Transforming growth factor-beta receptor type 1 (TGFBR1) is not associated with non-syndromic cleft lip with or without cleft palate in patients of Central European descent

Abstract Objective Transforming growth factor-beta (TGF-β) type 1 receptor (also known as activin receptor-like kinase 5, ALK5) is expressed in palatal tissue during embryogenesis. Experimental studies in transgenic mice with a genetic deletion of Alk5 showed that TGF-β type 1 receptor is required for upper lip and midline fusion of the hard and soft palate. In humans, association of TGF-β type 1 receptor gene ( TGFBR1 ) and the development of non-syndromic cleft lip with or without cleft palate (NSCL/P) had been observed in a multiethnic sample of Chinese, Philippine, Indian and Turkish families. In order to re-evaluate the relevance of these findings, we carried out a family-based association study among 218 NSCL/P families of Central European descent. Methods Genomic DNA was obtained from peripheral blood of 218 complete parent–offspring triads with NSCL/P. The sample comprised 14 patients with cleft lip only (CLO) and 204 patients with cleft lip and palate (CLP). Genotyping and transmission disequilibrium test (TDT) were performed on all 218 triads with a total of 17 tagging single-nucleotide polymorphisms (SNPs). We also performed testing for extended haplotypes and a log-linear model by Weinberg was used to screen parent-of-origin effects. Furthermore the use of estimates for the relative risks (RR) of Weinberg's model was obtained. Results TDT analysis revealed no significant transmission distortion, neither at the level of individual markers nor at the level of haplotypes. Similarly negative results were obtained when we restricted our analysis to the subgroup of patients with CLP ( n  = 204). Relative risk calculations (RR) of the children's and mothers’ genotypes obtained negative results, after correction of p -values for multiple testing. Likewise application of Weinberg's log-linear model did not find any evidence for parent-of-origin effects in our sample. Conclusion Despite the ample evidence supporting the role of TGF-β type 1 receptor as a critically important and widespread morphogenetic regulator of craniofacial development in murine models, our results do not support TGFBR1 as major risk factor for NSCL/P in patients of Central European descent.