Summary, published on MedScape
Different laboratories may show clinically substantial conflict in some interpretations of genetic variants in patients with epilepsy, according to a study published in the journal JAMA Network Open by researchers at the University of Texas Southwestern Medical Center. Senior author, Dr. Jason Y. Park notes that although previous studies have examined how genetic-test interpretations can change as time passes and new medical knowledge is accumulated, few studies have quantified the difference in genetic interpretations between laboratories. This is important because genomic testing is routine in the diagnosis and management of pediatric patients with epilepsy, and many genetic forms of epilepsy have specific therapeutic implications.
To examine how consistent such laboratory results might be, the researchers examined a set of 70 genes known to be associated with epilepsy and more than 22,000 variants (from an unknown number of patients) that were reported to “ClinVar,” a publicly-available database that lists the relationships between human variations in specific genes and how they manifest as symptoms of a disease. A total of 6,292 variants were reported by two or more laboratories. Almost half(47.4%) had conflicting interpretations. Although most of these were minor differences in confidence, for example “benign” versus “likely benign,” there was substantial clinical discordance in 201 variants (3.2%), 117 of which (58.2%) have potential therapeutic implications.
The researchers write, “Tertiary care centers routinely perform secondary reviews of surgical pathology cases before recommending definitive therapies, such as surgery, chemotherapy, or radiotherapy…such a practice of secondary review may be prudent in genomics when a variant is in conflict.” Dr. Park concludes, “Patients and physicians should know that gene-test results may have different interpretations depending on the laboratory that performs the test.”
Dr. David Dyment, a clinical geneticist at Children’s Hospital of Eastern Ontario, in Ottawa, Canada, who was not involved in the study, stresses “the need for commercial labs to rigorously apply the American College of Medical Genetics and Genomics guidelines for variant interpretation. The clinicians (the neurologists or medical geneticists) need to be well-versed in variant interpretation, the available tools and databases, and be able to explain the concepts to patients and families. The need for re-analysis/re-interpretation of a variant, over time, is important to provide clarity for families.”