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January 2019

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


Genetic testing for inherited abnormalities associated with disease risk is increasingly used in the practice of clinical medicine. Germline alterations include chromosomal abnormalities specific gene mutations with autosomal dominant or recessive patterns of transmission (Chap. 456), and single nucleotide polymorphisms (SNPs) with small relative risks associated with disease. Germline alterations are responsible for disorders beyond classic Mendelian conditions with genetic susceptibility to common adult-onset diseases such as asthma, hypertension, diabetes mellitus, macular degeneration, and a number of types of cancer. For many of these diseases, there is a complex interplay of genes (often multiple) and environmental factors that effect lifetime risk, age of onset, disease severity, and treatment options.

The expansion of human genetic knowledge is changing our understanding of pathophysiology and influencing our classification of diseases. Awareness of genetic etiology can have an impact on clinical management, including prevention and screening for or treatment of a range of diseases. Primary care physicians are relied upon to help patients navigate testing and treatment options. Consequently, they must understand the genetic basis for a large number of genetically influenced diseases, incorporate personal and family history to determine the risk for a specific mutation, and be positioned to provide counseling. Even if patients are seen by genetic specialists who assess genetic risk and coordinate testing, primary care providers should offer information to their patients regarding the indications, limitations, risks, and benefits of genetic counseling and testing. They must also be prepared to offer risk-based management following genetic risk assessment. Given the pace of genetics, this is an increasingly difficult task. The field of clinical genetics has rapidly transitioned from single gene testing to multigene panel testing, with techniques such as whole-exome and genome sequencing on the horizon, increasing the complexity of test selection and interpretation, as well as patient education and medical decision-making.



Adult-onset hereditary diseases follow multiple patterns of inheritance. Some are autosomal dominant conditions. These include many common cancer susceptibility syndromes such as hereditary breast and ovarian cancer (due to germline BRCA1 and BRCA2 mutations) and Lynch syndrome (caused by germline mutations in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2). In both of these examples, inherited mutations are associated with a high penetrance (lifetime risk) of cancer, although penetrance is incomplete (risk is not 100%). In other conditions, although there is autosomal dominant transmission, penetrance is lower, thereby making the disorders more difficult to recognize. For example, germline mutations in CHEK2 increase the risk of breast cancer, but with a moderate lifetime risk in the range of 20–30%, as opposed to 50–70% for mutations in BRCA1 or BRCA2. Other adult-onset ...

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