Abstract
Nonsyndromic Cleft Lip and/or Palate (NSCLP) is regarded as a multifactorial condition in which clefting is an isolated phenotype, distinguished from the largely monogenic, syndromic forms which include clefts among a spectrum of phenotypes. Nonsyndromic clefting has been shown to arise through complex interactions between genetic and environmental factors. However, there is increasing evidence that the broad NSCLP classification may include a proportion of cases showing familial patterns of inheritance and contain highly penetrant deleterious variation in specific genes. Through exome sequencing of multi-case families ascertained in Bogota, Colombia, we identify 28 non-synonymous single nucleotide variants that are considered damaging by at least one predictive score. We discuss the functional impact of candidate variants identified. In one family we find a coding variant in the MSX1 gene which is predicted damaging by multiple scores. This variant is in exon 2, a highly conserved region of the gene. Previous sequencing has suggested that mutations in MSX1 may account for ~2% of NSCLP. Our analysis further supports evidence that a proportion of NSCLP cases arise through monogenic coding mutations, though further work is required to unravel the complex interplay of genetics and environment involved in facial clefting.
Highlights
Growing evidence for involvement of rare variants of larger effect in nonsyndromic cleft lip and/or palate (NSCLP) including, for example, truncating mutations in the ARHGAP29 gene[8] and mutations in the IRF6 gene, which is known to contain mutations involved in malformation syndromes that include Cleft lip and/or palate (CLP) such as Van der Woude[9]
We consider here a number of NSCLP families with multiple affected individuals and undertake exome sequencing to investigate the contribution of rare variants in genes previously associated with any form of clefting phenotype
To understand the spectrum of potentially damaging variation, we considered the list of 865 genes previously implicated in any form of CLP phenotype presented by Pengelly et al.[11] (Supplementary Table 2)
Summary
Growing evidence for involvement of rare variants of larger effect in NSCLP including, for example, truncating mutations in the ARHGAP29 gene[8] and mutations in the IRF6 gene, which is known to contain mutations involved in malformation syndromes that include CLP such as Van der Woude[9]. We consider here a number of NSCLP families with multiple affected individuals and undertake exome sequencing to investigate the contribution of rare variants in genes previously associated with any form of clefting phenotype
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