Clinical Utility of Reinterpreting Previously Reported Genomic Epilepsy Test Results for Pediatric Patients

Abstract

IMPORTANCE 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. OBJECTIVE To investigate the value of reinterpreting previously reported genomic test results. DESIGN, SETTING, AND PARTICIPANTS This study 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. MAIN OUTCOMES AND MEASURES Patient reports from clinical genomic epilepsy tests were reviewed, and all reported genetic variants were reinterpreted using 2015 consensus standards and guidelines for interpreting hereditary genetic variants. Three classification tiers were used in the reinterpretation: pathogenic or likely pathogenic variant, variant of uncertain significance (VUS), or benign or likely benign variant. RESULTS A total of 309 patients had genomic epilepsy tests performed (mean [SD] age, 5.6 [0.8] years; 163 [52.8%] 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 5 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 2 years of the study identified reclassification of variants in 4 of 16 patients (25.0%) with a pathogenic or likely pathogenic variant and 11 of 41 patients (26.8%) with a VUS. CONCLUSIONS AND RELEVANCE The identified high rate of reinterpretation in this study suggests that interpretation of genomic test results has rapidly evolved during the past 5 years. These findings suggest that reinterpretation of genomic test results should be performed at least every 2 years.

Genomic testing in pediatric epilepsy

“…Neonatal-onset epilepsies (57%) followed by epileptic encephalopathies (32%) were most frequently diagnostic. Interestingly, in this study only 3% of cases reported had a variant of uncertain significance (VUS), whereas other studies have identified a VUS in >30% of cases (Lindy et al 2018; SoRelle et al 2018). This large difference in VUS detection rate probably can be attributed to differences in variant interpretation criteria; the use of recently published standardized interpretation guidelines (Richards et al 2015) shows a high rate of VUS detection in epilepsy panel studies (SoRelle et al 2018).…”

“…Periodic reanalysis of existing genetic data is not performed by all clinical laboratories. However, studies have shown that genetic diagnoses may significantly change over time (Costain et al 2018; Hiatt et al 2018; Mersch et al 2018; SoRelle et al 2018). The types of diagnostic changes include not only upgrades from uncertain diagnosis to disease-causative diagnosis, but also can include downgrades from pathogenic diagnoses to benign findings.…”

Clinical Genetic Screening in Adult Patients with Kidney Disease

“…Any discrepancy should be reviewed by both the molecular pathologist and clinician, and prior reports should be reviewed. Importantly, recent data suggest that many VUS will eventually be classified as benign (82)(83)(84)(85)(86) and can usually be resolved with subsequent clinical correlations, in discussions between the molecular diagnostician, clinician, and the patient.…”

Promises, promises, and precision medicine

“…Yet interventions making use of this new information have been limited, and a problematic side effect, especially for family members, is that estimates of the penetrance of pathogenic DNA variants decline as more unaffected individuals are screened. Reclassification of variants initially thought to be pathogenic has proven to be a common problem (5).…”