Recessive genetic contribution to congenital heart disease in 5,424 probands.
Summary
Whole-exome analysis of 5,424 CHD probands estimates that rare recessive genotypes explain at least 2.2% of CHD overall and 5.4% in laterality phenotypes, with clear enrichment in consanguinity. The study catalogs recessive hits across curated CHD genes, refining genetic counseling and research priorities.
Key Findings
- Rare damaging recessive genotypes contribute to ≥2.2% of CHD overall and 5.4% in laterality phenotypes.
- Among 108 curated recessive CHD genes, 66 recessive genotypes were identified; 11 genes harbored >1 recessive genotype.
- Recessive genotypes were more prevalent in consanguineous offspring (4.7%) than in nonconsanguineous probands (0.7%).
Clinical Implications
Enhances risk counseling, especially in consanguineous populations and laterality defects; informs gene panel design and prioritization for molecular diagnosis; sets baselines for recessive disease burden in CHD.
Why It Matters
Provides the largest systematic quantification of recessive contribution across CHD phenotypes and identifies target genes/phenotypes for future discovery. This shifts understanding beyond anecdotal consanguineous families to population-level estimates.
Limitations
- Abstract truncation suggests incomplete reporting of founder variants and full gene list in this extract.
- Exome-based approach may miss non-coding/regulatory variants and structural variants.
Future Directions
Expand to whole-genome sequencing for regulatory variants; deepen analyses of laterality pathways; integrate functional validation to confirm causality and mechanisms.
Study Information
- Study Type
- Cohort
- Research Domain
- Pathophysiology
- Evidence Level
- II - Large genetic cohort study with systematic exome analysis and phenotype stratification
- Study Design
- OTHER