Gene Tests Don't Detect Right Ventricular Myocardial Disease

From Reuters Health Information
Gene Tests Don't Help Detect Disease of Right Ventricular Myocardium

By Will Boggs MD

NEW YORK (Reuters Health) May 31 - Genetic testing should not be used to screen for arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC), according to a new report.

"The potential for false positives is currently among the highest of all genetic tests for inherited heart diseases," Dr. Michael J. Ackerman from Mayo Clinic, Rochester, Minnesota told Reuters Health in an email.

"If ARVC genetic testing were done on healthy people, about 16% of us would have a 'maybe' genetic test result with the identification of a rare, so-called Variant of Uncertain Significance (VUS)," Dr. Ackerman said. "This VUS issue for the ARVC genetic test is like Genetic Purgatory."

As reported in the June 7th Journal of the American College of Cardiology, Dr. Ackerman and colleagues investigated the spectrum and prevalence of background genetic variation that would meet the criteria of a mutation on the ARVC genetic test and sought to determine how best to interpret a positive test.

They performed genetic tests for ARVC on 175 patients known to have it and on 427 unrelated, apparently healthy control subjects from various racial and ethnic backgrounds.

Nearly 1 in 6 controls (69/427, or 16.2%) had genetic variants that met the authors' criteria for rare mutations that would have yielded a positive test result. In contrast, 58.3% (102/175) of ARVC patients had positive genetic tests.

All but one of the positive results among controls were missense mutations. Only 2 of 427 (0.47%) controls had radical mutations. Among the ARVC patients, 20.6% had missense mutations and 42.9% had radical mutations.

Healthy Caucasian controls had a much lower rate of missense mutations (6/103, 5.83%) than non-Caucasian controls (63/324, 19.4%).

The spectrum of mutations also differed by individual gene. Mutations in PKP2 and DSG2 were more common among ARVC cases than among Caucasian controls (but not among non-Caucasian controls), but there was no discernible difference between ARVC cases and either control subgroup in the percent of individuals with DSC2 or TMEM43 mutations.

In general, however, cases were more likely than controls to have mutations in critical domains or highly conserved residues of the genes tested.

But because of the high background noise rate, "ARVC genetic testing should never be thought of as a screening test or a test to order in a patient with insufficient clinical evidence to merit the diagnosis of ARVC in the first place," Dr. Ackerman said.

Instead, it should be used only for "index cases with clinically strong evidence for the disease," he added. "Even in this setting, a 'positive' genetic test result must be scrutinized with great care."

"Since the known ARVC-causative genes currently explain/account for less than 50% of the disease, the search continues for novel ARVC genes," Dr. Ackerman continued. "In addition, ARVC investigators are trying to find the determinants/biomarkers that underline the incomplete penetrance and variable expressivity in the disease."

"Stringent criteria ('radical' mutations, or missense mutations located in highly conserved and functionally important domains) and, whenever possible, cosegregation analysis can be used when applicable to help with genetic test result interpretation," write Dr. Luisa Mestroni and Dr. Matthew R. G. Taylor from University of Colorado Denver, Aurora, Colorado in an editorial.

"Until the specificity of these types of molecular genetic tests is robust and understood, the clinical application of such tests is probably still better performed at referral centers with expertise in cardiovascular genetics," they conclude.

SOURCE: http://bit.ly/keC0gX

J Am Coll Cardiol 2011.

Gene Tests Don't Detect Right Ventricular Myocardial Disease