American College of Medical Genetics and Genomics (ACMG) Recommendations
- 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism genotyping should not be ordered as part of the clinical evaluation for thrombophilia or recurrent pregnancy loss.
- MTHFR polymorphism genotyping should not be ordered for at-risk family members.
- A clinical geneticist who serves as a consultant for a patient in whom an MTHFR polymorphism(s) is found should ensure that the patient has received a thorough and appropriate evaluation for his or her symptoms.
- If the patient is homozygous for the "thermolabile" variant c.665C→T, the geneticist may order a fasting total plasma homocysteine, if not previously ordered, to provide more accurate counseling.
- MTHFR status does not change the recommendation that women of childbearing age should take the standard dose of folic acid supplementation to reduce the risk of neural tube defects as per the general population guidelines (Zacho et al., 2011; De Stefano et al., 2000; Institute of Medicine, Food and Nutrition Board, 1998; "Prevention of neural tube," 1991; Czeizel & Dudás, 1992; "Recommendations for the use of folic acid," 1992; Toriello, 2011).
Assessment of Therapeutic Effectiveness
Obstetrics and Gynecology
To review the latest evidence on 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism testing as part of a routine evaluation for thrombophilia
Women of childbearing age and patients at risk for thrombophilia
- 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism testing (not recommended)
- Evaluation of symptoms in patients in whom an MTHFR polymorphism(s) is found
- Fasting total plasma homocysteine
- Folic acid supplementation
Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases
The guideline authors searched PubMed and the Cochrane Database of Systematic Reviews from January 1995 to the present. In the literature search, priority was given to original research, with highest emphasis on meta-analyses, followed by case-control and cohort studies. The Literature search excluded review articles, case reports, and articles in languages other than English. Bibliographies of articles deemed to be of the highest quality for their specific topic were combed for additional articles that may have been missed by the initial literature search. In addition, the guidelines of other professional bodies on the same, or related, topic were reviewed.
The databases were searched using the following terms: MTHFR, MTHFR polymorphism, MTHFR thermolabile variant, methylenetetrahydrofolate reductase, and hyperhomocysteinemia. Combined searches were done on specific questions of interest including: MTHFR and stroke, MTHFR and recurrent pregnancy loss, MTHFR and venous thromboembolism, and MTHFR and coronary artery disease. The same combined searches were done for hyperhomocysteinemia and stroke, etc.
The articles were reviewed by the working group who provided expert consensus.
A formal cost analysis was not performed and published cost analyses were not reviewed.
Internal Peer Review
The final manuscript was reviewed by the American College of Medical Genetics and Genomics (ACMG) Policy & Practice Guideline Committee Members, followed by the Board of Directors, and then opened up for general college membership comment.
|Czeizel AE, Dudas I. Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med. 1992 Dec 24;327(26):1832-5. PubMed|
|De Stefano V, Casorelli I, Rossi E, Zappacosta B, Leone G. Interaction between hyperhomocysteinemia and inherited thrombophilic factors in venous thromboembolism. Semin Thromb Hemost. 2000;26(3):305-11. [32 references] PubMed|
|Institute of Medicine, Food and Nutrition Board. Dietary reference intakes: thiamin, riboflavin, niacin, vitamin B6, folate, vitamin B12, pantothenic acid, biotin, and choline. Washington (DC): National Academy Press; 1998.|
|Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. MRC Vitamin Study Research Group. Lancet. 1991 Jul 20;338(8760):131-7. PubMed|
|Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWR Recomm Rep. 1992 Sep 11;41(RR-14):1-7. [14 references] PubMed|
|Toriello HV, Policy and Practice Guideline Committee of the American College of Medical. Policy statement on folic acid and neural tube defects. Genet Med. 2011 Jun;13(6):593-6. PubMed|
|Zacho J, Yazdanyar S, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. Hyperhomocysteinemia, methylenetetrahydrofolate reductase c.677C>T polymorphism and risk of cancer: cross-sectional and prospective studies and meta-analyses of 75,000 cases and 93,000 controls. Int J Cancer. 2011 Feb 1;128(3):644-52. PubMed|
The type of evidence supporting the recommendations is not specifically stated.
Appropriate use of 5,10-methylenetetrahydrofolate reductase (MTHFR) polymorphism testing in routine evaluation for thrombophilia
An implementation strategy was not provided.
|Hickey SE, Curry CJ, Toriello HV. ACMG practice guideline: lack of evidence for MTHFR polymorphism testing. Genet Med. 2013 Feb;15(2):153-6. [77 references] PubMed|
Not applicable: The guideline was not adapted from another source.
American College of Medical Genetics and Genomics - Professional Association
American College of Medical Genetics and Genomics
Authors: Scott E. Hickey, MD, FACMG, Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio, USA; Cynthia J. Curry, MD, FACMG, Genetic Medicine Central California, University of California, San Francisco–Fresno, Fresno, California, USA; Helga V. Toriello, PhD, FACMG, Department of Pediatrics/Human Development, Spectrum Health Hospitals and College of Medicine, Michigan State University, Grand Rapids, Michigan, USA
The authors declare no conflict of interest.
This is the current release of the guideline.
Electronic copies: Available from the American College of Medical Genetics and Genomics (ACMG) Web site .
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