Functional analysis of HECA variants identified in congenital heart disease in the Chinese population

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.