An Evidence Framework for Genetic Testing (2017) / Chapter Skim
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2 Genetic Testing
2 Genetic Testing
Pages 19-34
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From page 19... ...
Developments in genetic testing methods and the categories of genetic tests that are available for clinical use are also discussed. Finally, the committee discusses the ethical, legal, and social implications of genetic testing.
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The third class contains variants that confer some risk of a complex trait or disease, but the phenotype occurs only in individuals with a combination of several risk variants and/or who are also are exposed to environmental risk experiences; these variants contribute risk for the common complex traits of adult life (such as hypertension, coronary artery disease, and neuropsychiatric disease)
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From page 21... ...
In addition, broad-based tests, such as WES or WGS, might identify known pathologic variants for conditions other than those for which the tests were performed. For example, a young child undergoing WES for evaluation of intellectual disability might be found to have a known pathologic variant in BRCA1, and thus the child, and the parent from whom the child inherited the variant, would be at high risk for breast and ovarian cancer in adulthood.
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. Monogenic disorders are inherited either as autosomal dominant disorders, in which a single defective copy of the responsible gene is sufficient to cause a phenotype, or as autosomal recessive disorders, in which both copies of the gene must be defective to produce a phenotype.
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defines genetic tests as an analysis of human DNA, RNA, chromosomes, proteins, and certain metabolites in order to detect heritable disease-related genotypes, mutations,
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A genetic test might be ordered by any of several health care providers, including a primary care physician, a medical specialist, a medical geneticist, an advance practice nurse, or a genetic counselor. In this section, the committee outlines testing methods, reviews the role of family history information in decision making about genetic testing, describes the types of genetics tests, and briefly considers the ethical, legal, and social implications of genetic testing.
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Multigene Panels Multigene panels allow testing of many genes in a single procedure, and they are particularly appropriate for disorders that are known to have locus heterogeneity. The functional segments (exons, splice sites, and so on)
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Finally, in contrast with the causative SNVs responsible for Mendelian disorders, the vast majority of risk variants that contribute to common complex traits are in non–protein-coding segments of the genome and therefore will be detected only with WGS (Maurano et al., 2012; Andersson et al., 2014)
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Family history might serve purposes unrelated to genetics, such as providing information about social relationships and important life events, but its primary function in clinical care is to identify people who have an increased likelihood of particular diseases. Family history might identify people who are at relatively high risk for a single-gene condition that is present in their family (such as Lynch syndrome, hereditary breast ovarian cancer syndrome, hemochromatosis, and familial hypercholesterolemia)
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From page 28... ...
In some cases, a diagnostic test performed on an affected person yields a result that can be used to recommend a predictive test for relatives. For example, if a woman who has breast cancer is found to have a BRCA1 variant, indicating hereditary breast ovarian cancer syndrome, her relatives can be offered the option of being tested to determine whether they also carry the risk variant for the cancer syndrome.
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From page 29... ...
. Reproductive Genetic Testing Reproductive genetic testing offers the opportunity to identify people who are at increased risk for having a child who is affected with a genetic disease or to identify an affected embryo or fetus.
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. If carrier testing identifies a risk for a child who will have a genetic disorder, prospective parents can accept the risk, choose to have prenatal testing with the option of considering pregnancy termination of an affected fetus, or pursue other reproductive options, including preimplantation genetic testing.
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From page 31... ...
For example, males who inherit the hereditary breast ovarian cancer syndrome have a moderately increased risk of breast and prostatic cancer, but most will not develop cancer; they can, however, pass the risk on to their daughters. In the case of Huntington disease, the symptoms typically occur in the fourth decade or later, so children of an affected person might not know that they are at risk until they are adults.
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As genomic technology develops, health care systems need to consider whether limits should be placed on the genetic testing to be offered prenatally. Genome-scale sequencing and noninvasive prenatal testing, in which fetal test results are derived early in pregnancy from testing of fetal DNA present in maternal serum, make it increasingly possible to generate a wide array of genetic information about the fetus.
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More knowledge of the relevant genetic variations will be needed to provide genetic tests that are of equal efficacy in all populations. Clinical Data Sharing Sequencing technologies and other approaches to genome-wide testing often identify novel and rare gene variants of uncertain clinical significance.
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From page 34... ...
. Thus, for example, testing done to evaluate a cardiomyopathy could also generate secondary information about inherited cancer susceptibilities, inherited arrhythmias, and a wide array of other genetic conditions, depending on what analysis of DNA sequence is undertaken.
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