Background
Congenital heart disease (CHD) is a class of cardiovascular defects that includes septal defects, outflow tract abnormalities, and valve defects. Human homolog of Drosophila headcase (
HECA
) is a novel cell cycle regulator whose role in CHD has not been elucidated. This is the first study to determine the frequency of
HECA
mutations in patients with CHD and the association between
HECA
variants and CHD.
Methods
In this study, we identified a candidate gene,
HECA
, by whole‐exome sequencing of an atrial septal defect family. To investigate the association between
HECA
variants and CHD risk, targeted exon sequencing was conducted in 689 individuals with sporadic CHD. We further analyzed the effect of
HECA
gene abnormalities on cardiomyocyte phenotype behavior and related signaling pathways by Western blotting, reverse transcription‐quantitative polymerase chain reaction, and scratch assay.
Results
We found a novel de novo mutation, c.409_410insA (p. W137fs), in the
HECA
gene and identified five rare deleterious variants that met the filtering criteria in 689 individuals with sporadic CHD. Fisher's exact test revealed a significant association between
HECA
variations and CHD compared with those in gnomADv2‐East Asians(
p
= 0.0027). Further functional analysis suggested that the variant p. W137fs resulted in a deficiency of the normal HECA protein, and HECA deficiency altered AC16 cell cycle progression, increased cell proliferation, and migration, and promoted the activation of the PDGF‐BB/PDGFRB/AKT pathway.
Conclusions
Our study identified
HECA
and its six rare variants, expanding the spectrum of genes associated with CHD pathogenesis in the Chinese population.