Clinical utility of multigene panel testing in adults with epilepsy and intellectual disability

Abstract

Objective To determine the diagnostic yield of a commercial epilepsy gene panel in adults with chronic epilepsy and accompanying intellectual disability, given that genetic evaluation is often overlooked in this group of patients. Methods This is a cross‐sectional study analyzing the results of epilepsy gene panels including up to 185 genes in adult epilepsy patients with intellectual disability, according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition. Patients with acquired structural brain abnormalities or known chromosomal abnormalities were excluded. Results From approximately 600 patients seen from January 2017 to June 2018 at a single academic epilepsy center, 64 probands and two affected relatives (32 males, mean age = 31 years ± 10) were selected and clinically tested. Fourteen probands (14/64 = 22%; four males, mean age = 32 years ± 10) were found to have pathogenic or likely pathogenic variants in the following genes: SCN1A, GABRB3, UBE3A, KANSL1, SLC2A1, KCNQ2, SLC6A1, HNRNPU, STX1B, SCN2A, PURA, and CHD2. Six variants arose de novo, and the inheritance was not determined in eight. Nine probands (64%) had severe or profound intellectual disability, and five (35%) had autistic features. Eight patients (57%) had a diagnostic change from presumptive clinical diagnosis prior to genetic testing. Significance We were able to demonstrate that a commercial epilepsy gene panel can be an important resource in clinical practice, identifying the etiology in 22% of adults with epilepsy and intellectual disability. The diagnostic yield is similar to previously reported pediatric cohorts. Larger samples would be required to evaluate the more prevalent genotypes among adult epilepsy patients.

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“…In our study, a genetic diagnosis was made in 13 (11%) of 118 adults, which was similar to the diagnostic yield found in pediatric epilepsy (p = 0.145). However, our yield was slightly lower than that obtained in previous studies in adults, in which a genetic cause was identified in 22 or 23% of cases, respectively (Borlot et al, 2019;Johannesen et al, 2020). The higher yield in the other studies may have been due to most patients also presenting with ID and/or developmental delay.…”

“…This may be the reason why patients with focal epilepsy were more likely to accompany with ID than patients with generalized epilepsy in our study (9/49, 18.5% vs. 11/101, 10.9%). Evidence from our study and the studies of some others suggested that epilepsy patients with ID were significantly more likely to have a positive result (Borlot et al, 2019;Johannesen et al, 2020). Thus, at least in part, explain that the diagnostic rate is higher in focal vs. generalized epilepsy in our study.…”

Muscle and brain sodium channelopathies: genetic causes, clinical phenotypes, and management approaches

“…For other EOEEs, gene panels or whole exome/genome sequencing (WES/WGS) analyses can lead to a diagnostic yield varying between 30% and 70% 70 . A recent study in adults with treatment-resistant epilepsy and intellectual disability using the same wide sequencing approach had a similar diagnostic rate, highlighting a significant unmet clinical need in older patients 71 .…”

Epilepsy gene panel yield and impact on outcomes for adults with unexplained seizures

“…We read with great interest the article entitled “Utility of Genetic Testing for Therapeutic Decision‐Making in Adults With Epilepsy” by Johannesen and colleagues, investigating 200 patients with gene panels over 6 years 1 . Their work achieved the same diagnostic yield as a smaller cohort published by us last year 2 . Both studies had similar study populations, consisting of adults with epilepsy, mostly accompanied by intellectual disability and medically refractory seizures.…”

“…Given that the genetic basis for many adults with unexplained seizures is still unsolved, it would be interesting to learn whether these patients could benefit more from distinct diagnostic approaches. Copy number variants and coding exon analysis are not enough to narrow the current diagnostic gap 1,2,6 . Whole‐genome sequencing is one strategy, despite the variant‐interpretation challenges.…”