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MTHFR (C677T) Mutation Analysis

CPT:

81291

The MTHFR mutation is one of the genetic risk factors for thrombosis. Indications for MTHFR testing as part of the screening for thrombophilia include: venous thromboembolism (especially if in an unusual site), deep vein thrombosis during pregnancy, venous thromboembolism while on oral contraceptive, fetal death after 10 weeks gestation, fetal growth restriction and/or preclampsia, and/or family history of stroke, pulmonary embolus, deep vein thrombosis in first degree relatives under age 50.

Test Details

Use

Follow-up evaluation in individuals with hyperhomocysteinemia; evaluation of patients with venous thrombosis

Synonyms

Hyperhomocysteinemia, C677T and A1298C Mutations; MTHFR;

Test Includes

This assay detects only the C677T and A1298C mutations in the MTHFR gene.

Methodology

Polymerase chain reaction (PCR) and restriction enzyme analysis

Pregnancy Week

0–13 Weeks
14–21 Weeks
22+ Weeks

Specimen Requirements

Specimen

Whole blood or LabCorp buccal swab kit (buccal swab collection kit contains instructions for use of a buccal swab)

 

Volume

7 mL whole blood or LabCorp buccal swab kit

Minimum Volume

3 mL whole blood or two buccal swabs

Container

Lavender-top (EDTA) tube, yellow-top (ACD) tube, or LabCorp buccal swab kit

Causes for Rejection

Frozen specimen; hemolysis; quantity not sufficient for analysis; improper container; one buccal swab; wet buccal swab

Storage Instructions

Maintain specimen at room temperature or refrigerate.

Additional Information

Hyperhomocysteinemia (high blood levels of homocysteine) is a risk factor for cerebrovascular disease, cerebral vein thrombosis, coronary artery disease, myocardial infarction, and venous thrombosis. The levels of homocysteine in the serum are influenced by both genetic and environmental factors. One of the genetic factors involves point mutations in the methylenetetrahydrofolate reductase (MTHFR) gene (OMIM 607093). Thermolabile variants of the MTHFR enzyme are mildly deficient at reducing 5,10-methylenetetrahydrofolate to 5-methylenetetrahydrofolate, a cofactor in the remethylation of homocysteine to methionine. The result is an elevation of serum homocysteine levels, especially in individuals with insufficient folate. One mutation, C677T, results in the MTHFR enzyme being 20% less efficient in metabolizing homocysteine, thus increasing serum levels, especially when plasma folate levels are at the lower end of normal. Five percent of Caucasians and 1.4% of African-Americans are C677T homozygotes, and are likely to have elevated serum homocysteine levels. A second mutation, A1298C, is also relatively common. Data suggests that combined heterozygosity for the two mutations may result in features similar to those of C677T homozygotes. Neither heterozygosity nor homozygosity for A1298C has been shown to be a risk factor for hyperhomocysteinemia. In patients with hyperhomocysteinemia, follow-up testing for the MTHFR mutation might be warranted to rule it out as a causative. Hyperhomocysteinemia has been found in women who have experienced two or more early pregnancy losses, placental infarction, and fetal growth retardation, but MTHFR mutation as a cause for early pregnancy loss is still controversial. Homozygosity for C677T has been shown to have a two- to threefold increased risk for neural tube defects (NTDs), such as anencephaly and spina bifida, and compound heterozygosity for C677T and A1298C may also be a risk factor for NTDs. Dietary folic acid supplementation before the fourth week of gestation is well documented in reducing the recurrence risk for open neural tube defects by approximately 75%. It may act by normalizing homocysteine levels. Thrombophilia investigations should include the most common genetic causes of thrombosis, the factor VLeiden mutation (R506Q), as well as the factor II/prothrombin mutation, G20210A. Beyond these, evaluation of plasma homocysteine levels, as well as testing for deficiencies of antithrombin III, protein C, and protein S may be indicated. Genetic counselors are available for healthcare providers to discuss results and for information on how to order additional testing, if desired, at 1-800-345-GENE.

Limitations

This assay detects only the C677T and A1298C mutations in the MTHFR gene. The diagnosis of hyperhomocysteinemia cannot rely on DNA testing alone but should take into consideration clinical findings and other studies, such as serum homocysteine levels. Prenatal testing is not available.

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