Department of Pediatrics (E.L.G., J.W., S.R., C.A., W.K.C.), Columbia University Irving Medical Center, New York, NY.
Nemours Cardiac Center, Nemours Children's Hospital, Wilmington, DE (S.N.N).
Circ Genom Precis Med. 2023 Apr;16(2):e003791. doi: 10.1161/CIRCGEN.122.003791. Epub 2023 Feb 21.
Congenital heart disease (CHD) is the most common major congenital anomaly and causes significant morbidity and mortality. Epidemiologic evidence supports a role of genetics in the development of CHD. Genetic diagnoses can inform prognosis and clinical management. However, genetic testing is not standardized among individuals with CHD. We sought to develop a list of validated CHD genes using established methods and to evaluate the process of returning genetic results to research participants in a large genomic study.
Two-hundred ninety-five candidate CHD genes were evaluated using a ClinGen framework. Sequence and copy number variants involving genes in the CHD gene list were analyzed in Pediatric Cardiac Genomics Consortium participants. Pathogenic/likely pathogenic results were confirmed on a new sample in a clinical laboratory improvement amendments-certified laboratory and disclosed to eligible participants. Adult probands and parents of probands who received results were asked to complete a post-disclosure survey.
A total of 99 genes had a strong or definitive clinical validity classification. Diagnostic yields for copy number variants and exome sequencing were 1.8% and 3.8%, respectively. Thirty-one probands completed clinical laboratory improvement amendments-confirmation and received results. Participants who completed postdisclosure surveys reported high personal utility and no decision regret after receiving genetic results.
The application of ClinGen criteria to CHD candidate genes yielded a list that can be used to interpret clinical genetic testing for CHD. Applying this gene list to one of the largest research cohorts of CHD participants provides a lower bound for the yield of genetic testing in CHD.
先天性心脏病（CHD）是最常见的重大先天畸形，会导致重大发病率和死亡率。流行病学证据支持遗传在 CHD 发展中的作用。遗传诊断可以提供预后和临床管理信息。然而，CHD 患者的基因检测并未标准化。我们试图使用既定方法制定一份经过验证的 CHD 基因列表，并评估在一项大型基因组研究中向研究参与者返还遗传结果的过程。
使用 ClinGen 框架评估了 295 个候选 CHD 基因。在儿科心脏基因组学联盟参与者中分析了涉及 CHD 基因列表中基因的序列和拷贝数变异。致病性/可能致病性结果在临床实验室改进修正案认证实验室的新样本中得到确认，并披露给符合条件的参与者。收到结果的成年先证者及其父母被要求完成一项披露后调查。
共有 99 个基因具有强烈或明确的临床有效性分类。拷贝数变异和外显子组测序的诊断率分别为 1.8%和 3.8%。31 名先证者完成了临床实验室改进修正案确认并收到了结果。完成披露后调查的参与者报告说，在收到遗传结果后，个人效用很高，没有决策后悔。
将 ClinGen 标准应用于 CHD 候选基因产生了一个可用于解释 CHD 临床遗传检测的列表。将该基因列表应用于 CHD 最大的研究参与者队列之一，为 CHD 中的基因检测提供了下限。
