Objective One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that MYBPC3 c.2149–1G>A is a founder pathogenic variant, (2) describe the phenotype and clinical characteristics of mutation carriers and (3) compare these patients with those with the most frequent pathogenic HCM variants: MYBPC3 p.Arg502Trp/Gln. Methods We reviewed genetic tests performed in HCM probands at our institution. We carried out transcript analyses to demonstrate the splicing effect, and haplotype analyses to support the founder effect of MYBPC3 c.2149–1G>A. Carriers with this mutation were compared with those from MYBPC3 p.Arg502Trp/Gln in terms of presentation features, imaging and outcomes. Results MYBPC3 c.2149–1G>A was identified in 8 of 570 probands and 25 relatives. Penetrance was age and sex dependent, 50.0% of the carriers over age 36 years and 75.0% of the carriers over 40 years showing HCM. Penetrance was significantly higher in males: in carriers older than 30 years old, 100.0% of males vs 50.0% of females had a HCM phenotype (p=0.01). Males were also younger at diagnosis (32±13 vs 53±10 years old, p<0.001). MYBPC3 c.2149–1G>A resulted in an abnormal transcript that led to haploinsufficiency and was segregated in two haplotypes. However, both came from one founder haplotype. Affected carriers showed a better functional class and higher left ventricular ejection fraction (LVEF) than patients with MYBPC3 p.Arg502Trp/Gln (p<0.05 for both). Nevertheless, the rate of major adverse outcomes was similar between the two groups. Conclusions MYBPC3 c.2149–1G>A splicing variant is a founder mutation. Affected males show an early onset of HCM and with higher penetrance than women. Carriers show better functional class and higher LVEF than MYBPC3 p.Arg502Trp/Gln carriers, but a similar rate of major adverse outcomes. Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as online supplemental information.

中文翻译：

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肌球蛋白结合蛋白 C 的创始人突变，男性发病早，外显率高

目的 肥厚型心肌病 (HCM) 的挑战之一是确定遗传变异的致病性并建立基因型/表型相关性。本研究旨在：(1) 证明 MYBPC3 c.2149-1G>A 是一种创始致病性变异，(2) 描述突变携带者的表型和临床特征，以及 (3) 将这些患者与最常见的致病性变异进行比较。 HCM 变体：MYBPC3 p.Arg502Trp/Gln。方法 我们回顾了在我们机构对 HCM 先证者进行的基因测试。我们进行了转录分析以证明剪接效应，并进行单倍型分析以支持 MYBPC3 c.2149-1G>A 的创始人效应。在表现特征、成像和结果方面，将具有这种突变的携带者与来自 MYBPC3 p.Arg502Trp/Gln 的携带者进行了比较。结果 MYBPC3 c.2149–1G> 在 570 名先证者中的 8 名和 25 名亲属中发现了 A。外显率与年龄和性别有关，50.0% 的 36 岁以上携带者和 75.0% 的 40 岁以上携带者显示 HCM。男性的外显率显着更高：在 30 岁以上的携带者中，100.0% 的男性和 50.0% 的女性具有 HCM 表型 (p=0.01)。男性在诊断时也更年轻（32±13 岁 vs 53±10 岁，p<0.001）。MYBPC3 c.2149-1G>A 导致转录异常，导致单倍体不足，并被分离为两种单倍体。然而，两者都来自一个创始人单倍型。与 MYBPC3 p.Arg502Trp/Gln 患者相比，受影响的携带者表现出更好的功能等级和更高的左心室射血分数 (LVEF)（两者 p<0.05）。尽管如此，两组之间主要不良结局的发生率相似。结论 MYBPC3 c．2149–1G>一个剪接变异是一个创始人突变。受影响的男性表现出较早的 HCM 发病率和比女性更高的外显率。与 MYBPC3 p.Arg502Trp/Gln 携带者相比，携带者显示出更好的功能等级和更高的 LVEF，但主要不良结果的发生率相似。可应合理要求提供数据。与研究相关的所有数据都包含在文章中或作为在线补充信息上传。