1. Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate.
- Author
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Brito LA, Yamamoto GL, Melo S, Malcher C, Ferreira SG, Figueiredo J, Alvizi L, Kobayashi GS, Naslavsky MS, Alonso N, Felix TM, Zatz M, Seruca R, and Passos-Bueno MR
- Subjects
- Alleles, Amino Acid Substitution, Animals, Antigens, CD, Cadherins chemistry, Cell Line, Cleft Lip diagnosis, Cleft Palate diagnosis, DNA Mutational Analysis, Genotype, Germ-Line Mutation, Humans, Mutation, Open Reading Frames, Penetrance, Brain abnormalities, Cadherins genetics, Cleft Lip genetics, Cleft Palate genetics, Genetic Variation
- 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., (© 2015 WILEY PERIODICALS, INC.)
- Published
- 2015
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