Masoumi Tannaz, Hesami Hamed, Maleki Majid, Kalayinia Samira
Rajaie Cardiovascular Institute, Tehran, Iran.
Cardiogenetic Research Center, Rajaie Cardiovascular Institute, Tehran, Iran.
BMC Med Genomics. 2025 Apr 30;18(1):82. doi: 10.1186/s12920-025-02150-3.
Restrictive cardiomyopathy (RCM) is a rare cardiac disorder characterized by diastolic dysfunction and myocardial stiffness, frequently associated with genetic variants. We aimed to explore the genetic basis of RCM in a diagnosed patient through comprehensive genetic analysis.
Whole exome sequencing (WES) was conducted on the proband, followed by Sanger sequencing for variant confirmation and familial segregation analysis. In silico tools and structural protein modeling were employed to assess the functional impact of the identified variant.
The c.406 C > T variant, classified as likely pathogenic, results in a truncated TNNI3 protein. Bioinformatics analysis highlighted significant structural disruptions, likely impairing sarcomere function. The patient presented with growth retardation, progressive dyspnea, and echocardiographic findings consistent with RCM. Both parents were heterozygous carriers, supporting an autosomal recessive inheritance pattern. The homozygosity of the novel variant identified in this study is a critical factor in the genotype-phenotype correlation observed in this case.
This study identified the novel c.406 C > T variant in TNNI3 as a potential pathogenic driver of RCM, emphasizing the critical role of genetic evaluations in early diagnosis and management of inherited cardiomyopathies. Further studies are warranted to explore therapeutic interventions targeting TNNI3-related pathologies.
限制性心肌病（RCM）是一种罕见的心脏疾病，其特征为舒张功能障碍和心肌僵硬，常与基因变异相关。我们旨在通过全面的基因分析，探究一名已确诊患者RCM的遗传基础。
先对先证者进行全外显子组测序（WES），随后进行Sanger测序以确认变异并进行家系分离分析。利用计算机工具和结构蛋白建模来评估所鉴定变异的功能影响。
c.406 C>T变异被归类为可能致病，导致TNNI3蛋白截短。生物信息学分析突出了显著的结构破坏，可能损害肌节功能。该患者表现为生长发育迟缓、进行性呼吸困难，且超声心动图检查结果与RCM相符。父母双方均为杂合携带者，支持常染色体隐性遗传模式。本研究中鉴定出的新变异的纯合性是该病例中观察到的基因型-表型相关性的关键因素。
本研究确定TNNI3基因中的新变异c.406 C>T是RCM的潜在致病驱动因素，强调了基因评估在遗传性心肌病早期诊断和管理中的关键作用。有必要开展进一步研究以探索针对TNNI3相关病变的治疗干预措施。
