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Molecular Tests: Should I Order a Diagnostic or Known-Mutation Analysis?



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January 2013

A common ordering error among molecular tests is ordering a diagnostic test when a known-mutation test is indicated, and vice versa. To explain, one category of molecular tests identify unknown genetic abnormalities. This can be done by a variety of laboratory methods including polymerase chain reaction (PCR), gene sequencing, and others. In these situations, the patient has a set of clinical and laboratory findings that suggest a certain genetic abnormality and the laboratory performs testing to determine if a genetic abnormality is present.

Another category of molecular testing occurs when a specific genetic abnormality has been previously identified in an individual’s DNA. The laboratory then performs targeted testing to determine if that specific, previously identified DNA abnormality also is present in a family member’s DNA. Tests of this second type include the phrase “known mutation” in their Mayo Clinic test name.

To illustrate, consider Wilson disease. This disease is an autosomal recessive disorder primarily characterized by hepatic dysfunction and neurologic manifestations resulting from the body’s inability to excrete excess copper. Patients with Wilson disease often show decreased serum ceruloplasmin and serum copper levels and elevated urinary copper excretion and hepatic copper concentration. If not treated, Wilson disease can cause liver failure, severe brain damage, and even death.

For patients with clinical symptoms and/or biochemical evidence of Wilson disease, diagnostic testing is available (WDMS/83697 Wilson Disease, Mutation Screen). This test includes full sequencing of the ATP7B gene associated with Wilson disease. Once mutations have been identified, known-mutation testing (WDKM/83698 Wilson Disease, Known Mutation) can assess for those specific mutations in other family members to determine carrier status or rule out a diagnosis of Wilson disease. When familial mutations have been identified, known-mutation testing for other family members is less expensive and more informative than full-gene sequencing.

Also frequently misordered is the test for multiple endocrine neoplasia type 2 (MEN2), which is an autosomal dominant cancer syndrome characterized by tumors of several different endocrine glands, including medullary carcinoma of the thyroid. For patients with findings suspicious for MEN2, Mayo Medical Laboratories offers a diagnostic test (MENMS/80573 Multiple Endocrine Neoplasia Type 2 (2A, 2B, FMTC) Mutation Screen).

Known-mutation testing is available when a MEN2 mutation has been identified in an affected family member. The known-mutation test is used to evaluate other family members for a specific familial mutation (MENKM/81082 Multiple Endocrine Neoplasia Type 2 (2A, 2B, FMTC) Known Mutation). Known-mutation tests are very focused—looking only for the previously identified mutation. Misordering of these 2 tests occurs so frequently that at Mayo Medical Laboratories, we routinely call to confirm each order. In a recent review of 1 month’s orders, 40% of the tests were ordered incorrectly, with either the screening test ordered when a known mutation was available in the patient’s family, or with the known-mutation test ordered when the diagnostic test was indicated.

To summarize, for many genetic diseases, Mayo Medical Laboratories offers tests to either diagnose 
the disease or determine if a previously identified genetic abnormality is present in a family member. Known-mutation testing is very focused and may not provide the desired information when ordered inappropriately. On the other hand, when a mutation has been previously identified in an affected family member, a known-mutation test result can be predictive or diagnostic for that specific disorder. The result also can be obtained more quickly and at a lower charge than its diagnostic counterpart. Understanding these distinctions is important when ordering molecular tests.

Genetic Test Ordering Algorithm


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