Program for Personalized and Genomic Medicine (E.A.S., L.B.J.J., K.A.M., M.L., T.I.P., M.D., K.A.R., J.A.P., J.O., A.B., K.P., B.D.M.), University of Maryland School of Medicine.
Department of Medicine (E.A.S., V.Y.S., L.B.J.J., K.A.M., M.L., T.I.P., M.D., K.A.R., J.A.P., J.O., A.B., B.D.M.), University of Maryland School of Medicine.
Circ Genom Precis Med. 2020 Dec;13(6):e003133. doi: 10.1161/CIRCGEN.120.003133. Epub 2020 Nov 3.
In population-based research exome sequencing, the path from variant discovery to return of results is not well established. Variants discovered by research exome sequencing have the potential to improve population health.
Population-based exome sequencing and agnostic ExWAS were performed 5521 Amish individuals. Additional phenotyping and in vitro studies enabled reclassification of a variant from variant of unknown significance to pathogenic. Results were returned to participants in a community setting.
A missense variant was identified in (c.671C>T, p.T224M), a gene associated with long QT syndrome type 1, which can cause syncope and sudden cardiac death. The p.T224M variant, present in 1/45 Amish individuals is rare in the general population (1/248 566 in gnomAD) and was highly associated with QTc on electro-cardiogram (=5.53E-24, β=20.2 ms/allele). Because of the potential importance of this variant to the health of the population, additional phenotyping was performed in 88 p.T224M carriers and 54 noncarriers. There was stronger clinical evidence of long QT syndrome in carriers (38.6% versus 5.5%, =0.0006), greater history of syncope (32% versus 17%, =0.020), and higher rate of sudden cardiac death in first degree relatives<age 30 (4.5% versus 0%, =0.026). Expression of p.T224M KCNQ1 in Chinese hamster ovary cells showed near complete loss of protein function. Our clinical and functional data enabled reclassification of p.T224M from a variant of unknown significance to pathogenic. Of the 88 carriers, 93% met criteria for beta-blocker treatment and 5/88 (5.7%) were on medications that may further prolong QTc. Carriers were provided a Clinical Laboratory Improvement Amendments confirmed report, genetic counseling, and treatment recommendations. Follow-up care was coordinated with local physicians.
This work provides a framework by which research exome sequencing can be rapidly translated in a culturally appropriate manner to directly benefit research participants and enable population precision health.
在基于人群的外显子组测序研究中，从变异发现到结果回报的路径尚不完善。通过研究性外显子组测序发现的变异有可能改善人群健康。
对 5521 名阿米什人进行基于人群的外显子组测序和未知意义的外显子组关联分析（agnostic ExWAS）。额外的表型和体外研究使一种变异从意义不明的变异重新分类为致病性变异。结果在社区环境中反馈给参与者。
在一个与长 QT 综合征 1 相关的基因 （c.671C>T，p.T224M）中发现了错义变异，该基因可导致晕厥和心源性猝死。在 1/45 的阿米什人中发现的 p.T224M 变异在一般人群中非常罕见（gnomAD 中为 1/248566），与心电图上的 QTc 高度相关（=5.53E-24，β=20.2ms/等位基因）。由于该变异对人群健康的重要性，对 88 名 p.T224M 携带者和 54 名非携带者进行了额外的表型分析。携带者中长 QT 综合征的临床证据更强（38.6%比 5.5%，=0.0006），晕厥史更多（32%比 17%，=0.020），一级亲属 30 岁以下心源性猝死发生率更高（4.5%比 0%，=0.026）。在中国仓鼠卵巢细胞中表达 p.T224M KCNQ1 几乎完全丧失了蛋白功能。我们的临床和功能数据使 p.T224M 从意义不明的变异重新分类为致病性变异。在 88 名携带者中，93%符合β受体阻滞剂治疗标准，5/88（5.7%）正在服用可能进一步延长 QTc 的药物。携带者获得了临床实验室改进修正案确认报告、遗传咨询和治疗建议。后续护理与当地医生协调。
这项工作提供了一个框架，通过这个框架，可以以一种文化上适当的方式快速转化研究性外显子组测序，直接使研究参与者受益，并使人群精准健康成为可能。
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