MTHFR genetic testing: Controversy and clinical implications

A polymorphism is a variant within a gene that does not necessarily affect its function, unlike a pathogenic mutation. Genetic testing for two common polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR), 677C>T and 1298A>C, is being accessed by general practitioners (GPs) and alternative medicine practitioners (based on in-house records from referrals), and promoted through some pharmacies in Western Australia (based on the authors' personal communication). Due to the large, varied and often conflicting data reported on MTHFR, these polymorphisms have been weakly associated with multiple conditions, including autism, schizophrenia, cardiac disease, fetal neural tube defects, poor pregnancy outcomes and colorectal cancer.

The aim of this review is to explain the difficulty in translating inconclusive results - and results of uncertain clinical relevance - of genetic-association studies on common polymorphisms into clinical practice. We will also explore why testing for polymorphisms needs to be reconsidered in a diagnostic clinical setting.

On the basis of the available scientific evidence, we propose that there are very limited clinical indications for testing for the 677C>T and the 1298A>C polymorphisms in the MTHFR gene, and that testing is not indicated as a non-specific screening test in the asymptomatic general population.