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Common Test-Ordering Errors
Part 3: Misordered Tests

"Known" Mutations
Molecular vs. Nonmolecular Test for Given Disease
Chromosome Analysis

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Published: June 2010

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Dr. Dale reviews test-ordering errors commonly seen at Mayo Medical Laboratories. This is the third presentation in the series and addresses misordered genetic tests including:

  • Known mutation tests
  • Molecular vs nonmolecular test for given disease
  • Chromosome analysis

Presenter: Jane C. Dale, MD

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Welcome to Mayo Medical Laboratories' Hot Topics. These presentations provide short discussions of current topics and may be helpful to you in your practice.

Our presenter for this 8-part series is Dr. Jane Dale, a consultant in the Department of Laboratory Medicine and Pathology at Mayo Clinic. Dr. Dale reviews test-ordering errors commonly seen at Mayo Medical Laboratories. This is the third presentation in the series and addresses misordered genetic tests including:

  • Known mutation tests
  • Molecular vs nonmolecular test for given disease
  • Chromosome analysis

Testing at Mayo Medical Laboratories

Here at Mayo Medical Laboratories we receive over 800,000 test orders each month. While by our estimation most of the orders we receive are appropriate orders, we do experience some recurring test-ordering problems. In this presentation, I will describe the most common problems that we see. I will also describe our efforts to decrease these problems and recommend ways that you too can help reduce these errors. Together, by decreasing inappropriate test orders, we can improve patient care and reduce costs.

Common Mayo Medical Laboratories Test-Ordering Errors

In this 8-part series, I will address 2 types of errors— misordered tests and overordered tests.

Misordered Tests

In the first part of this series, I will discuss misordered tests, that is, tests that are mistakenly ordered for the wrong purpose. This is a list of the most commonly misordered tests received by Mayo Medical Laboratories. In part 1, we focused on 3 chemistry tests--1,25-dihydroxyvitamin D, PTH-related peptide and uroporphyrinogen III synthase. In part 2, we covered the various T- and B-cell tests. Today, for part 3, we will cover the most commonly misordered genetic tests, including the use of known mutation tests, molecular vs nonmolecular tests, and chromosome analyses.

Genetic Testing

A common ordering error that we see among our molecular tests is ordering a diagnostic test when a known-mutation test is indicated and vice verse. Let me expand upon this a bit further. One category of molecular tests consists of those tests that identify unknown genetic abnormalities. This can be done by a whole variety of laboratory methods including 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 lab conducts testing to see 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 lab then conducts focused testing to see 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 test name.

Cystic Fibrosis

Let’s use genetic testing for cystic fibrosis as an example. Cystic fibrosis is an autosomal recessive disorder characterized by a varied degree of chronic obstructive lung disease and pancreatic enzyme insufficiency. The clinical diagnosis of cystic fibrosis is generally made based on these features, combined with a positive sweat chloride test.

Cystic fibrosis is caused by abnormalities in the CFTR gene (CFTR stands for cystic fibrosis transmembrane conductance regulator). CFTR gene mutations result in altered transport of ions across cell membranes in certain tissues, including sweat glands, pancreas, and lungs. To date, over 1,500 mutations have been described within the CFTR gene. Despite this very large number of described mutations, the most common mutation, termed deltaF508, accounts for approximately two-thirds of all mutations worldwide.

Cystic Fibrosis

7When a mutation has been previously identified in an affected family member, known-mutation testing (that is, the “CFTR Gene, Known Mutation Test”) can determine if a family member is a carrier of that mutation. Conversely, when a mutation has not been previously identified, a panel of the most common mutations known to occur or sequencing of the entire CFTR gene are indicated. Mayo’s CF panel includes the 70 most common mutations, including the 23 mutations recommended by the American College of Medical Genetics and American College of Obstetricians and Gynecologists. Because full gene sequencing is much more costly than the panel, we recommend the panel as a first-order diagnostic test, reserving gene sequencing for when the panel is negative. Once a mutation has been identified, subsequent family members can be tested for that mutation using the known-mutation test.

Multiple Endocrine Neoplasia Type 2 (MEN2)

Also frequently misordered is the test for multiple endocrine neoplasia type 2 (abbreviated as MEN2)an autosomal dominant cancer syndrome that is characterized by tumors of several different endocrine glands, including medullary carcinoma of the thyroid. For patients with findings suspicious for MEN2, we offer a diagnostic test (“Multiple Endocrine Neoplasia Type 2 Mutation Screen”). We also offer known-mutation testing when a MEN2 mutation has been identified in an affected family member and is used to test other family members for the same mutation. Known-mutation tests are very focused—we look only for the previously identified mutation. Misordering of these 2 tests occurs so frequently that we routinely call to confirm each order. In a recent review of 1 month’s orders, 40% of the tests were ordered incorrectly with the screening test ordered when, in fact, the known-mutation test was indicated.

Genetic Testing

To summarize, for many genetic diseases, Mayo Medical Laboratories offers tests to either diagnose the disease (these are typically named by the disease or the affected gene) or to determine if a previously identified genetic abnormality is present in a family member (the names of these tests include the disease or affected gene, followed by the phrase “known mutation”). Known-mutation testing is very focused and may not provide the desired information when ordered inappropriately. On the other hand, in the right situation, that is, 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. It also can be obtained more quickly and at a lower charge than its diagnostic counterpart. It is important to understand these distinctions when ordering.

Gene Test or Protein/Plasma Test?

A different kind of test-ordering error occurs when a genetic test for a specific disease is ordered, when the nongenetic test for the same disease is indicated, and vice verse. For many other disorders, we offer 2 different types of tests: tests that assess a patient’s DNA and tests that assess the composition of the patient’s plasma. While these 2 types of tests may relate to the same disease process, their indications are typically quite different.

Gene Test or Protein/Plasma Test?

Let me use our apolipoprotein tests to explain. For example, apolipoprotein B is the major protein component of low-density lipoprotein (abbreviated LDL) and increased plasma concentration of Apo B-containing lipoproteins is associated with an increased risk of developing atherosclerotic disease. In fact, some studies have shown that circulating levels of apolipoprotein B may be a better indicator of risk that LDL levels.

In addition to plasma apolipoprotein B, we also offer a genetic test that assesses the patient’s DNA for the presence of abnormalities in the gene that encodes apolipoprotein B. The gene is called APOB and the name of the gene test is shown here. Note that the test name includes the phrase “molecular analysis” and describes the common 2 mutations for which we test (R3500Q and R3500W). Patients may have high lipids due to dietary causes, as well as a variety of inherited causes. One of the inherited causes is abnormalitiesin the APOB gene, which occurs in approximately 15% of autosomal dominant hypercholesterolemia cases. So, in this situation, we can test for the gene (using the molecular analysis test) or we can measure circulating lipoprotein levels (using the plasma test).

Again, it is important to critically read our test names to make sure the appropriate test is ordered. If there are similar test names, and the names alone do not make it clear which test to order, it often helps to review the supporting information, such as “Useful For”, in our test catalogs. When necessary, we contact the ordering physicians to clarify orders. But, it is best to obtain that clarification before the specimen is collected.

Chromosome Analysis

Another common test-ordering error we encounter involves 2 of our chromosome analysis tests. We have 1 orderable for assessing congenital disorders and another for hematologic disorders. Often we find that the congenital disorder chromosome test is ordered when the hematologic disorder test is indicated and vice verse.

While both of these tests use the same specimen type and both begin with a cell culturing step, both the culturing processes and analyses differ significantly, making selection of the correct test critical. Culturing for congenital abnormalities is optimized for chromosome band resolution. This requires extended culturing with a stimulation step to produce high-resolution metaphases for analysis. Typically, the cells are cultured in the presence of phytohemagglutinin to induce mitosis. At culture harvest, agents are added to reduce chromosome condensation and to prevent spindle fiber formation. In contrast, in the culture process for hematologic abnormalities, cells are allowed to divide naturally, without stimulation, and can be cultured and analyzed in a shorter time period. The hematologic chromosome abnormality test is optimized to provide a rapid turnaround time, minimizing time to diagnosis and selection of appropriate treatment, which is critical for patients with hematologic malignancies.

Congenital chromosome studies are done on blood for a wide variety of indications including mental retardation, failure to thrive, Down syndrome, Turner syndrome, frequent miscarriages, infertility, multiple congenital anomalies, and sex determination, to name a few. Hematologic disorder chromosome analyses are done for patients with leukemias and lymphomas.

Chromosome Analysis, Mitomycin C Stress for Fanconi Anemia, Blood (#81332)

We offer another chromosome test that is for a specific hematologic disorder, namely Fanconi anemia. Clinically, Fanconi anemia is associated with progressive pancytopenia and a variety of developmental abnormalities. Fanconi anemia is a DNA repair disorder characterized by increased chromosome breakage. This abnormality can be visualized using special laboratory techniques. The cells of affected patients demonstrate increased chromosome breakage when cultured with cross-linking agents such mitomycin C, inducing specific abnormal formations that are diagnostic for Fanconi anemia. For this test, cells are cultured with a cell mitogen and are incubated 66 to 72 hours. Mitomycin C is added to cultures about 48 hours prior to harvesting. In the harvest process, the cells are exposed to an agent that arrests the cells in metaphase. They are then examined for the specific radial anomalies that are characteristic of the disorder.

Because the techniques employed during chromosome analyses vary depending on the suspected disorder, if the nature of the clinical question is not clear on the test requisition, it is important to query ordering physicians. For this reason, we request that our “additional test information forms” be completed, not only to provide information to laboratory staff performing and interpreting the test, but also to ensure that the correct test is ordered.


This concludes Part 3 of this series on some of the tests that, in our experience as a reference laboratory, are commonly ordered inappropriately.