Rare genetic variants in SEC24D modify orofacial cleft phenotypes

Area of Science:

• Genetics
• Developmental Biology
• Pediatric Research

Background:

• Orofacial clefts (OFCs) are common birth defects with known genetic influences.
• The role of rare, genome-wide genetic variation in OFC subtypes remains understudied.
• Previous research often focused on common variants or targeted genomic regions.

Approach:

• Utilized whole-genome sequencing data from the Gabriella Miller Kids First Pediatric Research Program.
• Performed a gene-based burden analysis to compare rare variant burdens between cleft lip (CL) and cleft lip and palate (CLP) cases.
• Investigated the functional impact of identified variants on transcription factor binding sites (TFBS).

Key Points:

• A significantly increased burden of rare variants in the SEC24D gene was observed in CL cases compared to CLP cases (p=6.86×10⁻⁷).
• Synonymous variants within SEC24D overlapped a craniofacial enhancer region.
• These variants altered predicted transcription factor binding sites, affecting key developmental genes like Pax1, Pax6, and Pax9.

Conclusions:

• Rare genetic variation contributes to the phenotypic diversity observed in orofacial clefts.
• Synonymous variants within regulatory regions may play a functional role in OFC development.
• Further investigation into regulatory variation is warranted for understanding OFC genetic risk.