Department of Translational Data Science and Informatics (E.D.C., C.D.N., B.K.F., C.M.H.), Geisinger, Danville, PA.
The Heart Institute (D.B., A.A., M.E.M., B.K.F., A.C.S., C.M.H.), Geisinger, Danville, PA.
Circ Genom Precis Med. 2021 Apr;14(2):e003302. doi: 10.1161/CIRCGEN.120.003302. Epub 2021 Mar 8.
Genomic screening holds great promise for presymptomatic identification of hidden disease, and prevention of dramatic events, including sudden cardiac death associated with arrhythmogenic cardiomyopathy (ACM). Herein, we present findings from clinical follow-up of carriers of ACM-associated pathogenic/likely pathogenic desmosome variants ascertained through genomic screening.
Of 64 548 eligible participants in Geisinger MyCode Genomic Screening and Counseling program (2015-present), 92 individuals (0.14%) identified with pathogenic/likely pathogenic desmosome variants by clinical laboratory testing were referred for evaluation. We reviewed preresult medical history, patient-reported family history, and diagnostic testing results to assess both arrhythmogenic right ventricular cardiomyopathy and left-dominant ACM.
One carrier had a prior diagnosis of dilated cardiomyopathy with arrhythmia; no other related diagnoses or diagnostic family history criteria were reported. Fifty-nine carriers (64%) had diagnostic testing in follow-up. Excluding the variant, 21/59 carriers satisfied at least one arrhythmogenic right ventricular cardiomyopathy task force criterion, 11 (52%) of whom harbored variants, but only 5 exhibited multiple criteria. Six (10%) carriers demonstrated evidence of left-dominant ACM, including high rates of atypical late gadolinium enhancement by magnetic resonance imaging and nonsustained ventricular tachycardia. Two individuals received new cardiomyopathy diagnoses and received defibrillators for primary prevention.
Genomic screening for pathogenic/likely pathogenic variants in desmosome genes can uncover both left- and right-dominant ACM. Findings of overt cardiomyopathy were limited but were most common in -variant carriers and notably absent in -variant carriers. Consideration of the pathogenic/likely pathogenic variant as a major criterion for diagnosis is inappropriate in the setting of genomic screening.
基因组筛查为预先识别隐匿性疾病提供了巨大的希望，并可预防包括心律失常性心肌病（ACM）相关的突发性心源性死亡在内的重大事件。在此，我们报告了通过基因组筛查确定的 ACM 相关致病性/可能致病性桥粒变体携带者的临床随访结果。
在 Geisinger MyCode 基因组筛查和咨询计划（2015 年至今）的 64548 名合格参与者中，有 92 名（0.14%）个体通过临床实验室检测确定为致病性/可能致病性桥粒变体，随后被转诊进行评估。我们回顾了预检测病史、患者报告的家族史和诊断检测结果，以评估心律失常性右心室心肌病和左优势型 ACM。
一名携带者曾被诊断为扩张型心肌病伴心律失常；未报告其他相关诊断或诊断家族史标准。59 名携带者（64%）在随访中进行了诊断性检测。排除变体后，21/59 名携带者至少符合一项心律失常性右心室心肌病工作组标准，其中 11 名（52%）携带变体，但只有 5 名携带者符合多项标准。6 名（10%）携带者表现出左优势型 ACM 的证据，包括磁共振成像的非典型晚期钆增强和非持续性室性心动过速的发生率较高。两名个体被诊断为新发心肌病，并接受植入式除颤器进行一级预防。
桥粒基因致病性/可能致病性变体的基因组筛查可发现左优势型和右优势型 ACM。明显的心肌病表现有限，但在变体携带者中最常见，而在无变体携带者中则明显不存在。在基因组筛查的背景下，将致病性/可能致病性变体视为主要诊断标准是不合适的。
