Friday, April 26, 2024
4/26/2024
Orofacial clefts (OFCs) are one of the most common craniofacial congenital anomalies, affecting 1 in 1,000 individuals worldwide. OFCs occur when the mouth or lip does not form properly during embryonic development. Most OFCs are non-syndromic, occurring as isolated cases, and are classified as a complex genetic disorder. Previous genome-wide association studies (GWAS) have identified common genetic variants associated with an increased OFC risk, altogether accounting for 25% of the known heritability. However, the remaining significant portion of heritability that is unaccounted for may be attributed to rare coding and non- coding genetic variants as they tend to have large effect sizes. Various studies in families with OFCs have successfully used whole-exome sequencing (WES) and whole-genome sequencing (WGS) to identify rare causal mutations, but rare variants have not been explored in large OFC cohorts. We hypothesize that rare variants contribute significantly to cleft risk in non-syndromic OFC families and we will investigate the role of these variants in two large non-syndromic OFC cohorts, one consisting of 72 families with WES data and the other cohort consisting of 815 OFC trios (parents and affected child) with WGS data. These cohorts will help us identify coding and non-coding variants that may contribute to the risk for non-syndromic OFCs, thereby elucidating some of the missing heritability of OFCs. As a method to investigate the contribution of rare genetic variants in non-syndromic OFCs, we created a gene panel containing 336 genes implicated in OFCs, compiling information from functional studies, OFC GWAS, and other published evidence. In the first aim, we will identify rare coding pathogenic variants in genes from our gene panel in non-syndromic OFC families by using segregation analyses and burden tests. In the second aim, we will identify non-coding pathogenic variants in putative craniofacial enhancers near the genes in the gene panel to help us focus our search and enrich for variants that are most likely implicated in OFCs. We will use publicly available functional epigenomic databases and association tests to locate pathogenic variants in craniofacial enhancers near OFC genes. Importantly, these results will provide new avenues to elucidate the missing heritability of OFCs and provide an understanding of OFC-associated and novel genes, and their mechanism leading to OFC pathogenesis.
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