MTHFR Testing Indications
MTHFR polymorphism testing should NOT be routinely ordered as part of thrombophilia evaluation or for most clinical scenarios, as it lacks clinical utility and does not guide management decisions. 1
Evidence-Based Recommendations Against Routine Testing
The American College of Medical Genetics (ACMG) explicitly states that MTHFR polymorphism testing has minimal clinical utility and should not be ordered as part of routine thrombophilia evaluation. 1 This recommendation is based on:
- No proven association between MTHFR polymorphisms and venous thromboembolism risk 1
- No proven association between hyperhomocysteinemia and coronary heart disease 1
- Plasma homocysteine measurement is more informative than MTHFR genetic testing when hyperhomocysteinemia assessment is needed 2
The common MTHFR 677C→T variant accounts for only about one-third of hyperhomocysteinemia cases, and the variant itself is not associated with arterial thrombosis in the absence of elevated homocysteine levels. 2 Additionally, this variant is not associated with venous thrombosis. 2
When MTHFR Testing May Be Considered
Severe MTHFR Deficiency (Rare Enzyme Deficiency)
MTHFR gene sequencing (not polymorphism testing) should be considered in:
- Neonates and infants with unexplained neurological distress in the first weeks of life, particularly with hyperhomocysteinemia and homocystinuria 3
- Patients with severe hyperhomocysteinemia (markedly elevated levels) combined with hypomethioninemia and progressive neurological symptoms 3, 4
- Siblings of confirmed severe MTHFR deficiency cases for prenatal diagnosis and early treatment planning 3
This represents testing for rare pathogenic mutations causing severe enzyme deficiency, not the common polymorphisms (C677T, A1298C). 3, 4
Testing NOT Indicated
MTHFR polymorphism testing is not indicated for:
- Routine thrombophilia workup 1
- Recurrent pregnancy loss evaluation 1, 5
- Cardiovascular disease risk assessment 1
- Unexplained recurrent miscarriages 5
Studies show no difference in MTHFR genotype variants between women with recurrent miscarriages and controls, and no correlation with plasma homocysteine levels in these populations. 5
Alternative Approach
When hyperhomocysteinemia assessment is clinically warranted, measure plasma homocysteine levels directly rather than performing MTHFR genetic testing. 2 If elevated homocysteine is found, treatment with folate supplementation can lower levels regardless of MTHFR genotype. 2
For dialysis patients specifically, testing for MTHFR variants does not add significant information beyond homocysteine measurement. 2
Key Clinical Pitfall
The most common error is ordering MTHFR polymorphism testing (C677T, A1298C) when investigating thrombophilia or pregnancy complications. 1 These common variants are present in 30-40% (heterozygous) and 10-15% (homozygous) of the general population and do not independently confer clinically significant risk. 2