Chapter 064. The Practice of Genetics in Clinical Medicine (Part 3)

Recall of family history is often inaccurate. This is especially so when the history is remote and families become more dispersed geographically. It can be helpful to ask patients to fill out family history forms before or after their visits, as this provides them with an opportunity to contact relatives. Attempts should be made to confirm the illnesses reported in the family history before making important and, in certain circumstances, irreversible management decisions. This process is often labor intensive and ideally involves interviews of additional family members or reviewing medical records, autopsy reports, and death certificates.Although many inherited disorders...
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Chapter 064. The Practice of Genetics in Clinical Medicine (Part 3) Chapter 064. The Practice of Genetics in Clinical Medicine (Part 3) Recall of family history is often inaccurate. This is especially so when thehistory is remote and families become more dispersed geographically. It can behelpful to ask patients to fill out family history forms before or after their visits, asthis provides them with an opportunity to contact relatives. Attempts should bemade to confirm the illnesses reported in the family history before makingimportant and, in certain circumstances, irreversible management decisions. Thisprocess is often labor intensive and ideally involves interviews of additionalfamily members or reviewing medical records, autopsy reports, and deathcertificates. Although many inherited disorders will be suggested by the clustering ofrelatives with the same or related conditions, it is important to note that diseasepenetrance is incomplete for most multifactorial genetic disorders. As a result, thepedigree obtained in such families may not exhibit a clear Mendelian inheritancepattern, as not all family members carrying the disease-associated alleles willmanifest a clinical disorder. Furthermore, genes associated with some of these disorders often exhibitvariable expression of disease. For example, the breast cancer–associated geneBRCA1 can predispose to several different malignancies in the same family,including cancers of the breast, ovary, and prostate (Chap. 79). For common diseases such as breast cancer, some family members withoutthe disease-causing mutation may also develop breast cancer, representing anotherconfounding variable in the pedigree analysis. Some of the aforementioned features of the family history are illustrated inFig. 64-1. In this example, the proband, a 36-year-old woman (IV-1), has a stronghistory of breast and ovarian cancer on the paternal side of her family. The earlyage of onset, as well as the co-occurrence of breast and ovarian cancer in thisfamily, suggests the possibility of an inherited mutation in BRCA1 or BRCA2. It isunclear though—without genetic testing—whether her father inherited such amutation and transmitted it to her. After appropriate genetic counseling of theproband and her family, one approach to DNA analysis in this family is to test thecancer-affected 42-year-old living cousin for the presence of a BRCA1 or BRCA2mutation. If a mutation is found, then it is possible to test for this particularalteration in the proband and other family members, if they so desire. In theexample shown, if the probands father has the BRCA1 mutation, there is a 50:50probability that the mutation was transmitted to her, and genetic testing can beused to establish the absence or presence of this alteration. Figure 64-1 A 36-year-old woman (arrow) seeks consultation because of her familyhistory of cancer. The patient expresses concern that the multiple cancers in her relativesimply an inherited predisposition to develop cancer. The family history is recordedand records of the patients relatives confirm the reported diagnoses. Genetic Testing for Adult-Onset Disorders A critical first step before initiating genetic testing is to ensure that thecorrect clinical diagnosis has been made, whether based on family history,characteristic physical findings, or biochemical testing. Careful clinical assessmentcan define the phenotype, thereby preventing unnecessary testing and directingtesting toward the most probable candidate genes (Fig. 64-2). For patients identified by population-based screening (e.g., diabetes,hypercholesterolemia), testing might involve known candidate genes, or genome-wide linkage studies (HapMap) of the population could be used as part of aresearch study to identify susceptibility alleles. For patients with a strong family history (e.g., breast cancer,hemochromatosis), testing often includes known candidate genes, or traditionallinkage analyses within pedigrees can identify disease-causing genes. Oncecandidate genes are known, mutational analyses can be performed after pretestgenetic counseling (see below).