Study Identifies Inconsistencies Among Genetic Testing for Epilepsy

May 11, 2020

Data suggest that discrepancies in genetic testing for epilepsy warrant second opinions for interpretations as well as clinical reports that become part of a patient’s medical record following a second opinion.

Jeffrey A. SoRelle, MD

Data from a recent cross-sectional study demonstrated that most interpretations of genetic variants associated with epilepsy were concordant among laboratories, but more than half of the variants with conflicting interpretations occurred in genes that have therapeutic implications.

Overall, a total of 6292 of 22,676 genetic variants related to epilepsy (27.7%) were interpreted by 2 or more clinical laboratories. Among those, 3307 (52.6%) had interpretations that were fully concordant compared with 2985 variants (47.4%) who reported with conflicting interpretations.

“Second opinions for genetic variant interpretations might resolve some discrepancies in variant interpretation. A second-opinion review should result in a clinical report that will become a part of the patient’s medical record, and the patient should be informed that diagnostic uncertainty exists among clinical laboratories,” lead author Jeffrey A. SoRelle, MD, pathologist, UT Southwestern Medical Center, and colleagues concluded. “We anticipate that discrepancies in genetic interpretations will increase as genetic testing becomes prominent in the practice of medicine.”

Clinically substantial differences in variants were defined as a variant that crossed the threshold between a likely pathologic variant and a variant of uncertain significance. Of the 6292 variants, 201 (3.2%) had clinically substantial conflicts identified. Additionally, differences in interpretation from genes with therapeutic complications were found in 117 of the 201 variants (58.2%).

Of the 70 genes included in the study, 50 were found to have variants with clinically substantial conflicting interpretations. DNA polymerase gamma (POLG) was documented as the gene with the highest number of clinically substantial variant conflicts (n = 35). The sodium channel voltage-gated type 8 alpha subunit gene (SCN8A) had 11 of 95 (11.6%) conflicting variants that were clinically substantial, the most frequent of any gene. Tuberous sclerosis complex subunit gene 1 (TSC1) was conflicting in 2 of 430 variants (0.5%), accounting for the least frequent of any gene.

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The cross-sectional study aimed to assess the interlaboratory variation in the interpretation of genetic test results with potential therapeutic implications. To that point, using the ClinVar public database, SoRelle and colleagues collected data on genes that are commonly used with epilepsy to identify the more than 20,000 genetic variants from an unknown number of patients.

Gene inheritance patterns observed included autosomal dominant (n = 31), autosomal recessive (n = 28), and X-linked dominant (n = 4). Conflicting interpretations of genetic variants associated with epilepsy were analyzed for clinically substantial differences between May 7 and June 29, 2019. The researchers accepted variant annotations submitted to ClinVar (data set version 2019-05) between November 16, 2012 and May 3, 2019 for analysis. Each variant used in the analysis had been interpreted by 2 or more clinical laboratories.

Conflicting types of variation were separated into conflicts of confidence (e.g., benign vs. likely benign variants, and pathogenic vs. likely pathogenic variants), benign conflicts (benign or likely benign variants vs. variants of uncertain significance), or clinically substantial conflicts (pathogenic or likely pathogenic [pathogenic/likely pathogenic] variants vs benign or likely benign [benign/likely benign] variants and variants of uncertain significance).

Interpretations labeled as clinically substantial conflicts implied that the genetic variant had implications for the clinical diagnosis and management of a patient. Each clinically substantial conflict was further analyzed to identify the types of discrepancies. Indication of a de novo variant was reported in 19 of the 201 discrepant variants.

Variants with clinically substantial conflicts were examined based on the interval between 2 conflicting interpretations and were ultimately sorted into 3 intervals (<1 year, 1-2 years, and >2 years). Longest interval (>2 years) had the fewest number of conflicting variants (n = 41) compared with the intervals of less than 1 year (n = 84) and 1 to 2 years (n = 76).

Pathogenic or likely pathogenic variants were observed in 43 of 84 genes (51.2%) in the interval of less than 1 year, 45 of 76 genes (59.2%) in the interval of 1 to 2 years, and 14 of 41 genes (34.1%) in the interval of more than 2 years.

Notably, SoRelle and colleagues wrote that the number of conflicting variants increased during the 5-year period of study. “This increase may have been associated with increased genetic testing and the identification of rare variants by multiple laboratories,” they explained. “A consensus guideline for the interpretation of variants is available; however, differences may exist regarding the ways in which criteria in the guidelines are applied. A previous survey of 9 laboratories identified potential subjectivity in the application of the consensus guidelines.”


SoRelle JA, Pascual JM, Gotway G, Park JY. Assessment of interlaboratory variation in the interpretation of genomic test results in patients with epilepsy. JAMA Neurol. 2020;3(4):e203812 doi: 10.1001/jamanetworkopen.2020.3812