Importance Familial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants.

Objective To identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)–based comprehensive testing.

Design, Setting, and Participants This cross-sectional study compared comprehensive genetic test results for clinically significant variants associated with FH with results for a subset of 24 variants screened by a limited-variant array. Data were deidentified next-generation sequencing results from indication-based or proactive gene panels. Individuals receiving next-generation sequencing–based genetic testing, either for an FH indication between November 2015 and June 2020 or as proactive health screening between February 2016 and June 2020 were included. Ancestry was reported by clinicians who could select from preset options or enter free text on the test requisition form.

Main Outcomes and Measures Number of pathogenic or likely pathogenic (P/LP) variants identified.

Results This study included 4563 individuals who were referred for FH diagnostic testing and 6482 individuals who received next-generation sequencing of FH-associated genes as part of a proactive genetic test. Among individuals in the indication cohort, the median (interquartile range) age at testing was 49 (32-61) years, 55.4% (2528 of 4563) were female, and 63.6% (2902 of 4563) were self-reported White/Caucasian. In the indication cohort, the positive detection rate would have been 8.4% (382 of 4563) for a limited-variant screen compared with the 27.0% (1230 of 4563) observed with the next-generation sequencing–based comprehensive test. As a result, 68.9% (848 of 1230) of individuals with a P/LP finding in an FH-associated gene would have been missed by the limited screen. The potential for missed findings in the indication cohort varied by ancestry; among individuals with a P/LP finding, 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed by the limited-variant screen, compared with 33.3% (4 of 12) of Ashkenazi Jewish individuals. In the proactive cohort, the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test, and 61.8% (21 of 34) of individuals with an FH-associated P/LP finding would have been missed by a limited-variant screen.

Conclusions and Relevance Limited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry.

重要性 家族性高胆固醇血症 (FH) 是最常见的遗传性心血管疾病，具有显着的发病率和死亡率风险。基因检测可以识别受影响的个体，但一些基于阵列的检测仅筛选一小部分已知的致病变异。

目的 确定与基于下一代测序 (NGS) 的综合测试相比，基于阵列的有限变异筛选会遗漏的与 FH 相关的临床显着变异的数量。

设计、设置和参与者 这项横断面研究比较了与 FH 相关的临床显着变异的综合基因检测结果与有限变异阵列筛选的 24 个变异子集的结果。数据是来自基于适应症或主动基因组的去识别的下一代测序结果。包括在 2015 年 11 月至 2020 年 6 月期间接受基于下一代测序的基因检测的个体，无论是针对 FH 适应症，还是在 2016 年 2 月至 2020 年 6 月期间作为主动健康筛查。血统由临床医生报告，他们可以从预设选项中进行选择或在测试申请表上输入自由文本。

主要结果和措施 确定的致病性或可能致病性 (P/LP) 变体的数量。

结果 这项研究包括 4563 名被转介进行 FH 诊断测试的人和 6482 名接受 FH 相关基因下一代测序作为主动基因测试的一部分的人。在适应症队列中的个体中，测试时的中位年龄（四分位距）为 49（32-61）岁，55.4%（4563 人中的 2528 人）是女性，63.6%（4563 人中的 2902 人）是自我报告的白人/高加索人. 在适应症队列中，有限变异筛查的阳性检出率为 8.4%（4563 人中的 382 人），而基于下一代测序的综合测试的阳性检出率为 27.0%（4563 人中的 1230 人）。因此，68.9%（1230 名中的 848 名）在 FH 相关基因中发现 P/LP 的个体会被有限的筛选遗漏。适应症队列中遗漏发现的可能性因血统而异；在发现 P/LP 的个体中，93.7%（63 名中的 59 名）自我报告的黑人/非裔美国人和 84.7%（144 名中的 122 名）的西班牙裔个体会被有限变异筛查遗漏，而 33.3 % (4 of 12) 的德系犹太人。在主动队列中，每个综合测试的临床显着 FH 变异的患病率约为 1:191，并且 61.8%（34 名中的 21 名）具有 FH 相关 P/LP 发现的个体会因有限变异而遗漏屏幕。

结论和相关性 有限变异筛查可能会错误地向大多数有 FH 风险的个体保证他们不携带致病变异，尤其是自我报告的黑人/非裔美国人和西班牙裔血统的个体。