title: Resolving clinical diagnoses for syndromic cleft lip and/or palate phenotypes using whole-exome sequencing.
abstract: Individuals from three families ascertained in Bogota, Colombia, showing syndromic phenotypes, including cleft lip and/or palate, were exome-sequenced. In each case, sequencing revealed the underlying causal variation confirming or establishing diagnoses. The findings include very rare and novel variants providing insights into genotype and phenotype relationships. These include the molecular diagnosis of an individual with Nager syndrome and a family exhibiting an atypical incontinentia pigmenti phenotype with a missense mutation in IKBKG. IKBKG mutations are typically associated with preterm male death, but this variant is associated with survival for 8-15 days. The third family exhibits unusual phenotypic features and the proband received a provisional diagnosis of Pierre Robin sequence (PRS). Affected individuals share a novel deleterious mutation in IRF6. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndrome and contribute to nonsyndromic cleft lip phenotypes but have not previously been associated with a PRS phenotype. Exome sequencing followed by in silico screening to identify candidate causal variant(s), and functional assay in some cases offers a powerful route to establishing molecular diagnoses. This approach is invaluable for conditions showing phenotypic and/or genetic heterogeneity including cleft lip and/or palate phenotypes where many underlying causal genes have not been identified.
authors.affiliation: Genetic Epidemiology and Genomic Informatics, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: R J
authors.initials: RJ
authors.lastname: Pengelly
authors.affiliation: Genetic Epidemiology and Genomic Informatics, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: R
authors.initials: R
authors.lastname: Upstill-Goddard
authors.affiliation: Department of Biomedical Sciences, Medical School, Universidad de La Sabana, Bogota, Colombia.
authors.forename: L
authors.initials: L
authors.lastname: Arias
authors.affiliation: Department of Biomedical Sciences, Medical School, Universidad de La Sabana, Bogota, Colombia.
authors.forename: J
authors.initials: J
authors.lastname: Martinez
authors.affiliation: Centre for Biological Sciences, Faculty of Natural & Environmental Sciences, University of Southampton, Southampton, UK.
authors.forename: J
authors.initials: J
authors.lastname: Gibson
authors.affiliation: Genetic Epidemiology and Genomic Informatics, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: M
authors.initials: M
authors.lastname: Knut
authors.affiliation: Department of Clinical Genetics, Southampton General Hospital, Southampton, UK.
authors.forename: A L
authors.initials: AL
authors.lastname: Collins
authors.affiliation: Genetic Epidemiology and Genomic Informatics, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: S
authors.initials: S
authors.lastname: Ennis
authors.affiliation: Genetic Epidemiology and Genomic Informatics, Faculty of Medicine, University of Southampton, Southampton, UK.
authors.forename: A
authors.initials: A
authors.lastname: Collins
authors.affiliation: Department of Biomedical Sciences, Medical School, Universidad de La Sabana, Bogota, Colombia.
authors.forename: I
authors.initials: I
authors.lastname: Briceno
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000328:Adult; D002648:Child; D002971:Cleft Lip / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D002972:Cleft Palate / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D003198:Computer Simulation; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics; D007223:Infant; D050835:Interferon Regulatory Factors / Q000378:metabolism; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome
chemical_list: C491731:IKBKG protein, human; C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors; D051550:I-kappa B Kinase
keywords: Nager syndrome; Pierre Robin sequence; cleft lip and palate; exome sequencing; incontinentia pigmenti; syndromic disease