Low-Cost High-Throughput Genotyping for Diagnosing Familial Hypercholesterolemia.

IF 6 2区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation: Genomic and Precision Medicine Pub Date : 2023-10-01 Epub Date: 2023-09-07 DOI:10.1161/CIRCGEN.123.004103
Shirin Ibrahim, Jeroen van Rooij, Annemieke J M H Verkerk, Jard de Vries, Linda Zuurbier, Joep Defesche, Jorge Peter, Willemijn A M Schonck, Bahar Sedaghati-Khayat, G Kees Hovingh, André G Uitterlinden, Erik S G Stroes, Laurens F Reeskamp
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Abstract

Background: 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.

Methods: 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).

Results: 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 LDLR, 250 in APOB, and 3 in PCSK9. 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%).

Conclusions: 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.

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诊断家族性高胆固醇血症的低成本高通量基因分型。
背景: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高和早发心血管疾病。目前诊断FH的测序方法既昂贵又耗时。在这项研究中,我们评估了低成本、高通量基因分型阵列诊断FH的准确性。方法:定制Illumina全球筛查阵列,包括636种变体的探针,这些变体以前被归类为FH引起的变体。首先,在荷兰2016年至2022年间通过下一代测序诊断的所有FH变异携带者中评估了其理论覆盖率(n=1772)。接下来,在荷兰FH级联筛查计划中先前确定的另一个FH变体携带者样本(n=1268)中验证了阵列的性能。结果:阵列对FH引起变体的理论覆盖率为91.3%。在1268名携带者样本中评估了阵列的验证,其中1015人携带LDLR变体,250人携带APOB变体,3人携带PCSK9变体。总体灵敏度为94.7%,在排除阵列设计中未包含变异的参与者后,灵敏度提高到98.2%。拷贝数变异分析的敏感性为89.4%。在18个载体中,该阵列总共识别出19个额外的FH引起变体。随后的DNA分析证实了另外鉴定的5种变体,在16名受试者中产生了假阳性结果(1.3%)。结论:FH基因分型阵列是一种很有前途的低成本遗传诊断FH的工具,并且有可能大大增加FH基因检测的可及性。阵列的持续定制将进一步提高其性能。
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来源期刊
Circulation: Genomic and Precision Medicine
Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
9.20
自引率
5.40%
发文量
144
期刊介绍: Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.
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