Spina bifida is caused by unsuccessful closure of the neural tube during early development (between embryonic day 17 and 30) and occurs with a frequency of 1-2 cases per 1000 births. The exact aetiology of spina bifida is poorly understood, but it is clear that both genetic and environmental factors are involved [168]. Since individuals with spina bifida often die prenatal or early postnatal and thus hardly any families exist with several affected members, this disease could well be the most difficult complex disorder to study at the genetic level. Based on animal and epidemiological studies, genes involved in folic acid (folate), vitamin B12 and homocysteine metabolism, or genes involved in neurulation have been hypothesized to play a role in spina bifida genesis [reviewed in 169]. However, until now, only a few genes have been reported to represent risk factors for spina bifida, including 5,10-methylenetetrahydrofolate reductase (MTHFR; 1p36.3) [170], methionine synthase reductase (MTRR; 5p15.3-p15.2) [171], platelet-derived growth factor receptor alpha (PDGFRA; 4q11-q13) [172] endothelial nitric oxide synthase 3 (NOS3; 7q36) [173] protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1; 6q24-q25) [174] and cofilin 1 (non-muscle) (CFL1; 11q13) [175].
