MTHFR gene testing

Ordering MTHFR gene testing in asymptomatic healthy patients could result in:

• unnecessary investigations for a range of conditions
• anxiety in pregnant women concerned about neural tube defects in the first trimester, recurrent pregnancy loss or congenital anomalies (even though the link between these and an MTHFR gene variant is weak^5,6)
• increased parental distress and unnecessary blood testing of children thought to have autism spectrum disorder, even though the presence of an MTHFR gene variant will not change the diagnosis or outcome⁷
•  false reassurance in instances when screening or other preventive action may be useful
• unnecessary financial cost to the patient⁸ (a variation in the MTHFR gene does not affect treatment of any condition a patient might have, therefore there is no Medicare Benefits Schedule rebate for this test and it cannot be bulk billed).

• Methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in folate metabolism.⁹
• Overwhelmingly, the evidence suggests that general practitioners (GPs) should not routinely use MTHFR testing.²
• The MTHFR gene test identifies two gene variants that, while common in healthy populations, are associated with mildly elevated homocysteine levels in the blood.^2,9
• Some studies have indicated a weak correlation between higher homocysteine levels and myocardial infarction and venous thromboembolism.^2,9,10
• Folic acid supplementation before and during early pregnancy has been shown to protect against neural tube defects in a pregnancy, for women with and without MTHFR¹
• In 2009, Australia introduced mandatory folate fortification of wheat flour used in bread and this has reduced the number of people with red blood cell folate levels below the reference range.¹¹
• Complementary and alternative practitioners often offer MTHFR testing to investigate recurrent pregnancy loss,^12,13 fertility, autism spectrum disorder,⁷ mental illness¹⁴ and cancer risk.²
• Although the MTHFR variants are associated with several medical conditions, clinical management is not changed by knowing which variant the patient has.
• When considering the usefulness of MTHFR testing for a patient, consider the following.¹¹

1. 1. Analytical validity: Does the test accurately reflect the biology of the patient (the two variants can be identified and appear to have caused a reduction in folate metabolism)?
   2. Clinical validity: Will the test increase your knowledge of the patient’s disorder of concern? There is conflicting evidence about the relevance of MTHFR variants in many disorders confounded by the complexity of folate metabolism, folate supplementation/fortification, genetic and dietary factors.
   3. Clinical utility: Will the test result change treatment of the disorder? In studies reporting an association between MTHFR and a disorder, the association is usually weak (many people with a variant will not develop the disorder, and many people without a variant will develop the disorder).

Although tests for MTHFR gene variants have analytical validity, the clinical validity is uncertain, and the clinical utility is not demonstrated in the evidence.¹¹

• If a patient is seeking a cause for an illness, or seeking evidence that the illness is genetic, discuss and define the possibilities.^2,15
• Explain the potential harms of over-investigation, including the cost of the test and the lack of a meaningful outcome.¹⁵
• Encourage open discussion about MTHFR gene testing, thereby building and supporting therapeutic relationships and shared decision making that is based on evidence.
• Continue to encourage standard care, including preventive exercises, folate supplements for women of childbearing age, management of comorbidity and lifestyle changes.^1,2,15
• Offer psychological support if the patient is distressed by a potential diagnosis.¹⁵
• Treat physical symptoms and continue to manage the patient’s expectations about current treatment of any condition they have, including relevant tests.¹⁵
• Refer to other specialist colleagues or a multidisciplinary team as appropriate.¹⁵

• The RACGP, First do no harm: a guide to choosing wisely in general practice - MTHFR gene testing patient resource
• The RACGP, Genomics in general practice – MTHFR gene testing
• The RACGP, Appropriate diagnostic testing – Patient information 
• Human Genetics Society of Australasia and Choosing Wisely Australia, Don’t undertake genetic testing for methylenetetrahydrofolate reductase (MTHFR), apolipoprotein E (APOE), and other such tests where the clinical utility for diagnostic purposes is extremely low 
• NSW Government and Centre for Genetics Education, MTHFR gene testing 
• Dean L, Medical genetics summaries
• The Royal College of Pathologists of Australasia, Position statement, MTHFR genetic tests