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January 2019

Updated to reflect a new reference on the effect of genetic diagnosis in patients with previously undiagnosed disease.


Human genetics refers to the study of individual genes, their role and function in disease, and their mode of inheritance. Genomics refers to an organism’s entire genetic information, the genome, and the function and interaction of DNA within the genome, as well as with environmental or nongenetic factors, such as a person’s lifestyle. With the characterization of the human genome, genomics not only complements traditional genetics in our efforts to elucidate the etiology and pathogenesis of disease, but it plays an increasingly prominent role in diagnostics, prevention, and therapy (Chap. 457). These transformative developments, emerging from the Human Genome Project, have been variably designated genomic medicine, personalized medicine, or precision medicine. Precision medicine aims at customizing medical decisions to an individual patient. For example, a patient’s genetic characteristics (genotype) can be used to optimize drug therapy and predict efficacy, adverse events, and drug dosing of selected medications (pharmacogenomics) (Chap. 64). The characterization of the mutational profile of a malignancy allows to identify driver mutations or overexpressed signaling molecules, which then facilitates the selection of targeted therapies. Genomic risk prediction models for common diseases are also beginning to emerge.

Genetics has traditionally been viewed through the window of relatively rare single-gene diseases. These disorders account for ~10% of pediatric admissions and childhood mortality. Historically, genetics has focused predominantly on chromosomal and metabolic disorders, reflecting the long-standing availability of techniques to diagnose these conditions. For example, conditions such as trisomy 21 (Down’s syndrome) or monosomy X (Turner’s syndrome) can be diagnosed using cytogenetics. Likewise, many metabolic disorders (e.g., phenylketonuria, familial hypercholesterolemia) are diagnosed using biochemical analyses. The advances in DNA diagnostics have extended the field of genetics to include virtually all medical specialties and have led to the elucidation of the pathogenesis of numerous monogenic disorders. In addition, it is apparent that virtually every medical condition has a genetic component. As is often evident from a patient’s family history, many common disorders such as hypertension, heart disease, asthma, diabetes mellitus, and mental illnesses are significantly influenced by the genetic background. These polygenic or multifactorial (complex) disorders involve the contributions of many different genes, as well as environmental factors that can modify disease risk. Genome-wide association studies (GWAS) have elucidated numerous disease-associated loci and are providing novel insights into the allelic architecture of complex traits. These studies have been facilitated by the availability of comprehensive catalogues of human single-nucleotide polymorphism (SNP) haplotypes (HapMap, International Genome Sample Resource/1000 genomes project). Next-generation DNA sequencing (NGS) technologies have evolved rapidly and the cost of sequencing whole exomes (the exons within the genome, WES) or genomes (WGS) has plummeted. Comprehensive unbiased sequence analyses are now frequently used to characterize individuals with complex undiagnosed conditions or ...

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