GENOMIC analysis of 11,555 congenital heart disease (CHD) probands identified 60 dominant genes contributing to 10.1% of cases, with equal contributions from inherited and spontaneous mutations, highlighting the critical role of genetic testing in diagnosis and management.
CHD, a leading cause of infant mortality, arises from complex genetic factors. This study analyzed rare damaging variants in 248 genes across 11,555 CHD patients, combining whole-exome sequencing and molecular inversion probe data. Results revealed 60 genes with significant mutation burdens, including NOTCH1 and MYH6, which accounted for ~1% of cases. De novo mutations (DNMs) contributed 58% of the genetic signal, while transmitted variants explained the remainder. Mutations in 33 genes correlated with specific CHD subtypes (e.g., GATA6 with outflow tract defects), and 37 genes were linked to extracardiac abnormalities. Notably, CHD7 mutations carried a 95% risk of neurodevelopmental delay (NDD), versus 4% for MYH6. Strikingly, 41% of probands with syndromic CHD mutations lacked clinical diagnoses due to incomplete phenotypic presentations.
The findings underscore the clinical urgency of genetic testing to identify high-risk patients, particularly those with mutations in genes like CHD7 or NOTCH1, where early intervention could mitigate complications. Isolated CHD was associated with cardiomyocyte-specific genes, while brain-expressed genes correlated with NDD. Traditional clinical assessments missed 45% of syndromic cases, emphasizing molecular diagnostics’ value. With 10.1% of CHD now attributable to these 60 genes, proactive screening could improve prognoses, family counseling, and personalized care. Future research should expand gene panels and explore therapeutic targets within identified pathways.
Reference
Sierant MC et al. Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes. Proc Natl Acad Sci U.S.A. 2025;122(13) e2420343122.
