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Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate
Author(s) -
Brito Luciano Abreu,
Yamamoto Guilherme Lopes,
Melo Soraia,
Malcher Carolina,
Ferreira Simone Gomes,
Figueiredo Joana,
Alvizi Lucas,
Kobayashi Gerson Shigeru,
Naslavsky Michel Satya,
Alonso Nivaldo,
Felix Temis Maria,
Zatz Mayana,
Seruca Raquel,
PassosBueno Maria Rita
Publication year - 2015
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22827
Subject(s) - cdh1 , biology , genetics , proband , candidate gene , penetrance , genetic heterogeneity , etiology , locus (genetics) , genome wide association study , multifactorial inheritance , genetic linkage , gene , cadherin , mutation , genotype , single nucleotide polymorphism , phenotype , medicine , pathology , cell
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.