目的:肥厚型心肌病(HCM)是一种常染色体显性遗传性心脏病,以无法解释的左心室肥厚为特征。它可以引起广泛的临床表现,从无症状到心力衰竭和心源性猝死(SCD)。大约一半的HCM病例是由肌节蛋白的变异引起的,包括α-原肌球蛋白(TPM1)。在这项研究中,我们旨在描述伊朗SCD家系中HCM的临床和分子表型。
结果:先证者和现有家庭成员接受了全面的临床评估,包括超声心动图,心脏磁共振(CMR)成像和心电图(ECG)。在所有可用的家族成员中进行全外显子组测序(WES)以鉴定因果变异,经过验证,并通过Sanger测序进行分离分析。WES发现了一个新的错义变体,c.761a>G:p.D254G(NM_001018005.2),在TPM1基因中,在先证者中,他的父亲和他的一个姐妹。生物信息学分析预测其可能是致病性的。受影响个体的临床特征与HCM一致。
结论:在患有HCM和SCD的家庭中鉴定出一种新的TPM1变异,强调了遗传筛查在高危家庭中的关键作用。及早发现致病变异,有利于及时干预和管理,潜在地降低患有HCM的个体的SCD风险。
OBJECTIVE: Hypertrophic cardiomyopathy (HCM) is an autosomal dominant genetic cardiac disorder characterized by unexplained left ventricular hypertrophy. It can cause a wide spectrum of clinical manifestations, ranging from asymptomatic to heart failure and sudden cardiac death (SCD). Approximately half of HCM cases are caused by variants in sarcomeric proteins, including α-
tropomyosin (TPM1). In this study, we aimed to characterize the clinical and molecular phenotype of HCM in an Iranian pedigree with SCD.
RESULTS: The proband and available family members underwent comprehensive clinical evaluations, including echocardiography, cardiac magnetic resonance (CMR) imaging and electrocardiography (ECG). Whole-exome sequencing (WES) was performed in all available family members to identify the causal variant, which was validated, and segregation analysis was conducted via Sanger sequencing. WES identified a novel missense variant, c.761A>G:p.D254G (NM_001018005.2), in the TPM1 gene, in the proband, his father and one of his sisters. Bioinformatic analysis predicted it to be likely pathogenic. Clinical features in affected individuals were consistent with HCM.
CONCLUSIONS: The identification of a novel TPM1 variant in a family with HCM and SCD underscores the critical role of genetic screening in at-risk families. Early detection of pathogenic variants can facilitate timely intervention and management, potentially reducing the risk of SCD in individuals with HCM.