Mutations in the tail domain of MYH3 contributes to atrial septal defect

Atrial septal defect (ASD) is one of the most common congenital heart defects diagnosed in children. Sarcomeric genes has been attributed to ASD and knockdown of MYH3 functionally homologues gene in chick models indicated abnormal atrial septal development. Here, we report for the first time, a case-control study investigating the role of MYH3 among non-syndromic ASD patients in contributing to septal development. Four amplicons which will amplifies the 40 kb MYH3 were designed and amplified using long range-PCR. The amplicons were then sequenced using indexed paired-end libraries on the MiSeq platform. The STREGA guidelines were applied for planning and reporting. The non-synonymous c. 3574G>A (p.Ala1192Thr) [p = 0.001, OR = 2.30 (1.36–3.87)] located within the tail domain indicated a highly conserved protein region. The mutant model of c. 3574G>A (p.Ala1192Thr) showed high root mean square deviation (RMSD) values compared to the wild model. To our knowledge, this is the first study to provide compelling evidence on the pathogenesis of MYH3 variants towards ASD hence, suggesting the crucial role of non-synonymous variants in the tail domain of MYH3 towards atrial septal development. It is hoped that this gene can be used as panel for diagnosis of ASD in future.

心房间隔缺损（ASD）是儿童中诊断出的最常见的先天性心脏病之一。研究表明，肌节基因与ASD有关，且在鸡模型中敲低MYH3功能同源基因功能表明心房间隔发育异常。本研究首次报道了一项病例对照研究，旨在探讨MYH3在非综合征性ASD患者中促进房间隔发育的作用。我们设计了四个扩增子，用于扩增40 kb的MYH3基因，并通过长距离PCR技术进行扩增。随后，使用MiSeq平台上的索引配对末端文库对扩增子进行测序。本研究遵循STREGA指南进行规划和报告。位于尾结构域的非同义突变c.3574G>A（p.Ala1192Thr）[p = 0.001，OR = 2.30 (1.36–3.87)]表明了一个高度保守的蛋白区域。与野生型模型相比，c.3574G>A（p.Ala1192Thr）突变模型的均方根偏差（RMSD）值较高。据我们所知，这是首项提供有力证据的研究，证明了MYH3基因变异在ASD发病机制中的作用，从而表明非同义变异在MYH3尾结构域对心房间隔发育的重要性。我们期望该基因未来能作为ASD诊断的检测面板。