Deleterious coding variants in multi-case families with non-syndromic cleft lip and/or palate phenotypes

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.

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Identifiers

ORCID for Reuben Pengelly: orcid.org/0000-0001-7022-645X

ORCID for Eleanor G. Seaby: orcid.org/0000-0002-6814-8648

ORCID for Jane Gibson: orcid.org/0000-0002-0973-8285

ORCID for Sarah Ennis: orcid.org/0000-0003-2648-0869

ORCID for Andrew Collins: orcid.org/0000-0001-7108-0771

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