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Am J Hum Genet. 2001 Nov; 69(5): 1150–1152.
PMCID: PMC1274361

Examinations of Methylenetetrahydrofolate Reductase C677T and A1298C Mutations—and In Utero Viability

To the Editor:

The recently published study by Isotalo et al. (2000) analyzed the methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C mutations in neonatal and fetal groups, to determine whether particular MTHFR genotype combinations are associated with decreased in utero viability. Isotalo et al. (2000) observed all possible genotype combinations in the fetal group, but combined 677CT/1298CC and 677TT/1298CC genotypes were not observed in the neonatal group. Therefore, they hypothesized that decreased viability exists among fetuses carrying the 677CT/1298CC and 677TT/1298CC genotypes, with a possible selection disadvantage in fetuses with an increased number of mutant MTHFR alleles. They also did not observe the 677CT/1298CC and 677TT/1298CC genotypes in a population consisting of healthy adult controls.

We have tested for the MTHFR C677T and A1298C mutations in a Hispanic population of Mexican descent, to determine risk for spina bifida (SB) (Volcik et al. 2000). Although we observed all possible MTHFR 677/1298 genotype combinations in this Hispanic population, the 677TT/1298CC combination was observed only once, in the mother of an affected individual (table 1). We have analyzed the MTHFR C677T and A1298C mutations in a U.S. population of European descent, composed of patients with SB, their parents, and controls, and have observed the 677CT/1298CC genotype combination (table 2). In addition, we have observed the MTHFR C677T and A1298C mutations in a Canadian population of European descent, composed of patients with SB and their parents (table 3). We observed only a single individual, a patient with SB, with the 677TT/1298AC genotype. However, because of the small size of our sample, we expected that only one or two individuals in each of the groups would have the 677TT/1298AC genotype. It is therefore difficult to reach conclusions, on the basis of the absence of this genotype in the small Canadian population that we studied. The presence of these genotypes in healthy parents and controls militates against the hypothesis, proposed by Isotalo et al. (2000), that the absence of the 677CT/1298CC genotype suggests that “additional MTHFR mutations in cis are potentially deleterious or lethal” (Isotalo et al. 2000, p. 989). Perhaps it is the combination of two mutant alleles at both sites (677TT/1298CC), reaching a threshold of four, rather than three, mutations that creates a disadvantage. Other groups have also identified individuals with the 677T and 1298C alleles in the cis configuration and individuals with the mutations in the trans configuration (Weisberg et al. 1998; Friedman et al. 1999).

Table 1
Combined MTHFR C677T/A1298C Genotype or Allele Frequencies in a Hispanic Population of Mexican Descent, Composed of Patients with SB, Their Parents, and Controls
Table 2
Combined MTHFR C677T/A1298C Genotype or Allele Frequencies in a U.S. Population of European Descent, Composed of Patients with SB, Their Parents, and Controls
Table 3
Combined MTHFR C677T/A1298C Genotype or Allele Frequencies in a Canadian Population of European Descent, Composed of Patients with SB and Their Parents

An additional concern is that Isotalo et al. (2000) fail to indicate the ethnicity of the population that they studied. Therefore, we have provided data from three ethnic groups (Hispanics of Mexican descent, U.S. individuals of European descent, and Canadians of European descent), to compare genotype and allele frequencies. If the population studied by Isotalo et al. (2000) was Canadian, it is notable that they did not observe the 677CT/1298CC genotype in their neonatal group, whereas we observed this genotype in 2%–6% of the Canadian population, of patients with SB and their parents, that we studied. Our data support the conclusion of Isotalo et al. (2000) concerning decreased viability among fetuses with the 677TT/1298CC genotype, because we did not observe this genotype in the U.S. and Canadian populations that we studied. Because we observed, in three different populations, the 677CT/1298CC genotype at frequencies nearing those expected, we conclude that this genotype does not result in a significant selective disadvantage.


Friedman G, Goldschmidt N, Friedlander Y, Ben-Yehuda A, Selhub J, Babaey S, Mendel M, Kidron M, Bar-On H (1999) A common mutation A1298C in human methylenetetrahydrofolate reductase gene: association with plasma total homocysteine and folate concentrations. J Nutr 129:1656–1661 [PubMed]
Isotalo PA, Wells GA, Donnelly JG (2000) Neonatal and fetal methylenetetrahydrofolate reductase genetic polymorphisms: an examination of C677T and A1298C mutations. Am J Hum Genet 67:986–990 [PMC free article] [PubMed]
Volcik KA, Blanton SH, Tyerman GH, Jong ST, Rott EJ, Page TZ, Romaine NK, Northrup H (2000) Methylenetetrahydrofolate reductase and spina bifida: an evaluation of level of defect and maternal genotype risk in Hispanics. Am J Med Genet 95:21–27 [PubMed]
Weisberg I, Tran P, Christensen B, Sibani S, Rozen R (1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Mol Genet Metab 64:169–172 [PubMed]

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