Division of Human Genetics, Department of Internal Medicine (A.M., D.D.K., E.J., C.S., J.M., T.A., R.E.H.), The Ohio State University, Columbus.
Stanford Center for Inherited Cardiovascular Disease, Stanford University, Palo Alto, CA (J.P.).
Circ Genom Precis Med. 2020 Apr;13(2):e002480. doi: 10.1161/CIRCGEN.119.002480. Epub 2020 Mar 11.
The hypothesis of the Dilated Cardiomyopathy Precision Medicine Study is that most dilated cardiomyopathy has a genetic basis. The study returns results to probands and, when indicated, to relatives. While both the American College of Medical Genetics and Genomics/Association for Molecular Pathology and ClinGen's -cardiomyopathy specifications provide relevant guidance for variant interpretation, further gene- and disease-specific considerations were required for dilated cardiomyopathy. To this end, we tailored the ClinGen -cardiomyopathy variant interpretation framework; the specifications implemented for the study are presented here.
Modifications were created and approved by an external Variant Adjudication Oversight Committee. After a pilot using 81 probands, further adjustments were made, resulting in 27 criteria (9 modifications of the ClinGen framework and reintroduction of 2 American College of Medical Genetics and Genomics/Association of Molecular Pathology criteria that were deemed not applicable by the ClinGen working group).
These criteria were applied to 2059 variants in a test set of 97 probands. Variants were classified as benign (n=1702), likely benign (n=33), uncertain significance (n=71), likely pathogenic (likely pathogenic; n=12), and pathogenic (P; n=3). Only 2/15 likely pathogenic/P variants were identified in Non-Hispanic African ancestry probands.
We tailored the ClinGen criteria for our study. Our preliminary data show that 15/97 (15.5%) probands have likely pathogenic/P variants, most of which were identified in probands of Non-Hispanic European ancestry. We anticipate continued evolution of our approach, one that will be informed by new insights on variant interpretation and a greater understanding of the genetic architecture of dilated cardiomyopathy.
URL: https://www.clinicaltrials.gov; Unique identifier: NCT03037632.
扩张型心肌病精准医学研究的假设是，大多数扩张型心肌病都有遗传基础。该研究向先证者和有指征的亲属报告结果。虽然美国医学遗传学与基因组学学院/分子病理学协会和临床遗传学会的 -心肌病规范都为变异解释提供了相关指导，但扩张型心肌病还需要进一步考虑基因和疾病特异性因素。为此，我们对临床遗传学会 -心肌病变异解释框架进行了调整；本文介绍了在此研究中实施的规范。
修改内容由外部变异裁决监督委员会创建和批准。在使用 81 个先证者进行试点后，进一步进行了调整，最终制定了 27 条标准（9 项对临床遗传学会框架的修改，以及重新引入 2 项因被临床遗传学会工作组认为不适用而被排除的美国医学遗传学与基因组学学院/分子病理学协会标准）。
这些标准应用于 97 个先证者的测试集中的 2059 个变体。变体被分类为良性（n=1702）、可能良性（n=33）、意义不明（n=71）、可能致病性（可能致病性；n=12）和致病性（P；n=3）。在非西班牙裔非洲裔先证者中，仅发现了 15 个可能致病性/P 变体中的 2 个。
我们为我们的研究调整了临床遗传学会的标准。我们的初步数据显示，15/97（15.5%）的先证者有致病性/P 变体，其中大多数在非西班牙裔欧洲裔先证者中发现。我们预计我们的方法会不断发展，这将受到变异解释新见解的影响，并对扩张型心肌病的遗传结构有更深入的了解。
