To date, the strongest candidate thus far for a potential NTD screening gene is the methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) polymorphism in populations of non-Latin origin (meta-analysis study) . In recent meta-analysis study, Zhang et al. support the significant association between C677T and NTDs in case-control studies (22 studies, 2,602 cases, and 4,070 controls) . The second most studied MTHFR variant is A1298C, which did not report any significant increase in risk of NTDs . Another meta-analysis study by Blom et al. (2006) reported increased risk in mothers and associated with NTD infants who are homozygous for C677T variant . In spina bifida case studies, MTHFR C677T variant was clearly reported as associated gene or risk factors in Irish (451 spina bifida patients), mixed USA, mixed UK, and Italian cohort but not in other 180 Dutch patients (Table 3), while A1298C variant was reported with no association to spina bifida cases in Italian, Mexican (Yucatan), and Dutch population (Table 3). MTHFR is the most studied human spina bifida gene, as its role in folate one-carbon metabolism fits into a clear mechanism of NTD. However, the studies have not been well replicated in many other populations across the world, indicating that it is not likely to be either a major contributor or a common factor in NTD globally.