Due to the proven clinical benefit of cascade testing, further research on obstacles to systematic implementation and uptake of testing for relatives of any proband with a medically actionable variant is warranted.Ĭascade testing is the process of providing genetic counseling and testing to at-risk blood relatives following the detection of a pathogenic variant in a disease-causing gene in a family member (i.e., the proband). Consistently higher rates of cascade testing among families of diagnostic probands may be due to a perceived urgency because of personal or family history of disease. A positive result in an FH gene was returned to 1,647 diagnostic probands (25.3%) and 67 proactive probands (0.62%), leading to cascade testing among families of 360 diagnostic probands (21.9%) and 4 proactive probands (6.0%) ( p < 0.01). Cascade testing due to a positive result in an HCS gene was more commonly pursued when the diagnostic proband was White, had a finding in a gene associated with a CDC Tier 1 condition, or had a personal history of cancer, or when the proactive proband was female. A positive result in an HCS gene was returned to 23,272 diagnostic probands (9.4%) and 970 proactive probands (6.1%), leading to cascade testing among families of 6,611 diagnostic probands (28.4%) and 89 proactive probands (9.2%) ( p < 0.0001). A positive result in a gene associated with a CDC Tier 1 condition was identified in 10,520 diagnostic probands (4.1%) and 337 proactive probands (2.1%), leading to cascade testing among families of 3,305 diagnostic probands (31.4%) and 36 proactive probands (10.7%) ( p < 0.0001). A total of 270,715 probands were eligible for inclusion in the study (diagnostic n = 254,281,93.9% proactive n = 16,434, 6.1%). Among probands with a positive finding, cascade testing rates and influencing factors were assessed. The proportion of probands with a medically actionable (positive) finding were calculated based on genes associated with Centers for Disease Control and Prevention (CDC) Tier 1 conditions, HCS genes, and FH genes. We performed a retrospective, cross-sectional study comparing cascade genetic testing rates among relatives of probands who received either diagnostic germline testing or non-indication-based proactive screening via next-generation sequencing (NGS)-based multigene panels for hereditary cancer syndromes (HCS) and/or familial hypercholesterolemia (FH). Invitae, San Francisco, CA, United StatesĪlthough multiple factors can influence the uptake of cascade genetic testing, the impact of proband indication has not been studied.
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