Rare variant modifier analysis identifies variants in SEC24D associated with orofacial cleft subtypes

Area of Science:

• Genetics
• Developmental Biology
• Pediatric Research

Background:

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

Purpose of the Study:

• To investigate the contribution of rare genetic variation to different OFC phenotypes.
• To differentiate genetic modifiers between cleft lip (CL) and cleft lip and palate (CLP).

Main Methods:

• Utilized whole-genome sequencing data from the Gabriella Miller Kids First Pediatric Research Program.
• Conducted a gene-based burden analysis comparing CL and CLP cases.
• Analyzed variants within SEC24D for overlap with craniofacial enhancers and potential impact on transcription factor binding sites (TFBS).

Main Results:

• A significantly increased burden of rare variants in SEC24D was observed in CL cases compared to CLP cases (p=6.86x10⁻⁷).
• Synonymous variants in SEC24D overlapped a known craniofacial enhancer.
• These variants were predicted to disrupt binding sites for 9 transcription factors, including Pax1, and create binding sites for 23 transcription factors, including Pax6 and Pax9.

Conclusions:

• Rare genetic variation contributes to the phenotypic heterogeneity observed in orofacial clefts.
• Regulatory variations, particularly within genes like SEC24D, may play a functional role in OFC development.
• Further investigation into regulatory variations is warranted for understanding genetic risk factors for OFCs.