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Childhood Epilepsy Diagnoses Shift With Genomic Reinterpretation

NEW YORK (GenomeWeb) – Periodically re-analyzing genomic variant data can lead to new diagnoses for children with epilepsy, according to a new retrospective analysis.

Researchers from the University of Texas Southwestern Medical Center focused on results from genomic tests performed for 309 children with epilepsy-like symptoms between July 2012 and August 2015 — 185 of these children had variants reported as pathogenic, likely pathogenic, or of uncertain significance.

The reinterpretation was done in the spring of 2017 using population allele frequency, clinical variant association, and American College of Medical Genetics and Genomics variant classification recommendations available at the time. The team's results, reported online yesterday in JAMA Pediatrics, led to variant re-classifications for 67 of the 185 children with a previously reported genetic variant. Of those 67 cases, 21 patients received new diagnoses following the variant re-interpretation step.

"I was surprised how much change we saw," co-author Drew Thodeson, a pathology, neurology, and neurotherapeutics researcher affiliated with the University of Texas Southwestern Medical Center, said in a statement. "It's a testament to how quickly genetics is evolving and how much we are learning with new laboratory techniques and with more people getting their genes tested."

The team found new variants of clinical significance in nearly one-third of patients who had pathogenic or likely pathogenic variants identified in the past, leading to re-classification for 19 of the 61 individuals with prior diagnoses. Among the 124 individuals who had not been diagnosed already, but carried variants of uncertain significance (VUS), the researchers reported, the re-interpretation prompted new genetic diagnoses in 48 of the epilepsy cases.

When the team focused on genomic reports done most recently — during the last two years of the initial study — it still managed to reclassify several cases through variant re-interpretation. There, four of 16 individuals already known to carry pathogenic or likely pathogenic variants were re-classified, as were 11 of the 41 individuals previously found to carry VUS.

"Before the initiation of the study, we had anticipated that the variants requiring reclassification might decrease after the publication of the 2015 ACMG guidelines or the release of population databases in 2014," the authors wrote. "On the contrary, the pattern of reclassifications was unchanged."

Based on their findings, they recommended that genetic tests be re-interpreted at least every two years for pediatric patients with epilepsy. Moreover, they noted that "reinterpretation should not be limited to genomic tests but should include all previously reported genetic tests."

More broadly, the team's findings line up with results reported by other groups who have updated the interpretation of clinical genome or exome sequence data over time. For example, researchers from the University of Texas Southwestern Medical Center, Myriad Genetic Laboratories, and elsewhere presented data at the National Society of Genetic Counselors annual meeting in Ohio last year on the patient impact of variant re-classification for individuals who received hereditary cancer testing.

And at the ACMG annual meeting in 2016, a Baylor College of Medicine- and Johns Hopkins University-led team touched on the value of clinical exome re-analysis.

Based on his team's latest findings, Thodeson argued that it is "up to both families and doctors to have test results periodically reviewed to make sure the best care is being given" since "knowledge of the human genome is growing so fast."