Utility of genetic testing for therapeutic decision‐making in adults with epilepsy

Abstract

Objective: Genetic testing has become a routine part of the diagnostic workup in children with early onset epilepsies. In the present study, we sought to investigate a cohort of adult patients with epilepsy, to determinate the diagnostic yield and explore the gain of personalized treatment approaches in adult patients. Methods: Two hundred patients (age span = 18-80 years) referred for diagnostic gene panel testing at the Danish Epilepsy Center were included. The vast majority (91%) suffered from comorbid intellectual disability. The medical records of genetically diagnosed patients were mined for data on epilepsy syndrome, cognition, treatment changes, and seizure outcome following the genetic diagnosis. Results: We found a genetic diagnosis in 46 of 200 (23%) patients. SCN1A, KCNT1, and STXBP1 accounted for the greatest number of positive findings (48%). More rare genetic findings included SLC2A1, ATP6A1V, HNRNPU, MEF2C, and IRF2BPL.Gene-specific treatment changes were initiated in 11 of 46 (17%) patients (one with SLC2A1, 10 with SCN1A) following the genetic diagnosis. Ten patients improved, with seizure reduction and/or increased alertness and general well-being. Significance: With this study, we show that routine diagnostic testing is highly relevant in adults with epilepsy. The diagnostic yield is similar to previously reported pediatric cohorts, and the genetic findings can be useful for therapeutic decisionmaking, which may lead to better seizure control, ultimately improving quality of life.

Clinical Utility of Exome Sequencing and Reinterpreting Genetic Test Results in Children and Adults With Epilepsy

“…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.…”

Investigating Developmental and Epileptic Encephalopathy Using Drosophila melanogaster

“…Several SLC genes expressed in the brain have been reported as a monogenic cause of DEEs. Among them, SLC2A1 is an important causative gene from the viewpoint of therapeutic decision-making [ 16 ]. SLC2A1 encodes GLUT1, the most prominent glucose transporter of the human brain and haploinsufficiency of SLC2A1 causes GLUT1 deficiency syndrome (GLUT1-DS), characterized by varying degrees of intellectual disability, epilepsy and movement disorders.…”

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 .…”

“…It has become clear that Dravet patients will benefit from a molecular diagnosis at any stage. However, there are other forms of genetic epilepsies whose late diagnosis can have therapeutic implications, such as GLUT1 deficiency, as beautifully demonstrated by Johannesen et al 1 …”

“…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.…”