title: 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.
authors.affiliation: Genetic Epidemiology and Genomic Informatics, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Reuben J
authors.initials: RJ
authors.lastname: Pengelly
authors.affiliation: Department of Biomedical Sciences, Medical School, Universidad de La Sabana, Bogota, Colombia.
authors.forename: Liliana
authors.initials: L
authors.lastname: Arias
authors.affiliation: Department of Biomedical Sciences, Medical School, Universidad de La Sabana, Bogota, Colombia.
authors.forename: Julio
authors.initials: J
authors.lastname: Martínez
authors.affiliation: Genetic Epidemiology and Genomic Informatics, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Upstill-Goddard
authors.affiliation: Genetic Epidemiology and Genomic Informatics, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Eleanor G
authors.initials: EG
authors.lastname: Seaby
authors.affiliation: Centre for Biological Sciences, Faculty of Natural &Environmental Sciences, University of Southampton, Southampton, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Gibson
authors.affiliation: Genetic Epidemiology and Genomic Informatics, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Genetic Epidemiology and Genomic Informatics, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Collins
authors.affiliation: Department of Biomedical Sciences, Medical School, Universidad de La Sabana, Bogota, Colombia.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Briceño
mesh_terms: D001921:Brain / Q000002:abnormalities* / Q000473:pathology; D002971:Cleft Lip / Q000235:genetics* / Q000473:pathology*; D002972:Cleft Palate / Q000235:genetics* / Q000473:pathology*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D054643:INDEL Mutation / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D016366:Open Reading Frames / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics