Impact of Genetics on Medical Practice Impact of Genetics on Medical Practice: Introduction The beginning of the new millennium was marked by the announcementthat the vast majority of the human genome had been sequenced. This milestone inthe exploration of the human genome was preceded by numerous conceptual andtechnological advances. They include, among others, the elucidation of the DNAdouble-helix structure, the discovery of restriction enzymes and the polymerasechain reaction (PCR), the development and automatization of DNA sequencing,and the generation of genetic and physical maps by the Human Genome Project(HGP). The consequences of this wealth of knowledge for the practice of medicineare profound. To date, the most significant impact of genetics has been to enhanceour understanding of disease etiology and pathogenesis. However, genetics israpidly playing a more prominent role in the diagnosis, prevention, and treatmentof disease (Chap. 64). Genetic approaches have proven invaluable for thedetection of infectious pathogens and are used clinically to identify agents that aredifficult to culture such as mycobacteria, viruses, and parasites. In many cases,molecular genetics has improved the feasibility and accuracy of diagnostic testingand is beginning to open new avenues for therapy, including gene and cellulartherapy (Chaps. 65 and 67). Molecular genetics has already significantly changedthe treatment of human disease. Peptide hormones, growth factors, cytokines, andvaccines can now be produced in large amounts using recombinant DNAtechnology. Targeted modification of these peptides provides the practitioner withimproved therapeutic tools, as illustrated by genetically modified insulinanalogues with more favorable kinetics. There is hope that a better understandingof the genetic basis of human disease will also have an increasing impact ondisease prevention. Genetics has traditionally been viewed through the window of relativelyrare single-gene diseases. Taken together, these disorders account for ~10% ofpediatric admissions and childhood mortality. It is, however, increasingly apparentthat virtually every medical condition, maybe with the exception of simple trauma,has a genetic component. As is often evident from a patients family history, manycommon disorders such as hypertension, heart disease, asthma, diabetes mellitus,and mental illnesses are significantly influenced by the genetic background. Thesepolygenic or multifactorial (complex) disorders involve the contributions of manydifferent genes, as well as environmental factors, that can modify disease risk(Chap. 64). A major current challenge is to elucidate the genetic components thatcontribute to the pathogenesis of complex disorders. The recent publication of acomprehensive catalogue of human single-nucleotide polymorphism (SNP)haplotypes, the HapMap Project, provides an essential resource for genome-wideassociation studies (see below). Cancer has a genetic basis since it results from acquired somatic mutationsin genes controlling growth, apoptosis, and cellular differentiation (Chap. 79). Inaddition, the development of many cancers is associated with a hereditarypredisposition. The prevalence of genetic diseases, combined with their severityand chronic nature, imposes a great financial, social, and emotional burden onsociety. Genetics has historically focused on chromosomal and metabolic disorders,reflecting the long-standing availability of techniques to diagnose these conditions.For example, conditions such as trisomy 21 (Down syndrome) or monosomy X(Turner syndrome) can be diagnosed using cytogenetics (Chap. 63). Likewise,many metabolic disorders (e.g., phenylketonuria, familial hypercholesterolemia)are diagnosed using biochemical analyses. Recent advances in DNA diagnosticshave extended the field of genetics to include virtually all medical specialties. Incardiology, for example, the molecular basis of inherited cardiomyopathies andion channel defects that predispose to arrhythmias is being defined (Chaps. 226and 231). In neurology, genetics has unmasked the pathophysiology of a startlingnumber of neurodegenerative disorders (Chap. 360). Hematology has evolveddramatically, from its incipient genetic descriptions of hemoglobinopathies to thecurrent understanding of the molecular basis of red cell membrane defects, clottingdisorders, and thrombotic disorders (Chaps. 99 and 110). New concepts derived from genetic studies can sometimes clarify thepathogenesis of disorders that were p ...