MTHFR: Addressing Genetic Counseling Dilemmas Using Evidence-Based Literature

J Genet Couns. 2016 Oct;25(5):901-11. doi: 10.1007/s10897-016-9956-7. Epub 2016 Apr 30.


The 5, 10 methylenetetrahydrofolate reductase (MTHFR) enzyme is a catalyst in the folate metabolism pathway, the byproducts of which are involved in the remethylation of homocysteine to methionine. Methionine is a precursor for a major DNA methyl donor and is important for DNA methylation and gene regulation. Rare mutations in the MTHFR gene have been associated with autosomal recessive MTHFR deficiency leading to homocystinuria. In addition, two polymorphic variants in this gene (C677T and A1298C) have been implicated in a mild form of MTHFR deficiency associated with hyperhomocysteinemia. Mild to moderate hyperhomocysteinemia has been previously implicated as a risk factor for cardiovascular disease. Further, the presence of these variants, with and without mildly elevated levels of homocysteine, has been studied in relation to several multifactorial disorders including recurrent pregnancy loss, neural tube defects and congenital anomalies, cancer, and neurodevelopmental disorders. Given this wide spectrum of purported clinical implications and the prevalence of these polymorphisms, genetic counselors may encounter questions regarding the significance of MTHFR polymorphisms in a variety of settings. Here we present a brief background of the MTHFR polymorphisms, review of the literature regarding clinical considerations, and discussion of relevant genetic counseling aspects through case vignettes. Educational resources for patients and providers are also included.

Keywords: Genetic counseling; Methylenetetrahydrofolate reductase (MTHFR); Polymorphism.

Publication types

  • Review

MeSH terms

  • Cardiovascular Diseases / epidemiology
  • Cardiovascular Diseases / etiology
  • Female
  • Genetic Counseling*
  • Homocystinuria / genetics
  • Homocystinuria / metabolism*
  • Homocystinuria / physiopathology
  • Humans
  • Hyperhomocysteinemia / complications
  • Hyperhomocysteinemia / genetics
  • Hyperhomocysteinemia / metabolism*
  • Hyperhomocysteinemia / physiopathology
  • Male
  • Methylenetetrahydrofolate Reductase (NADPH2) / deficiency*
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Methylenetetrahydrofolate Reductase (NADPH2) / metabolism
  • Muscle Spasticity / genetics
  • Muscle Spasticity / metabolism*
  • Muscle Spasticity / physiopathology
  • Mutation*
  • Polymorphism, Genetic*
  • Pregnancy
  • Psychotic Disorders / genetics
  • Psychotic Disorders / metabolism
  • Psychotic Disorders / physiopathology
  • Risk Factors


  • Methylenetetrahydrofolate Reductase (NADPH2)

Supplementary concepts

  • Methylenetetrahydrofolate reductase deficiency