Abstract
BackgroundNonsyndromic oral clefts are craniofacial malformations, which include cleft lip with or without cleft palate. The etiology for oral clefts is complex with both genetic and environmental factors contributing to risk. Previous genome‐wide association (GWAS) studies have identified multiple loci with small effects; however, many causal variants remain elusive.MethodsIn this study, we address this by specifically looking for rare, potentially damaging variants in family‐based data. We analyzed both whole exome sequence (WES) data and whole genome sequence (WGS) data in multiplex cleft families to identify variants shared by affected individuals.ResultsHere we present the results from these analyses. Our most interesting finding was from a single Syrian family, which showed enrichment of nonsynonymous and potentially damaging rare variants in two genes: CASP9 and FAT4.ConclusionNeither of these candidate genes has previously been associated with oral clefts and, if confirmed as contributing to disease risk, may indicate novel biological pathways in the genetic etiology for oral clefts.
Highlights
Nonsyndromic oral clefts, including cleft lip with or without cleft palate (CL/P) and cleft palate (CP) alone, are the most common craniofacial malformations in humans
Neither of these candidate genes has previously been associated with oral clefts and, if confirmed as contributing to disease risk, may indicate novel biological pathways in the genetic etiology for oral clefts
Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc
Summary
Nonsyndromic oral clefts, including cleft lip with or without cleft palate (CL/P) and cleft palate (CP) alone, are the most common craniofacial malformations in humans. Previous linkage and genome-wide association studies (GWAS) have identified multiple genes and regions associated with risk for CL/P. We have identified a novel, potentially damaging variant in CDH1 in one multiplex CL/P family based on whole exome sequence (WES) data (Bureau et al 2014). For this analysis, we used WES and whole genome sequence (WGS) data in families with distantly related affected individuals (second or third degree relationships) to identify genes containing shared rare variants. Previous genome-wide association (GWAS) studies have identified multiple loci with small effects; many causal variants remain elusive
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