期刊
HUMAN MUTATION
卷 36, 期 11, 页码 1029-1033出版社
WILEY
DOI: 10.1002/humu.22827
关键词
CDH1; oral clefts; gastric cancer; two-hit model; rare variant
资金
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2013/08028-1]
- Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [401952/2010-0]
- Fundos FEDER atraves do Programa Operacional Factores de Competitividade (COMPETE)
- Portuguese Foundation for Science and Technology (FCT) [PTDC/SAU-ONC/110294/2009, PTDC/BIM-ONC/0171/2012, PEst-OE/EEI/LA0009/2013, SFRH/BPD/87705/2012]
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 = 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.
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