EC Gynaecology

Objectives: To identify the most frequent clinical phenotype among cases with neural tube defects and to establish the association between maternal C677T polymorphism in MTHFR gene and the risk of appearing of neural tube defects in their offspring.

Patients and Methods: An analytical cases-control design and population-based study was conducted in the Villa Clara province, Cuba, between years 2013 and 2018. The prevalence rates were determined according to the different clinical phenotypes of the neural tube defects. The genotyping of the sequence variant C677T in the MTHFR gene was performed using PCR-RFLP method. The genotype and allelic frequencies were compared between cases and control groups according seven different models of genetic association.

Results: Spina bifida was the most frequent clinical phenotype among neural tube defects cases, with an adjusted prevalence rate of 0,63 per 1000 births. The frequency of homozygote TT genotype were 0,21 among mothers with affected offspring with neural tube defects and 0,06 in the control group, these differences were statistical (this word would be removed) significant (p = 0,015). The distribution of genotype and allelic frequencies among different clinical phenotypes was homogeneous. Significant associations between T allele and these congenital defects was identified in three genetic models of codominance TT vs CC [OR 4,87 (IC 95% 1,31 - 18,06), (TT vs CT) and (CC vs TT), besides recessive TT vs CT + CC [OR 3,88 (IC) 95% 1,22 - 12,35)] and additive models (T vs C). When the genetic association was analyzed for the codominant genetic model CC vs TT, OR: 0,21 (IC 95% 0,05 - 0,76) p = 0,011, a protective effect was found when maternal T allele was absent, with respect to the risk for neural tube defects in their offspring.

Conclusion: The current study provides evidence on the maternal MTHFR C677T polymorphism might be associated to the increased risk of neural tube defects in their offspring, which it’s in fact related with diminished enzymatic activity reported in individuals with TT genotype.

Keywords: Single Nucleotide Polymorphism; Neural Tube Defects; Anencephaly; Spina Bifida; Encephalocele; MTHFR Gene, Genotype Frequency, Allelic Frequency; Cuba

1. Kancherla V and Black R. “Historical perspective on folic acid and challenges in estimating global prevalence of neural tube defects”. Annals of the New York Academy of Sciences 1414 (2018): 20-30.
2. Bourouba R., et al. “Risk factors of neural tube defects: A reality of Batna region in Algeria”. Egyptian Journal of Medical Human Genetics3 (2018): 225-229.
3. Forci K., et al. “Incidence of neural tube defects and their risk factors within a cohort of Moroccan newborn infants”. BMC Pediatrics 21 (2021): 124-134.
4. Martinez H., et al. “Improving maternal folate status to prevent infant neural tube defects: working group conclusions and a framework for action”. Annals of the New York Academy of Sciences 1414 (2018): 5-19.
5. De Joung M., et al. “Contribution of voluntary fortified foods to micronutrient intake in The Netherlands”. European Journal of Nutrition 1 (2022): 1-15.
6. Taboada N. “Implication of molecular and cellular mechanisms in congenital defects sensitive to folate deficiency”. EC Gynaecology6 (2021): 57-68.
7. Goyal A., et al. “Study of C677T methylene tetrahydrofolate reductase gene polymorphism as a risk factor for neural tube defects”. The Asian Journal of Neurosurgery 16 (2021): 554-561.
8. 5,10-Methylenetetrahydrofolate Reductase; Mthfr. OMIM (2018).
9. Castrense S., et al. “A glance into MTHFR deficiency at a molecular level”. International Journal of Molecular Sciences1 (2022): 167-186.
10. Nasri K., et al. “Association of MTHFR C677T, MTHFR A1298C and MTRR A66G polymorphisms with neural tube defects in Tunisian parents”. Pathobiology 86 (2019): 190-200.
11. Sadat R., et al. “Association of fetal MTHFR C677T polymorphism with susceptibility to neural tube defects: A systematic Review and Update Meta- Analysis”. Fetal and Pediatric Pathology2 (2022): 225-241.
12. Talita C., et al. “Association between MTHFR C677T and A1298C gene polymorphisms and maternal risk for Down syndrome: A protocol for systematic review and meta-analysis”. Medicine 101 (2022): 1-6.
13. Vidmar G., et al. “Folate insufficiency due to MTHFR deficiency is bypassed by 5-Methyltetrahydrofolate”. Journal of Clinical Medicine 9 (2020): 2836-2854.
14. Liu P., et al. “Association between MTHFR C677T polymorphism and congenital heart disease”. International Heart Journal 61 (2020): 553-561.
15. National Office of Statistics and Information. Republic of Cuba (2022).
16. International Classification of Diseases-10^th National Center for Health Statistics (2021).
17. Taboada LN. “Genetic and environmental risk factors in mothers with offspring affected by folate-sensitive birth defects in Villa Clara”. [doctoral thesis] University of Medical Sciences of Villa Clara (2022).
18. Lardoeyt R., et al. “Fundamentos de Genética Médica Poblacional”. La Habana: ECIMED (2016): 366.
19. Shrestha B and Dunn L. “The declaration of Helsinki on medical research involving human subjects: a review of seven revision”. Journal of Nepal Health Research Council4 (2020): 548-552.
20. Oluwafemi RO and Abiodun MT. “Incidence, Spectrum and Outcome of Congenital Anomalies Seen in a Neonatal Intensive Care Unit in Southern Nigeria”. The Nigerian Postgraduate Medical Journal 26 (2019): 239-243.
21. Gashaw A., et al. “Risk factors associated to neural tube defects among mothers who gave birth in North Shoa Zone Hospitals, Amhara Region, Ethiopia 2020: Case control study”. PLoS One4 (2021): 1-12.
22. Golalipour M., et al. “Prevalence of anencephaly in Gorgan, northern Iran”. Archives of Iranian Medicine1 (2010): 34-37.
23. Nauman N., et al. “Low maternal folate concentrations and maternal MTHFR C677T polymorphism are associated with an increased risk for neural tube defects in offspring: a case-control study among Pakistani case and control mothers”. Asia Pacific Journal of Clinical Nutrition1 (2018): 253-260.
24. Romero C., et al. “C677T (rs1801133) MTHFR gene-polyporphism frequency in a colombian population”. Colombia Médica2 (2015): 75-79.
25. Cai C., et al. “Association of neural tube defects with maternal alterations and genetic polymorphisms in one-carbon metabolic pathway”. Italian Journal of Pediatrics 45 (2019): 1-7.
26. Shi H., et al. “Study on maternal SNPs of MTHFR gene and HCY level related to congenital heart diseases”. Pediatric Cardiology1 (2021): 42-46.
27. Fang Y., et al. “Association of main folate metabolic pathway gene polymorphisms with neural tube defects in Han population of Northern China”. Child's Nervous System 34 (2018): 725-729.
28. Zhang C., et al. “Meta-analysis on relationship between the Chinese maternal MTHFR gene polymorphism(C677T) and neural tube defects in offspring”. Wei Sheng Yan Jiu2 (2018): 312-317.
29. Aranda S., et al. “MTHFR C677T and A1298C variants in Mexican mestizo infants with neural tube defects from Western Mexico”. Congenital Anomalies5 (2021): 188-192.
30. Amooee A., et al. “Association of fetal MTHFR 677C > T polymorphism with non-syndromic cleft lip with or without palate risk: A systematic review and meta-analysis”. Fetal and Pediatric Pathology4 (2021): 337-353.