RESUMO
The BCL3 gene has been considered a susceptibility locus for nonsyndromic cleft lip with or without cleft palate (NSCL/P), based on association and linkage studies in some populations. We evaluated an intragenic marker at the BCL3 gene and the microsatellite D19S178 (1.1 cM distant from the BCL3 gene) among 98 infants born with NSCL/P and their parents, using the transmission disequilibrium test (TDT) and a method for haplotype analysis. Our analysis, based on BCL3 alleles, revealed the existence of a marginal association of allele 135pb of the BCL3 gene with NSCL/P (chi(2)=3.60; P=0.058; 1 df), with a major effect in female (chi(2)=5.77; P=0.016; 1 df) and in familial cases (chi(2)=3.79; P=0.051; 1 df). However, the haplotype analysis detected no significant segregation distortion, even if the alleles of the D19S178 were grouped into two classes. These findings support previous findings that BCL3 plays a role in the etiology of NSCL/P as an allele of low penetrance or as a modifier locus. We hypothesize that there might be more than one mutation in this gene associated with NSCL/P, or alternatively, that more than one mutation has arisen associated with the 135-bp allele. Genet. Epidemiol. 23:364-374, 2002
Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Ligação Genética , Proteínas Proto-Oncogênicas/genética , Alelos , Proteína 3 do Linfoma de Células B , Brasil/epidemiologia , Distribuição de Qui-Quadrado , Fenda Labial/epidemiologia , Fissura Palatina/epidemiologia , DNA/análise , Feminino , Genótipo , Haplótipos , Humanos , Recém-Nascido , Escore Lod , Masculino , Fenótipo , Reação em Cadeia da Polimerase , Fatores de TranscriçãoAssuntos
Fenda Labial/genética , Fissura Palatina/genética , Predisposição Genética para Doença , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/genética , Polimorfismo Genético/genética , Brasil , Estudos de Casos e Controles , Etnicidade , Feminino , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2) , Classe Social , SíndromeRESUMO
van der Woude syndrome (VWS), which has been mapped to 1q32-41, is characterized by pits and/or sinuses of the lower lip, cleft lip/palate (CL/P), cleft palate (CP), bifid uvula, and hypodontia (H). The expression of VWS, which has incomplete penetrance, is highly variable. Both the occurrence of CL/P and CP within the same genealogy and a recurrence risk <40% for CP among descendants with VWS have suggested that the development of clefts in this syndrome is influenced by modifying genes at other loci. To test this hypothesis, we have conducted linkage analysis in a large Brazilian kindred with VWS, considering as affected the individuals with CP, regardless of whether it is associated with other clinical signs of VWS. Our results suggest that a gene at 17p11.2-11.1, together with the VWS gene at 1p32-41, enhances the probability of CP in an individual carrying the two at-risk genes. If this hypothesis is confirmed in other VWS pedigrees, it will represent one of the first examples of a gene, mapped through linkage analysis, which modifies the expression of a major gene. It will also have important implications for genetic counseling, particularly for more accurately predicting recurrence risks of clefts among the offspring of patients with VWS.