Rare Variants in the Epithelial Cadherin Gene Underlying the Genetic Etiology of Nonsyndromic Cleft Lip with or without Cleft Palate

Autor(es):Mostrar menos -

Brito, Luciano Abreu ^[1] ; Yamamoto, Guilherme Lopes ^[1] ; Melo, Soraia ^{[2, 3]} ; Malcher, Carolina ^[1] ; Ferreira, Simone Gomes ^[1] ; Figueiredo, Joana ^{[2, 3]} ; Alvizi, Lucas ^[1] ; Kobayashi, Gerson Shigeru ^[1] ; Naslavsky, Michel Satya ^[1] ; Alonso, Nivaldo ^[4] ; Felix, Temis Maria ^[5] ; Zatz, Mayana ^[1] ; Seruca, Raquel ^{[6, 2, 3]} ; Passos-Bueno, Maria Rita ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Biociencias, Dept Genet & Biol Evolut, Ctr Pesquisa Genoma Humano & Celulas Tronco, Sao Paulo - Brazil

^[2] Univ Porto, Inst Mol Pathol & Immunol, IPATIMUP, P-4100 Oporto - Portugal

^[3] Univ Porto, Inst Invest & Inovacao Saude, P-4100 Oporto - Portugal

^[4] Univ Sao Paulo, Fac Med, Hosp Clin, Sao Paulo - Brazil

^[5] Hosp Clin Porto Alegre, Ctr Pesquisa Expt, Lab Med Genom, Porto Alegre, RS - Brazil

^[6] Univ Porto, Fac Med, P-4100 Oporto - Portugal

• Tipo de documento: Artigo Científico
• Fonte: Human mutation; v. 36, n. 11, p. 1029-1033, NOV 2015.
• Citações Web of Science: 19

Resumo

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. (AU)

• Processo FAPESP: 13/08028-1 - CEGH-CEL - Centro de Estudos do Genoma Humano e de Células-Tronco
• Beneficiário: Mayana Zatz
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs