Case Report: A rare stop-gained MYZAP mutation is associated with atrioventricular septal defects in an Arabian...

Atrioventricular septal defects (AVSDs) represent a diverse group of congenital cardiac malformations arising from abnormal development of the endocardial cushions. Although several transcription factors have been implicated in septation, the contributions of structural proteins involved in cardiomyocyte integrity remain incompletely understood.

We investigated an Arabian family presenting with a spectrum of AVSD phenotypes, including complete AVSD, partial AVSD, and an isolated cleft of the anterior mitral leaflet. Whole-exome sequencing identified a novel homozygous stop-gain variant in the MYZAP gene (NM_001018100.5:c.229C > T; p.Arg77Ter) in two affected siblings. Segregation analysis confirmed heterozygous carriage in the father and absence in the unaffected mother. The variant is extremely rare in population databases and meets ACMG criteria for likely pathogenicity.

This report expands the phenotypic spectrum associated with MYZAP and suggests a potential role in cardiac septation. While MYZAP is primarily linked to cardiomyopathy, our findings raise the possibility that it may contribute to congenital cardiac malformations, potentially through disruption of cardiomyocyte adhesion or developmental signaling pathways controling cardiogenesis. Further functional studies are required to validate this association.