Is MTHFR (methylenetetrahydrofolate reductase) testing still indicated?

MTHFR Testing Is No Longer Indicated in Clinical Practice

MTHFR genetic testing is not recommended or indicated in clinical practice as it lacks clinical utility and does not meaningfully impact patient management decisions or outcomes.

Evidence Against Routine MTHFR Testing

The evidence clearly demonstrates that MTHFR genetic testing has limited clinical value:

• The American College of Medical Genetics consensus statement indicates that while MTHFR variants (particularly the 677C→T variant) are common in the general population (homozygous in 10-15% and heterozygous in 30-40%), these variants by themselves are not associated with venous thrombosis and are only associated with arterial thrombosis when they cause hyperhomocysteinemia 1.

• Multiple guidelines and expert opinions emphasize that measuring plasma homocysteine levels directly is more informative than MTHFR genetic testing 1, 2.

• The EGAPP Working Group (Evaluation of Genomic Applications in Practice and Prevention) did not recommend genomic profiling for cardiovascular risk assessment, which would include MTHFR testing 1.

Homocysteine Testing vs. MTHFR Testing

If there are concerns about hyperhomocysteinemia:

• Direct measurement of plasma homocysteine levels is the preferred approach rather than MTHFR genetic testing 1, 2.
• Homocysteine levels >10 μmol/L are considered elevated and may warrant intervention 1, 2.

Management of Hyperhomocysteinemia

If hyperhomocysteinemia is detected:

• Standard multivitamin preparations with adequate B6 (1.7 mg/d), B12 (2.4 μg/d), and folate (400 μg/d) are reasonable to reduce homocysteine levels 1, 2.
• For patients with ischemic stroke and hyperhomocysteinemia, folate supplementation may be considered (Class IIb; Level of Evidence B) 1.
• Higher doses of B vitamins may be required in patients with renal dysfunction 2.

Important Caveats

1. No Impact on Outcomes: Despite effectively lowering homocysteine levels, multiple randomized controlled trials have failed to demonstrate that B-vitamin supplementation reduces cardiovascular events or mortality 2.

2. Limited Clinical Scenarios: There are very few clinical scenarios where MTHFR testing might be considered:

   • Neural tube defects: While MTHFR mutations have been implicated in neural tube defects 3, universal folate supplementation is recommended for all women of childbearing age regardless of MTHFR status.
   • Recurrent pregnancy loss: Evidence does not support routine MTHFR testing, as studies show no significant association between MTHFR polymorphisms and recurrent pregnancy loss 4.

3. Potential Harm: Unnecessary MTHFR testing can lead to:

   • Patient anxiety
   • Unnecessary supplementation
   • False reassurance
   • Distraction from evidence-based preventive strategies

Practical Approach

For patients concerned about cardiovascular risk:

• Focus on established risk factors (hypertension, diabetes, smoking, dyslipidemia)
• If homocysteine testing is performed and levels are elevated:
  • Provide standard B-vitamin supplementation
  • Address modifiable risk factors
  • Consider renal function assessment

Conclusion

The scientific consensus across multiple medical organizations is clear: MTHFR genetic testing has very limited clinical utility and is not recommended as a routine test for cardiovascular risk assessment, thrombophilia evaluation, or other common indications. Direct measurement of homocysteine levels, when clinically indicated, is preferred over genetic testing.