Childhood Epilepsy Diagnoses Shift with Genomic Reinterpretation

Clinical genomic tests that examine the DNA sequence of large numbers of genes are commonly used in the diagnosis and management of epilepsy in pediatric patients. The permanence of genomic test result interpretations is not known.

A number of distinct clinical syndromes of pediatric genetic epilepsy have been described and linked to specific gene defects. Phenotypes may include, in addition to epilepsy, variable degrees of intellectual disability, elements of autism spectrum disorders, other psychiatric disorders, and motor impairment.


Scientists at the University of Texas Southwestern Medical Center (Dallas TX, USA) retrospectively reviewed and reinterpreted genomic test results from July 1, 2012, to August 31, 2015, for pediatric patients who previously underwent genomic epilepsy testing at a single tertiary care pediatric health care facility. Reinterpretation of previously reported variants was conducted in May 2017. Three classification tiers were used in the reinterpretation: pathogenic or likely pathogenic variant, variant of uncertain significance (VUS), or benign or likely benign variant.

The team reported that a total of 309 patients had genomic epilepsy tests performed (mean age, 5.6 ± 0.8 years; 52.8% were male), and 185 patients had a genetic variant reported. The reported variants resulted in 61 patients with and 124 patients without a genetic diagnosis (VUS variants only). On reinterpretation of all reported variants, 67 of the 185 patients (36.2%) had a change in variant classification. Of the 67 patients with a genetic variant change in interpretation, 21 (31.3%) experienced a change in diagnosis. During the five years of the study, 19 of 61 patients (31.1%) with a genetic diagnosis and 48 of 124 patients (38.7%) with undiagnosed conditions (VUS only) had their results reclassified. Review of genomic reports issued during the final two years of the study identified reclassification of variants in four of 16 patients (25.0%) with a pathogenic or likely pathogenic variant and 11 of 41 patients (26.8%) with a VUS.

The scientists recommended, based on their findings, 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. The study was published on November 5, 2018, in the journal JAMA Pediatrics.

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University of Texas Southwestern Medical Center