Predisposition to Elevated Homocysteine (Folate Cycle Enzyme Genes)

The Predisposition to Elevated Homocysteine (Folate Cycle Enzyme Genes) panel, also referred to as folate pathway polymorphism testing or MTHFR/MTRR/MTR genotyping, is used to assess inherited susceptibility to hyperhomocysteinemia. Detection of common variants in MTHFR, MTRR, and MTR supports differentiation of hereditary versus acquired hyperhomocysteinemia, informs cardiovascular risk stratification, and frames reproductive risk discussions, including neural tube defects and other adverse pregnancy outcomes. Results may also assist in anticipating intolerance or toxicity to antifolate therapies such as methotrexate.

Elevated homocysteine has been linked to endothelial dysfunction and atherothrombotic processes. Reduced activity of folate cycle enzymes impairs remethylation of homocysteine to methionine, which can increase circulating homocysteine, especially when folate or vitamin B12 status is low. Commonly evaluated polymorphisms include MTHFR C677T and A1298C, as well as MTRR A66G and MTR A2756G, which affect methionine synthase reductase and methionine synthase, respectively. Clinical expression is influenced by nutritional status and coexisting disorders, and reported associations include cardiovascular disease, venous thrombosis, adverse pregnancy outcomes, and neural tube defects.