Genetic variations at 10q26 regions near FGFR2 gene and its association with non-syndromic cleft lip with or without cleft palate.

OBJECTIVES: In our study, we focussed on three SNPs in the non-coding regions near FGFR2 gene, as studies on non-coding variants in the genome are the novel trends to identify the susceptible loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P). FGFR2 gene is selected as a candidate gene based on knock out animal models and the role played in syndromic forms of clefting. FGFR2 gene also plays an important role in FGF signaling pathway during craniofacial development. METHODS: In the present study 148 case-parent triads were assessed for three SNPs rs10749408, rs11199874 and rs10788165 near FGFR2 gene by using TaqMan allelic discrimination method. Transmission disequilibrium test (TDT) was used to find the allelic association. Linkage disequilibrium (LD) between the markers was analysed using Haploview program 4.2. Haplotype transmission effects were estimated using FAMHAP package. The possible parent-of-origin effects were assessed by likelihood based approach. RESULTS: TDT analysis of three SNPs failed to show significant transmission disortion from heterozygous parents to the affected child and are not associated with NSCL/P. Linkage disequilibrium analysis showed strong LD between rs11199874 and rs10788165 SNPs. In the haplotype TDT analysis, GG haplotype of rs11199874-rs10788165 showed significant undertransmission to affected child. No significant parent-of-origin effects were observed. CONCLUSION: The present study on noncoding variants near FGFR2 gene is not associated with NSCL/P. As the numbers of triads included in the study are less, further studies are needed including large sample size to find association with NSCL/P.

Transmission analysis of TGFB1 gene polymorphisms in non-syndromic cleft lip with or without cleft palate.

OBJECTIVES: Transforming growth factor beta1 (TGF-ß1) plays a significant role in craniofacial development. Previous linkage studies reported that the TGF-ß1-locus at 19q13.1 harbour predisposing genes for non-syndromic oral clefts. In the present study case parents triads were evaluated to find the transmission effects of genetic variants in TGF- ß1 towards non-syndromic cleft lip or palate (NSCL/P). METHODS: Using allelic discrimination method148 families (case-parent triads) were assessed for single nucleotide polymorphisms (SNPs) in TGF-ß1 gene. The SNPs were checked for mendelian errors and Hardy-Weinberg equilibrium (HWE). Transmission disequilibrium test and haplotype frequencies were estimated. RESULTS: The TGF-ß1 SNPs showed very low minor allele frequencies (MAFs) and observed heterozygosity (Hobs). The transmission disequilibrium test (TDT) and parent-of-origin likelihood ratio tests (PO-LRT) were not significant for any of the SNPs tested. Strong linkage disequilibrium (r2 = 0.722) was found between rs1800469 and rs1800470 SNPs. Haplotype analysis ignoring parent of origin showed strong evidence of excess transmission but it is not significant (p-value = 0.293). CONCLUSION: Transmission of minor alleles were not observed from either parent indicating that the TGF-ß1 gene polymorphisms by themselves do not confer risk for non-syndromic oral clefts but, rather, modify the stability and the activation process of TGF-ß1. As the number of families included in the study are less, results must be considered still preliminary and require replication using more families.