Genomic analyses implicate noncoding de novo variants in congenital heart disease

Area of Science:

• Genetics
• Genomics
• Cardiovascular Biology

Background:

• Congenital heart disease (CHD) has a known genetic component, with coding de novo variants (DNVs) accounting for 8% of cases.
• The role of noncoding DNVs in CHD etiology remains less understood, despite their potential to influence gene regulation.

Purpose of the Study:

• To investigate the contribution of noncoding DNVs to the genetic basis of CHD.
• To identify specific noncoding regions and regulatory elements where DNVs are enriched in CHD patients.

Main Methods:

• Genome sequencing data from 749 CHD probands and their parents were compared with 1,611 unaffected trios.
• Neural network models predicted the transcriptional impact of noncoding DNVs.
• Enhancer regions and RNA-binding protein regulatory sites were analyzed for DNV burden.

Main Results:

• A significant burden of noncoding DNVs was identified in CHD individuals compared to controls (P = 8.7 × 10⁻⁴).
• An excess of DNVs was found in genes associated with enhancers (P = 1 × 10⁻⁵) and RNA-binding protein sites (P = 8.8 × 10⁻⁵).
• Functional assays confirmed that CHD-associated DNVs can alter enhancer transcription levels.

Conclusions:

• Potentially disruptive regulatory noncoding DNVs are enriched in a substantial fraction of CHD cases.
• These findings highlight the critical role of noncoding variants in CHD pathogenesis, comparable to that of coding variants.