The MTHFD1 1958G>A polymorphism (rs2236225), leading to Arg653Gln, reduces enzyme stability and activity and was first investigated as a maternal risk factor for trisomy 21 in Southern Italian women, showing association with DS risk in combination with the RFC1 80G>A polymorphism (the combined MTHFD1 1958AA/RFC1 80GG genotype) (Scala et al., 2006). The gene discussed is MTHFD1; the disease is trisomy 21.