Cardiovascular Genetics Department, Health in Code, A Coruña, Spain; Genetics Department, Universitat Autònoma de Barcelona, Barcelona, Spain; Clinical Genetics Department, Hospital Universitario de Bellvitge, Barcelona, Spain.
Inherited Cardiac Diseases Unit, Cardiology Department, Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain.
Eur J Med Genet. 2020 Dec;63(12):104079. doi: 10.1016/j.ejmg.2020.104079. Epub 2020 Oct 7.
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.
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.
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.
The p.(Cys150Tyr) variant in CSRP3 causes late-onset and low risk form of hypertrophic cardiomyopathy in heterozygous carriers.
多达 50%的肥厚型心肌病 (HCM) 患者在基因研究中未显示出致病变异。CSRP3 突变与 HCM 相关，但支持其致病性的证据尚无定论。在这项研究中，我们描述了一个具有 CSRP3 错义变异（p.Cys150Tyr）的 HCM 队列，该变异具有支持其致病性的证据，并描述了相关表型。
在 6456 名诊断为 HCM 的索引病例和 5012 名患有其他心肌病的先证者中对 CSRP3 进行测序。此外，还将 3372 名患有遗传性心血管疾病（主要为通道病和大血管病）而非心肌病的索引病例作为对照。
在 6456 名 HCM 先证者中，有 11 名无亲缘关系的个体发现了 p.(Cys150Tyr) 变异，而在患有其他心肌病的患者（p < 0.0001）或我们的对照人群中（p < 0.0001）未发现该变异。10 名索引病例为杂合子，1 名为纯合子。纯合子的表型更为严重。家系筛查发现了另外 17 名携带者。野生型个体无疾病迹象。受影响个体的平均诊断年龄为 55 ± 13 岁，平均左心室壁厚度为 18 ± 3 mm。该变异显示出高度依赖年龄的外显率。在平均 11（±8）年的随访后，没有报告任何 HCM 患者出现不良事件。
CSRP3 中的 p.(Cys150Tyr) 变异导致杂合子携带者发生迟发性和低风险形式的肥厚型心肌病。
