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ABBREVIATIONS MTHFD1Methylenetetrahydrofolate dehydrogenase NTD Neural tube defect POE Parent-of-origin effects TDT Transmission disequilibrium test AIM This study aimed to evaluate the role of methylenetetrahydrofolate dehydrogenase (MTHFD1) G1958A variant (rs2236225) as a 'maternal, paternal, or embryonic' genetic risk factor for neural tube defect (NTD) susceptibility. It also estimated differential associations based on type of NTD, offspring sex, maternal-paternal-offspring genotype incompatibility, and parent-of-origin effects (POE) using both case-control and family-based approach. In addition, genotype impact on serum folate levels was also assessed.METHOD The study population (n=900) consisted of 120 NTD case-parent triads (n=12093=360) and 180 healthy control-parent triads (n=18093=540) from South India. Umbilical cord tissues were collected from those with NTD and control newborn infants, and blood samples from case and control parents. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism. Statistical analysis used were SPSS, transmission disequilibrium test and POE. Serum folate levels were estimated using enzyme-linked immunosorbent assay. RESULTSIn the case-control study, those with the MTHFD1 G1958A variant were associated with around twofold risk of anencephaly (p=0.01) and spina bifida (p<0.01). Among parents, fathers were associated with around twofold risk of having an offspring with anencephaly (p<0.01). Considering offspring sex, the A allele in single or double dose conferred around two-to fourfold risk of anencephaly (p=0.01), spina bifida (p<0.01), and encephalocele (p<0.05) in females only. Maternal AA genotype was not associated independently but conferred threefold risk when combined with paternal GA genotype (p=0.01). Transmission disequilibrium and POE were not observed in controls (p>0.05) but revealed excess total (odds ratio [OR]=2.21; p<0.01) and paternal transmission (OR=7.00; p<0.01) of the G1958A allele to those with spina bifida, which remained the same for female cases (total transmission OR=3.00, p=0.01; paternal transmission OR=12.00, p<0.01). Increased serum folate levels were observed in case fathers with GA and AA genotypes than control fathers (p<0.01).INTERPRETATION Our research provides the first evidence supporting a paternal, rather than a maternal, transmission bias of MTHFD1 G1958A variant for NTD susceptibility in the offspring.Neural tube defects (NTDs) are a group of severe congenital malformations that develop when the neural tube fails to close properly during early embryogenesis. They include a range of malformations (e.g. anencephaly, spina bifida, and encephalocele), which further complicates the identification of risk factors. 1 Despite the successful establishment of folic acid supplementation and recent advances in genetics, epidemiology, and surgery, NTDs still represent the second most serious human birth defects after congenital heart defects.

This study, using family-based case-parent and control-parent triad approach, is the first to report influence of maternal transmission of DHFR 19 bp deletion in the development of anencephaly in the foetus.

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