Background: Folate metabolism dysfunctions can result in DNA hypomethylation and abnormal chromosome segregation. Two common polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) encoding gene (C677T and A1298C) reduce MTHFR activity, but when associated with aneuploidy, the results are conflicting. Turner Syndrome (TS) is an interesting model for investigating the association between MTHFR gene polymorphisms and nondisjunction because of the high frequency of chromosomal mosaicism in this syndrome. Objective: To investigate the association of MTHFR gene C677T and A1298C polymorphisms in TS patients and their mothers and to correlate these polymorphisms with maternal risk of TS offspring. Subjects and Methods: MTHFR C677T and A1298C polymorphisms were genotyped in 33 TS patients, their mothers and 15 healthy females with their mothers as controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing technique. Results: Genotype and allele frequencies of both C677T and A1298C were not significantly different between TS cases and controls. There were no significant differences in C677T genotype distribution between the TS mothers and controls (p=1). The MTHFR 1298AA and 1298AC genotypes were significantly increased in TS mothers Vs. control mothers (p=0.002). The C allele frequency of the A1298C polymorphism was significantly different between the TS mothers and controls (p=0.02). The association of A1298C gene polymorphism in TS patients was found to increase with increasing age of both mothers (p=0.026) and fathers (p=0.044) of TS cases. Conclusion: Our findings suggest a strong association between maternal MTHFR A1298C and risk of TS in Egypt.
Folate metabolism deficiency has been related to increased occurrence of maternal non-disjunction resulting in trisomy 21. Several polymorphisms in genes coding for folate metabolism enzymes have been investigated for association with the maternal risk of Down syndrome (DS) yielding variable results. We performed a meta-analysis of case-control studies obtained through the PubMed database. The studies on polymorphisms in the MTHFR, MTRR, MTR, RFC1 and CBS genes were included. The summary OR demonstrated a statistically significant increased risk of giving birth to a child with DS in mothers carrying the mutant allele of the MTHFR/C677T gene polymorphism (both genetic models) and in mothers homozygous for the mutant allele of the MTRR/A66G polymorphism (recessive genetic model). Analyses of other polymorphisms, MTHFR/A1298C, MTR/A2756G, RFC1/A80G, and CBS/844ins68, resulted in borderline or no statistical significance. In conclusion, our meta-analysis showed the significance of genetic alterations in the folate metabolism genes in maternal susceptibility to DS offspring. Our results suggest that the importance of folate supplementation to women in reproductive age in prevention of non-disjunction be revised. Further genetic studies on a combined effect of multiple folate metabolism genes is recommended. Additionally, more thorough studies on the haplotype analyses of genes is recommended as well, especially in populations that have not yet been investigated thus far.
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.