Susceptibility to spina bifida; an association study of five candidate genes

Ann Hum Genet. 1998 Sep;62(Pt 5):379-96. doi: 10.1046/j.1469-1809.1998.6250379.x.


Clues regarding candidate genes which influence susceptibility to spina bifida and anencephaly come from the identification of folate-associated risk factors and from studies of mouse mutants showing neural tube anomalies. On this basis we selected five candidate genes; CBS, MS, MTHFR, T (Brachyury) and BRCA1 for genetic analysis in 31 Dutch and 48 British NTD families. Ten polymorphisms, two for each gene, were used in transmission tests for disequilibrium (TDT). In six instances more than 50 transmissions from heterozygous parents could be examined. Using TDT we find evidence for an association between an allele at the T gene and liability to NTD in the embryo. Data from British and Dutch populations showed the same trend and in combination gave a chi 2TDT = 4.89, P = 0.03 (OR 2.39, CI 95% 1.02-5.61). No association, in either population group, was found for CBS, MS and MTHFR, the enzymes most directly associated with the known risk factors in folate metabolism. The possibility of complex genetic interactions was explored; the data show that a Gly919 MS variant occurs more frequently in combination with the MTHFR thermolabile variant in mothers of NTD offspring (OR 3.94, CI 95% 1.0-16.3).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / genetics
  • Alleles
  • Animals
  • BRCA1 Protein / genetics
  • Cystathionine beta-Synthase / genetics
  • DNA Primers
  • DNA-Binding Proteins / genetics
  • Female
  • Fetal Proteins*
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • Mice
  • Oxidoreductases Acting on CH-NH Group Donors / genetics
  • Polymorphism, Genetic
  • Polymorphism, Single-Stranded Conformational
  • Sequence Analysis, DNA
  • Spinal Dysraphism / genetics*
  • T-Box Domain Proteins*
  • Transcription Factors / genetics


  • BRCA1 Protein
  • DNA Primers
  • DNA-Binding Proteins
  • Fetal Proteins
  • T-Box Domain Proteins
  • Transcription Factors
  • Oxidoreductases Acting on CH-NH Group Donors
  • Methylenetetrahydrofolate Reductase (NADPH2)
  • 5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase
  • Cystathionine beta-Synthase
  • Brachyury protein