MYH7基因罕见变异作为双腔左心室的致病基因及相关机制研究

Double-chambered left ventricle (DCLV) is an extremely rare congenital heart malformation with severe conditions such as heart failure or death. It is characterized by two chambers in the left ventricle separated by abnormal muscle bundle or muscle fiber tissue. Only a few sporadic cases have been reported to date. The genetic etiolgy of DCLV is still unknown. In our preliminary study, we collected a DCLV pedigree and identified a MYH7 rare variant (c.A998T, p.D333V) by whole-exome sequencing co-segregated in the family. In this proposal, we will screen the mutations in the MYH7 gene in sporadic DCLV patients to confirm its genetic basis in DCLV. Meanwhile, we will further explore the pathogenesis of the rare variant in the MYH7 gene by generating a mouse mutant using Cas9 genome editing technology. In addition, we will perform functional analyses of the MYH7 mutation in vitro and in vivo, to elucidate its pathogenesis in DCLV. The study is expected to reveal the genetic basis and the pathogenesis of MYH7 gene in DCLV, which will be utilized in its early diagnosis, prevention and treatment.

双腔左心室（Double-chambered left ventricle, DCLV）是一种极其罕见的先天性心脏畸形，主要表现为左心室被异常肌束或肌性纤维分隔成两个腔室，严重者可致心力衰竭甚至死亡。DCLV发病原因不明，目前国际上没有相关的遗传学研究报道。我们在前期工作中收集到一个罕见的DCLV高发家系，并通过外显子组测序分析，初步识别致病突变为MYH7基因编码区的一个错义突变（c.A998T, p.D333V）。在此基础上，我们拟在散发病例中扩大对MYH7基因的突变筛查，进一步确定该基因的罕见变异为DCLV的遗传学病因；利用Cas9技术建立MYH7基因定点突变小鼠模型，对其进行心脏发育表型鉴定及组织病理分析，并结合MYH7的功能分析探索其基因突变导致DCLV的致病机制。本项目有望首次揭示MYH7作为DCLV的致病基因及病理机制，为其早期诊断、预防和治疗提供理论基础。

双腔左心室（DCLV）是一种罕见的先天性心脏畸形，它的特点是通过隔膜或肌带异常将左心室分为两个腔室，但是在临床上较难与左室憩室、左室室壁瘤及左室心肌致密化不全等相似疾病鉴别诊断。.在本研究中，我们首先通过病例分析，通过对DCLV患者的超声心动图影像的特点进行分析，总结出通过超声心动图对DCLV的鉴别诊断方法。进而，对全部通过病例鉴别诊断及家系调查收集的DCLV样本进行候选致病MYH7基因的突变筛查和家系先证者样本的全外显子组测序研究，检出潜在DCLV致病基因。第三，围绕通过前期工作发现的DCLV致病基因MYH7基因突变，利用Cri/cas9技术，建立了基因编辑突变小鼠动物模型，根据对小鼠模型心脏结构和功能的检测，证实Myh7 p.D333V突变可导致小鼠典型的DCLV表型，为MYH7 p.D333V的致病性提供了可靠的证据。