Abstract
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.
Highlights
Atrial septal defect (ASD) is one of the most common forms of congenital heart defects (CHD), with an estimated incidence of an approximately 100 per 100 000 live births [1] and accounting for 10–15% of CHD worldwide [2,3,4]
The entire 40 kb of myosin heavy chain 3 (MYH3) was successfully sequenced in 51 non-syndromic ASD patients using LRPCR-NGS approach
Evolutionary conservation analysis of MYH3 amino acid sequence showed that these variants are highly conserved in the sarcomeric MYH genes expressed in the heart, and orthologous sequence alignment showed it to be conserved in chimp, mouse, rat, human and dog
Summary
Atrial septal defect (ASD) is one of the most common forms of congenital heart defects (CHD), with an estimated incidence of an approximately 100 per 100 000 live births [1] and accounting for 10–15% of CHD worldwide [2,3,4]. Based on the location relative to the fosa ovalis, ASD refers to a communication between the right and left atria, anatomically classified. MYH3 variants and the risk of atrial septal defect. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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