Dong Jiangtao, Zhang Wenjuan, Chen Qianwen, Zha Lingfeng
Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, People's Republic of China.
J Multidiscip Healthc. 2024 Nov 20;17:5363-5373. doi: 10.2147/JMDH.S494831. eCollection 2024.
Restrictive cardiomyopathy (RCM) is a heterogenous cardiomyopathy with various causes, and genetic variants take an important part of the pathogenesis. Whole-exome sequencing (WES) is effective to discover genes that cause genetic diseases. By using WES, we attempted to identify the genetic cause of an RCM family and clarify the clinical diagnosis of the patient and then provide a personalized treatment plan.
Blood samples were obtained from the proband and his healthy parents. WES and Sanger sequencing were performed to identify the possible pathogenic gene. Co-segregation analysis was conducted for candidate variants, and the allele frequency was checked in databases including Ensembl, Exome Aggregation Consortium (ExAC) and Human Gene Mutation Database (HGMD). Furthermore, the potential effect of variant was predicted using various-free software such as SIFT, Polyphen-2 and Mutation Taster and the conservation was tested using multiple sequence alignments by ClustalX.
The proband was a 20 years old boy with severe heart failure symptoms including dyspnea, massive ascites, edema of both lower limbs and chest congestion. Echocardiography showed significant biatrial enlargement, normal left ventricular wall thickness and preserved systolic function of both ventricles. A missense mutation in (c.6451G>A, p.G2151S), encoded filamin-C was detected in proband by WES and Sanger sequencing, while it was not be found in his parents, we supposed that the mutation (c.6451G>A, p.G2151S) may be a de-novo mutation. Through multiple functional predictions, we found that it is a deleterious mutation and the mutation in filamin-C could alter its structure and normal function, contributing to RCM.
Here, an missense mutation (c.6451G>A, p.G2151S) known to be pathogenic in hypertrophic cardiomyopathy, was found to be associated with RCM, indicating the genetic overlap among cardiomyopathies. This study provides insights into Phenotype-Genotype Correlations of RCM in patients with mutations.
限制型心肌病（RCM）是一种病因多样的异质性心肌病，遗传变异在其发病机制中起重要作用。全外显子组测序（WES）对于发现导致遗传疾病的基因很有效。通过使用WES，我们试图确定一个RCM家族的遗传病因，明确患者的临床诊断，进而提供个性化治疗方案。
采集先证者及其健康父母的血样。进行WES和Sanger测序以确定可能的致病基因。对候选变异进行共分离分析，并在包括Ensembl、外显子聚合联盟（ExAC）和人类基因突变数据库（HGMD）等数据库中检查等位基因频率。此外，使用诸如SIFT、Polyphen-2和Mutation Taster等多种免费软件预测变异的潜在影响，并通过ClustalX进行多序列比对来测试保守性。
先证者是一名患有严重心力衰竭症状的20岁男孩，症状包括呼吸困难、大量腹水、双下肢水肿和胸部充血。超声心动图显示双房显著扩大，左心室壁厚度正常，双心室收缩功能保留。通过WES和Sanger测序在先证者中检测到编码细丝蛋白C的基因（c.6451G>A，p.G2151S）中的一个错义突变，而在其父母中未发现，我们推测该 突变（c.6451G>A，p.G2151S）可能是一个新发突变。通过多种功能预测，我们发现它是一个有害突变，细丝蛋白C中的突变可能会改变其结构和正常功能，导致RCM。
在此，发现一个已知在肥厚型心肌病中致病的 错义突变（c.6451G>A，p.G2151S）与RCM相关，表明心肌病之间存在遗传重叠。本研究为 突变患者的RCM表型-基因型相关性提供了见解。
