Genomic analysis of 11,555 probands identifies 60 dominant congenital heart disease genes.

Summary

In 11,555 CHD probands, burden testing across 248 genes identified 60 dominant genes explaining 10.1% of cases, with similar contributions from de novo and transmitted variants and incomplete penetrance. Tissue- and subtype-specific patterns emerged, including NOTCH1 EGF-like domain cysteine-altering missense variants enriched in tetralogy of Fallot/conotruncal defects and brain-expressed genes linked to neurodevelopmental delay.

Key Findings

• Identified 60 genes with significant heterozygous damaging variant burdens among 248 prespecified genes in 11,555 probands.
• Variants in these genes explained 10.1% of CHD cases with similar contributions from de novo and transmitted variants and incomplete penetrance.
• NOTCH1 EGF-like domain cysteine-altering missense variants were enriched in tetralogy of Fallot and conotruncal defects, whereas loss-of-function variants had broader CHD associations.
• Gene expression patterns linked cardiomyocyte-lineage genes to isolated CHD and brain-expressed genes to CHD with neurodevelopmental delay.

Clinical Implications

Findings support expanded gene panels and trio testing in CHD, refine genetic counseling (penetrance, extracardiac risks), and suggest mechanistic stratification (e.g., NOTCH1 cysteine variants) for subtype-tailored management.

Limitations

• Analysis limited to 248 prespecified genes; genetic contributors outside this panel were not assessed.
• Functional validation of specific variants/mechanisms was not described in the abstract.

Future Directions

Expand to genome/exome-wide analyses with functional validation, integrate polygenic risk and noncoding variants, and translate subtype-specific mechanisms into precision diagnostics and interventions.