Novel insertion mutation (R1822_E1823dup) in MYH6 coiled-coil domain
causing familial atrial septal defect
Atrial septal defect, secundum (ASD Ⅱ, OMIM: 603642) is the second
common congenital heart defect (CHD) in China. However, the genetic
etiology of familial ASD II remains elusive. Using whole-exome
sequencing (WES) and Sanger sequencing, we identified a novel myosin
heavy chain 6 (MYH6) gene insertion variation,
NM_002471.3:c.5465_5470dup (R1822_E1823dup), in a large Chinese Han
family with ASD II. The variant R1822_E1823dup co-segregated with the
disease in this family with autosomal dominant inheritance. The
insertion variant located in the coiled-coil domain of the MYH6 protein,
which is highly conserved across homologous myosin proteins and species.
In transfected myoblast C2C12 cell lines, the MYH6 R1822_E1823dup
variant significantly impaired myofibril formation and increased
apoptosis but did not significantly reduce cell viability. Furthermore,
molecular simulations revealed that the R1822_E1823dup variant impaired
the myosin α-helix, increasing the stability of the coiled-coil myosin
dimer, suggesting that this variant has an effect on the coiled-coil
domain self-aggregation. These findings indicate that R1822_E1823dup
variant plays a crucial role in the pathogenesis of ASD II.
Collectively, our findings expand the spectrum of MYH6 variations
associated with familial ASD II and may provide a molecular basis in
genetic counseling and prenatal diagnosis for this Chinses family.