title: Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate.
abstract: Nonsyndromic orofacial cleft (NSOFC) is a complex disease of still unclear genetic etiology. To investigate the contribution of rare epithelial cadherin (CDH1) gene variants to NSOFC, we target sequenced 221 probands. Candidate variants were evaluated via in vitro, in silico, or segregation analyses. Three probably pathogenic variants (c.760G>A [p.Asp254Asn], c.1023T>G [p.Tyr341*], and c.2351G>A [p.Arg784His]) segregated according to autosomal dominant inheritance in four nonsyndromic cleft lip with or without cleft palate (NSCL/P) families (Lod score: 5.8 at θ = 0; 47% penetrance). A fourth possibly pathogenic variant (c.387+5G>A) was also found, but further functional analyses are needed (overall prevalence of CDH1 candidate variants: 2%; 15.4% among familial cases). CDH1 mutational burden was higher among probands from familial cases when compared to that of controls (P = 0.002). We concluded that CDH1 contributes to NSCL/P with mainly rare, moderately penetrant variants, and CDH1 haploinsufficiency is the likely etiological mechanism.
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Luciano Abreu
authors.initials: LA
authors.lastname: Brito
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Guilherme Lopes
authors.initials: GL
authors.lastname: Yamamoto
authors.affiliation: IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Soraia
authors.initials: S
authors.lastname: Melo
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Carolina
authors.initials: C
authors.lastname: Malcher
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Simone Gomes
authors.initials: SG
authors.lastname: Ferreira
authors.affiliation: IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
authors.forename: Joana
authors.initials: J
authors.lastname: Figueiredo
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Lucas
authors.initials: L
authors.lastname: Alvizi
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Gerson Shigeru
authors.initials: GS
authors.lastname: Kobayashi
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Michel Satya
authors.initials: MS
authors.lastname: Naslavsky
authors.affiliation: Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Nivaldo
authors.initials: N
authors.lastname: Alonso
authors.affiliation: Laboratório de Medicina Genômica, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brasil.
authors.forename: Temis Maria
authors.initials: TM
authors.lastname: Felix
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Mayana
authors.initials: M
authors.lastname: Zatz
authors.affiliation: IPATIMUP, Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.|Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.|Faculty of Medicine, University of Porto, Porto, Portugal.
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.affiliation: Centro de Pesquisa sobre o Genoma Humano e Células-Tronco, Departamento de Genética e Biologia Evolutiva, Instituto de Biociências, Universidade de São Paulo, São Paulo, Brasil.
authors.forename: Maria Rita
authors.initials: MR
authors.lastname: Passos-Bueno
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD; D001921:Brain / Q000002:abnormalities*; D015820:Cadherins / Q000737:chemistry / Q000235:genetics*; D002460:Cell Line; D002971:Cleft Lip / Q000175:diagnosis / Q000235:genetics*; D002972:Cleft Palate / Q000175:diagnosis / Q000235:genetics*; D004252:DNA Mutational Analysis; D014644:Genetic Variation; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D009154:Mutation; D016366:Open Reading Frames; D019683:Penetrance
chemical_list: D015703:Antigens, CD; C513384:CDH1 protein, human; D015820:Cadherins
keywords: CDH1; gastric cancer; oral clefts; rare variant; two-hit model