Role of Rare Variants in Craniofacial Enhancer Regions in the Etiology of Non‐Syndromic Orofacial Clefts

다국어 초록 (Multilingual Abstract)

Orofacial clefts are the most common congenital birth defects accounting for 65% of all head and neck deformities. To date, Genome Wide Association Studies (GWAS) have identified over 60 common risk loci for Non syndromic orofacial clefts (NSOFCs). Collectively, these loci only explain 20‐30% of its heritability. Interestingly, a substantial number of these loci are in the non‐coding regulatory elements of the genome. Thus, to provide more explanation for the “missing heritability”, we investigated putative craniofacial and ectodermal enhancer elements for rare variants with probable etiological implication in the pathogenesis of NSOFCs.
Candidate craniofacial enhancer elements were identified from previous literatures and mouse models. Following filtration to include only those with more than one rare (MAF < 1%) SNP from our data. The final test datasets included 73 regions, which consisted of 168 unique SNPs. Two different burden tests (combined multivariate and collapsing (CMC) test and sequence kernel association test (SKAT) were performed.
We found a suggestive significant association (p = 0.009) with a putative craniofacial enhancer located within an intronic region of PRDM16 gene (Chr1:3148388‐3149216) after correcting for multiple testing. PRDM16 is a known cleft candidate gene and analysis is on‐going to determine the enhancer activity of this region using ATAC‐Seq data from relevant craniofacial tissues.
Our findings suggest a role for rare variants within craniofacial enhancer regions in the complex etiology of NSOFCs.