The Food and Drug Administration's approval of a genotyping test for cystic fibrosis detection should improve screening accuracy and availability and could result in more uniform reporting of test results to physicians, experts say.

The new test—coined the “Tag-It Cystic Fibrosis Kit”—is the first multiplexed genotyping test to be cleared by the FDA as an in vitro device for diagnosing human disease.

Laboratories traditionally have purchased what are known as “analyzed specific reagents” and then have had to establish and validate assays and test kits themselves. The newly approved device, on the other hand, is a “standardized, validated testing kit. … It moves us past the 'home brews,' and makes for a more accurate test,” said Michael Watson, Ph.D., executive director of the American College of Medical Genetics.

Dr. Watson was a lead author of the clinical and laboratory guidelines for cystic fibrosis (CF) carrier screening that were published in 2001, and updated in 2004, by the ACMG and the American College of Obstetricians and Gynecologists (ACOG).

The kit is approved for use in carrier testing, as an aid in newborn screening, and in confirmatory diagnostic testing in newborns and children.

It can be used to detect and identify simultaneously 39 mutations in the gene for CF—known as the cystic fibrosis transmembrane conductance regulator (CFTR) gene—as well as 4 polymorphisms.

These variations include the 23 mutations recommended in the updated ACOG-ACMG guidelines as a “core mutation panel” for carrier screening in the general population. According to the manufacturer, the kit covers additional mutations seen in the African American and Hispanic communities.

“The percent of carriers picked up in [these communities] will go up,” said Graham Henderson, marketing manager for Tm Bioscience Corp. of Toronto.

The original 2001 guidelines recommended a standard screening panel covering 25 mutations, but one mutation subsequently was found to occur less frequently than expected, and another was found not to be a true mutation.

Laboratories today typically use the recommended 23-mutation panel and then supplement this, if possible, with tests for such additional mutations when screening particular racial or ethnic groups.

According to the ACOG-ACMG guidelines, the standard “pan-ethnic” 23-mutation panel has an expected sensitivity of 80% in Caucasians of European descent, 90% in Caucasians of Northern European descent, and 97% in Ashkenazi Jews. Even when the panel is supplemented with additional mutations, there is always some “residual risk,” or “small possibility of an affected offspring,” the guidelines say.

Donna Galehouse, Ph.D., technical director of the molecular diagnostics lab at Akron (Ohio) Children's Hospital, said the new device will enable more labs to perform screening, and will enable them to accurately handle high test volumes.

If use of the device becomes a standard of care, Dr. Watson said, physicians should get more “uniform” test result reports. “Right now, residual risks vary, depending on where testing is done” for instance, he said. “Physicians have to check carefully on what exactly was done and how it translates” into clinical meaning.

According to the ACOG-ACMG guidelines, screening should be offered to couples with a family history of CF, partners of individuals with CF, and Caucasian couples of European or Ashkenazi Jewish descent that are planning a pregnancy or seeking prenatal care.

Information about CF screening should be provided to patients in other ethnic and racial groups, the guidelines say.

A survey done 2 years after the guidelines were first issued showed that the vast majority of 632 ob.gyns.—89% of the respondents—ask obstetric patients about their family history of CF and offer CF carrier screening. Nearly two-thirds offer screening to all prenatal patients.

In the gynecologic setting, practice patterns were much different. Almost one-half of physicians who responded to the survey indicated that they do not ask nonpregnant patients about their family history of CF or provide them with information about screening (Genet. Med. 2004:6;450–5). (The survey was mailed to 1,165 ACOG members—approximately half of whom participate in the College's Collaborative Ambulatory Research Network, and half of whom were randomly selected.)

Reports on CF screening, according to the guidelines, should include the reported ethnicity of the patient and the indication for testing as well as the mutations tested and the method of testing. Negative screening tests should define “as accurately as possible” the residual risk of the person tested. “This will vary by ethnic or racial group and should be so specified in the test report,” the guidelines say.

Since the CFTR gene and the most common genetic mutation causing CF were identified about 15 years ago, more than 1,300 genetic variations have been identified in the gene. Many of these, Dr. Watson said, “are rare or private to an individual or family.” The newly approved device is not indicated for use in fetal diagnostic or preimplantation testing, and it is not indicated for stand-alone diagnostic purposes, according to a statement issued by the FDA.

Physicians should “interpret test results in the context of the patient's clinical condition, ethnicity, and family history,” the statement said.

70613_fx1.sml

The Tag-It Cystic Fibrosis Kit is approved for use in carrier testing and can identify 39 mutations in the CF gene. Tm Bioscience Corp.

New CF Screen Expected to Improve Accuracy : Genotyping test may allow more labs to perform CF screening and allow greater uniformity of result reports.