OBJECTIVE: To determine the prevalence of mutations in transforming growth factor beta 3 (TGFβ3) and Jagged2 genes and their association with nonsyndromic cleft lip with or without cleft palate (CL±P) patients.
DESIGN: Cross-sectional study on nonsyndromic CL±P and noncleft patients.
SETTING: Reconstructive clinic and outpatient dental clinic, Hospital Universiti Sains Malaysia.
PATIENTS: Blood samples of 96 nonsyndromic CL±P and 96 noncleft subjects.
MAIN OUTCOME MEASURE: Prevalence and association of mutations in TGFβ3 and Jagged2 genes with nonsyndromic CL±P.
RESULTS: Most of the nonsyndromic CL±P patients (53.1%) had left unilateral CLP. There were slightly more females (56.6%) compared with males. The prevalence of the mutations in the TGFβ3 gene was 17.7% (95% confidence interval [CI]: 9.5, 24.5) and in the Jagged2 gene was 12.5% (95% CI: 5.5, 18.5), which was higher compared with the noncleft group. For the TGFβ3 gene, there was no mutation in the coding region in either of the groups. All variants were single nucleotide polymorphisms located within the intronic flanking region. Two variants were identified (g.15812T>G and g.15966A>G) in both nonsyndromic CL±P and noncleft patients. However, the association was not significant (P > .05). Three variants (g.19779C>T, g.19547G>A, and g.19712C>T) were identified in the Jagged2 gene among nonsyndromic CL±P and noncleft patients. Only g.19712C>T showed a significant association with nonsyndromic CL±P patients (P = .039).
CONCLUSION: g.19712C>T might play a crucial role in the development of cleft lip and palate. To the best of our knowledge, this is the first report of the mutation found within intron 13 of the Jagged2 gene among nonsyndromic CL±P Malay patients.
Study site:Reconstructive and outpatient dental clinic, Hospital Universiti Sains Malaysia (HUSM)
Oral clefts are clinically and genetically heterogeneous disorders that are influenced by both genetic and environmental factors. The present family-based association study investigated the role of the MSX1 and TGFB3 genes in the etiology of non-syndromic oral cleft in a Malay population. No transmission distortion was found in the transmission disequilibrium analysis for either MSX1-CA or TGFB3-CA intragenic markers, whereas TGFB3-CA exhibited a trend to excess maternal transmission. In sequencing the MSX1 coding regions in 124 patients with oral cleft, five variants were found, including three known variants (A34G, G110G and P147Q) and two novel variants (M37L and G267A). The P147Q and M37L variants were not observed in 200 control chromosomes, whereas G267A was found in one control sample, indicating a very rare polymorphic variant. Furthermore, the G110G variant displayed a significant association between patients with non-syndromic cleft lip, with or without cleft palate, and normal controls (P=0.001, odds ratio=2.241, 95% confidence interval, 1.357-3.700). Therefore, these genetic variants may contribute, along with other genetic and environmental factors, to this condition.