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.

Figure 1.. Patients With Diagnostic Changes Based on Variant Classification

A, Patients with reclassification of gene variants from each of the categories. There were patients with both a variant of uncertain significance (VUS) and a pathogenic or likely pathogenic (P-LP) variant reclassified; these patients are represented only once in this figure. B, Reclassification rate plotted as the fraction of reclassified variants for each year testing was performed. Solid lines indicate the fraction of patients with a reclassified variant; dotted lines, the extrapolated slopes for the change in VUS classification (9% per year) and P-LP variant classification (6% per year). The R² and slope values were calculated using linear regression. B-LB indicates benign or likely benign.

Figure 2.. Variants Reinterpreted in the Study

Number of downgraded pathogenic or likely pathogenic (P-LP) variants (A) and evidence for downgrade (B) and number of changed variant of uncertain significance (VUS) types (C) and evidence for change (D). The most frequently downgraded P-LP variant type was missense (n = 13) followed by protein truncating variants (structural, n = 3; stop-loss, n = 2) and duplications (n = 1). For VUS types that changed, the most frequent type was missense (n = 62) followed by synonymous (n = 2) and deletions (n = 1). The dominant category of protein consequence was missense variants in the P-LP variant (68.4%) and VUS (95.4%). The evidence used to reclassify the variants was as follows: ClinVar, information posted to the ClinVar database; lack of data, no evidence in the ClinVar database or the Human Gene Mutation Database; HGMD, population frequency in the Human Gene Mutation Database; 1000Gen, population frequency in the 1000 Genomes database; ExAC, population frequency information in the Exome Aggregation Consortium database; and manual, determined when variant was synonymous or a protein-truncating variant.