Department of Vascular Medicine (S.I., J.P., W.A.M.S., G.K.H., E.S.G.S., L.F.R.), Amsterdam UMC, University of Amsterdam, the Netherlands.
Department of Internal Medicine, Erasmus MC, Rotterdam, the Netherlands (J.v.R., A.J.M.H.V., J.d.V., B.S.-K., A.G.U.).
Circ Genom Precis Med. 2023 Oct;16(5):462-469. doi: 10.1161/CIRCGEN.123.004103. Epub 2023 Sep 7.
Familial hypercholesterolemia (FH) is a common but underdiagnosed genetic disorder characterized by high low-density lipoprotein cholesterol levels and premature cardiovascular disease. Current sequencing methods to diagnose FH are expensive and time-consuming. In this study, we evaluated the accuracy of a low-cost, high-throughput genotyping array for diagnosing FH.
An Illumina Global Screening Array was customized to include probes for 636 variants, previously classified as FH-causing variants. First, its theoretical coverage was assessed in all FH variant carriers diagnosed through next-generation sequencing between 2016 and 2022 in the Netherlands (n=1772). Next, the performance of the array was validated in another sample of FH variant carriers previously identified in the Dutch FH cascade screening program (n=1268).
The theoretical coverage of the array for FH-causing variants was 91.3%. Validation of the array was assessed in a sample of 1268 carriers of whom 1015 carried a variant in , 250 in , and 3 in . The overall sensitivity was 94.7% and increased to 98.2% after excluding participants with variants not included in the array design. Copy number variation analysis yielded a 89.4% sensitivity. In 18 carriers, the array identified a total of 19 additional FH-causing variants. Subsequent DNA analysis confirmed 5 of the additionally identified variants, yielding a false-positive result in 16 subjects (1.3%).
The FH genotyping array is a promising tool for genetically diagnosing FH at low costs and has the potential to greatly increase accessibility to genetic testing for FH. Continuous customization of the array will further improve its performance.
家族性高胆固醇血症（FH）是一种常见但诊断不足的遗传性疾病，其特征是低密度脂蛋白胆固醇水平升高和心血管疾病发病早。目前用于诊断 FH 的测序方法既昂贵又耗时。在这项研究中，我们评估了一种低成本、高通量基因分型阵列诊断 FH 的准确性。
定制了一个 Illumina 全球筛查阵列，其中包括 636 个变体的探针，这些变体之前被归类为导致 FH 的变体。首先，在 2016 年至 2022 年期间通过下一代测序在荷兰诊断为 FH 变异携带者的所有 FH 变异携带者中评估其理论覆盖范围（n=1772）。接下来，在先前在荷兰 FH 级联筛查计划中确定的 FH 变异携带者的另一个样本中验证该阵列的性能（n=1268）。
该阵列对导致 FH 的变体的理论覆盖范围为 91.3%。在 1268 名携带者的样本中评估了该阵列的验证情况，其中 1015 名携带 中的变体，250 名携带 中的变体，3 名携带 中的变体。总体敏感性为 94.7%，排除不在阵列设计中包含的变体的参与者后，敏感性增加到 98.2%。拷贝数变异分析的敏感性为 89.4%。在 18 名携带者中，该阵列总共鉴定出 19 个其他导致 FH 的变体。随后的 DNA 分析证实了另外鉴定出的 5 个变体，导致 16 名受试者出现假阳性结果（1.3%）。
FH 基因分型阵列是一种有前途的低成本诊断 FH 的工具，有潜力大大增加 FH 基因检测的可及性。该阵列的持续定制将进一步提高其性能。
