Schmidlen Tara J, Bristow Sara L, Hatchell Kathryn E, Esplin Edward D, Nussbaum Robert L, Haverfield Eden V
Invitae, San Francisco, CA, United States.
Front Genet. 2022 Jun 16;13:867226. doi: 10.3389/fgene.2022.867226. eCollection 2022.
Although multiple factors can influence the uptake of cascade genetic testing, the impact of proband indication has not been studied. 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). 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. Among probands with a positive finding, cascade testing rates and influencing factors were assessed. A total of 270,715 probands were eligible for inclusion in the study (diagnostic = 254,281,93.9%; proactive = 16,434, 6.1%). 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%) ( < 0.0001). 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%) ( < 0.0001). 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 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%) ( < 0.01). 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. 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.
尽管多种因素会影响级联基因检测的接受度，但先证者指征的影响尚未得到研究。我们进行了一项回顾性横断面研究，比较了通过基于下一代测序（NGS）的多基因检测板对遗传性癌症综合征（HCS）和/或家族性高胆固醇血症（FH）进行诊断性种系检测或非指征性主动筛查的先证者亲属的级联基因检测率。根据与疾病控制和预防中心（CDC）一级疾病相关的基因、HCS基因和FH基因，计算出有医学可操作（阳性）结果的先证者比例。在有阳性结果的先证者中，评估级联检测率和影响因素。共有270,715名先证者符合纳入研究的条件（诊断性检测 = 254,281，占93.9%；主动筛查 = 16,434，占6.1%）。在10,520名诊断性先证者（4.1%）和337名主动筛查先证者（2.1%）中发现与CDC一级疾病相关基因的阳性结果，导致3,305名诊断性先证者（31.4%）和36名主动筛查先证者（10.7%）的家族进行了级联检测（P < 0.0001）。在23,272名诊断性先证者（9.4%）和970名主动筛查先证者（6.1%）中返回了HCS基因的阳性结果，导致6,611名诊断性先证者（28.4%）和89名主动筛查先证者（9.2%）的家族进行了级联检测（P < 0.0001）。当诊断性先证者为白人、在与CDC一级疾病相关的基因中有发现、有个人癌症病史时，或当主动筛查先证者为女性时，因HCS基因阳性结果而进行级联检测的情况更为常见。在1,647名诊断性先证者（25.3%）和67名主动筛查先证者（0.62%）中返回了FH基因的阳性结果，导致360名诊断性先证者（21.9%）和4名主动筛查先证者（6.0%）的家族进行了级联检测（P < 0.01）。诊断性先证者家族中持续较高的级联检测率可能是由于个人或家族疾病史导致的紧迫感。由于级联检测已被证实具有临床益处，因此有必要进一步研究对任何有医学可操作变异的先证者亲属进行系统检测实施和接受检测的障碍。
