Evidence that BCL3 plays a role in the etiology of nonsyndromic oral clefts in Brazilian families

Abstract

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

A genome wide linkage scan for cleft lip and palate and dental anomalies

“…We have previously studied the 19q13 region and have found a strong association with a marker in PVR in two independent cleft populations (South America, P =0.0007; and Iowa, P =0.0009) [Warrington et al, 2006]. Previous publications have also suggested the 19q13 region and the BCL3 gene [Stein et al, 1995;Amos et al, 1996;Maestri et al, 1997;Wyszynski et al, 1997;Martinelli et al, 1998;Yoshiura et al, 1998;Carreño et al, 2002;Gaspar et al, 2002;Marazita et al, 2002a, b;Blanco et al, 2004;Morkûniené et al, 2007] although a few studies did not replicate the association between the 19q13 region and clefts [Wong et al, 2000;Beaty et al, 2001;Fujita et al, 2004;Pezzetti et al, 2007]. Our results further support a gene contributing to clefts resides in this region, which appears to be upstream from 19q13 based on our preliminary linkage results.…”

Maternal MTHFR interacts with the offspring's BCL3 genotypes, but not with TGFA, in increasing risk to nonsyndromic cleft lip with or without cleft palate

“…Because the 135 bp allele is, by far, the most frequent allele in all the populations studied to date, it is very likely that the associations reported of CL/P with this allele are mainly due to its high frequency and not to a causal effect. As we have suggested earlier, 20 multiple predisposing mutations may exist close to or within the BCL3 locus, because a specific haplotype with markers of this region in significant linkage disequilibrium with CL/P has not been found.…”

“…Some of the BCL3 and TGFA data have already been included in previous reports. 20,22 Gene -gene interactions were tested using a two-step approach. First, we applied a linkage disequilibrium test to verify if a combination of alleles at two different loci is preferentially present in the considered sample.…”

Study of the Clptm1 Gene in South American Non-Syndromic Cleft Lip Patients With or Without Palate

“…So many genetic and environmental factors possibly seems to be contributing to the development ns CL/P. So far linkage analysis and associations studies suggested that several chromosomal regions including chromosome 19q13 and several candidate genes might be involved in the aetiology of the non-syndromic clefting malformation (11,12,15,16,17). CLPTM1 was also considered as a candidate gene which was initially identified at translocation break-point segregated 2-3 generation in a family with cleft lip and palate and it is localized at chromosome 19q13 (23).…”

“…In this region, chromosome 19q13, some of the candidate genes tested for the involvement in the nsCL/P formation were BCL3, PVR, PVRL2 and CLPTM1and the studies are focused on mainly these four candidate genes. First, BCL3 has been considered as the most prominent candidate gene (8,16) and has been suggested to play a role in nsCL/P. Recently PVR and PVRL2 has been also added to the list due to two reasons: 1.…”