Introduction and objectives

Up to 50% of patients with hypertrophic cardiomyopathy (HCM) show no disease-causing variants in genetic studies. Mutations in CSRP3 have been associated with HCM, but evidence supporting pathogenicity is inconclusive. In this study, we describe an HCM cohort with a missense variant in CSRP3 (p.Cys150Tyr) with supporting evidence for pathogenicity and a description of the associated phenotype.

Methods

CSRP3 was sequenced in 6456 index cases with a diagnosis of HCM and in 5012 probands with other cardiomyopathies. In addition, 3372 index cases with hereditary cardiovascular disorders other than cardiomyopathies (mainly channelopathies and aortopathies) were used as controls.

Results

The p.(Cys150Tyr) variant was identified in 11 unrelated individuals of the 6456 HCM probands, and it was not identified in patients with other cardiomyopathies (p < 0.0001) or in our control population (p < 0.0001). Ten of the index cases were heterozygous and one was homozygous. Homozygous had a more severe phenotype. Family screening identified 17 other carriers. Wild-type individuals showed no signs of disease. The mean age at diagnosis of affected individuals was 55 ± 13 years, and the mean left ventricular wall thickness was 18 ± 3 mm. The variant showed highly age-dependent penetrance. After a mean follow-up of 11 (±8) years, no adverse events were reported in any of the HCM patients.

Conclusions

The p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hypertrophic cardiomyopathy in heterozygous carriers.

中文翻译：

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在P（Cys150Tyr）变种CSRP3与杂合子个体迟发性肥厚型心肌病有关

介绍和目标

多达50％的肥厚型心肌病（HCM）患者在基因研究中未显示任何致病变异。CSRP3中的突变与HCM有关，但尚无支持致病性的证据。在这项研究中，我们描述了在CSRP3（p.Cys150Tyr）中具有错义变异的HCM队列，并提供了致病性证据和相关表型的描述。

方法

CSRP3在6456例诊断为HCM的索引病例中和5012例其他心肌病先证者中进行了测序。另外，以3372例除心肌病（主要是通道病和主动脉病）以外的遗传性心血管疾病的索引病例作为对照。

结果

p。（Cys150Tyr）变体在6456个HCM先证者中的11个无关个体中发现，在其他心肌病患者（p <0.0001）或我们的对照人群（p <0.0001）中未发现。索引病例中有10例为杂合子，其中1例为纯合子。纯合子具有更严重的表型。家庭筛查确定了其他17个携带者。野生型个体未显示疾病迹象。诊断出患病个体的平均年龄为55±13岁，平均左心室壁厚为18±3 mm。该变体表现出高度的年龄依赖性。在平均随访11（±8）年之后，没有任何HCM患者报告不良事件。

结论

在P（Cys150Tyr）的变型CSRP3导致杂合子携带者肥厚型心肌病的迟发性及低风险的形式。