Introduction

The MYH7 c.5135G > A p.(Arg1712Gln) variant has been identified in several patients worldwide and is classified as pathogenic in the ClinVar database. We aimed to delineate its associated phenotype and evaluate a potential founder effect.

Methods

We retrospectively collected clinical and genetic data of 22 probands and 74 family members from an international cohort.

Results

In total, 53 individuals carried the MYH7 p.(Arg1712Gln) variant, of whom 38 (72%) were diagnosed with hypertrophic cardiomyopathy (HCM). Mean age at HCM diagnosis was 48.8 years (standard deviation: 18.1; range: 8–74). The clinical presentation ranged from asymptomatic HCM to arrhythmias (atrial fibrillation and malignant ventricular arrhythmias). Aborted sudden cardiac death (SCD) leading to the diagnosis of HCM occurred in one proband at the age of 68 years, and a family history of SCD was reported by 39% (5/13) probands. Neither heart failure deaths nor heart transplants were reported. Women had a generally later-onset disease, with 14% of female carriers diagnosed with HCM at age 50 years compared with 54% of male carriers. In both sexes, the disease was fully penetrant by age 75 years. Haplotypes were reconstructed for 35 patients and showed a founder effect in a subset of patients.

Conclusion

MYH7 p.(Arg1712Gln) is a pathogenic founder variant with a consistent HCM phenotype that may present with delayed penetrance. This suggested that clinical follow-up should be pursued after the seventh decade in healthy carriers and that longer intervals between screening may be justified in healthy women < 30 years.

中文翻译：

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MYH7 p.(Arg1712Gln) 是导致肥厚性心肌病的致病性创始人变异，总体上发病相对延迟

介绍

MYH7 c.5135G > A p.(Arg1712Gln) 变异已在全球数名患者中被发现，并在 ClinVar 数据库中被归类为致病性。我们的目的是描绘其相关的表型并评估潜在的创始人效应。

方法

我们回顾性收集了国际队列中 22 名先证者和 74 名家庭成员的临床和遗传数据。

结果

总共有 53 人携带MYH7 p.(Arg1712Gln) 变异，其中 38 人 (72%) 被诊断患有肥厚型心肌病 (HCM)。HCM 诊断时的平均年龄为 48.8 岁（标准差：18.1；范围：8-74）。临床表现范围从无症状肥厚性心肌病到心律失常（房颤和恶性室性心律失常）。一名先证者在 68 岁时发生了导致 HCM 诊断的中止心源性猝死 (SCD)，39% (5/13) 的先证者报告有 SCD 家族史。没有报告心力衰竭死亡和心脏移植。女性通常患有晚发型疾病，14% 的女性携带者在 50 岁时被诊断出患有 HCM，而男性携带者的这一比例为 54%。到 75 岁时，这种疾病在男女中都已完全渗透。重建了 35 名患者的单倍型，并在一部分患者中显示出创始人效应。

结论

MYH7 p .(Arg1712Gln) 是一种致病性创始人变异，具有一致的 HCM 表型，可能表现为外显延迟。这表明，健康携带者应在七十岁之后进行临床随访，并且对于 < 30 岁的健康女性，较长的筛查间隔可能是合理的。