Genetic testing and counseling for the unexplained epilepsies: An evidence‐based practice guideline of the National Society of Genetic Counselors

Abstract

Epilepsy, defined by the occurrence of two or more unprovoked seizures or one unprovoked seizure with a propensity for others, affects 0.64% of the population and can lead to significant morbidity and mortality. A majority of unexplained epilepsy (seizures not attributed to an acquired etiology, such as trauma or infection) is estimated to have an underlying genetic etiology. Despite rapid progress in understanding of the genetic underpinnings of the epilepsies, there are no recent evidence-based guidelines for genetic testing and counseling for this population. This practice guideline provides evidence-based recommendations for approaching genetic testing in the epilepsies using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Evidence to Decision framework. We used evidence from a recent systematic evidence review and meta-analysis of diagnostic yield of genetic tests in patients with epilepsy. We also compiled data from other sources, including recently submitted conference abstracts and peer-reviewed journal articles. We identified and prioritized outcomes of genetic testing as critical, important or not important and based our recommendations on outcomes deemed critical and important. We considered the desirable and undesirable effects, value and acceptability to relevant stakeholders, impact on health equity, cost-effectiveness, certainty of evidence, and feasibility of the interventions in individuals with epilepsy. Taken together, we generated two clinical recommendations: (1) Genetic testing is strongly recommended for all individuals with unexplained epilepsy, without limitation of age, with exome/genome sequencing and/or a multi-gene panel (>25 genes) as first-tier testing followed by chromosomal microarray, with exome/genome sequencing conditionally recommended over multi-gene panel. (2) It is strongly recommended that genetic tests be selected, ordered, and interpreted by a qualified healthcare provider in the setting of appropriate pre-test and post-test genetic counseling. Incorporation of genetic counselors into neurology practices and/or referral to genetics specialists are both useful models for supporting providers without genetics expertise to implement these recommendations.

Clinical utility of exome sequencing in a pediatric epilepsy cohort

“…This finding expands on the work by Mulhern et al 38 that for epilepsy cases, ES facilitates diagnoses that may be missed through targeted testing. This analysis is consistent with recommendations made by NSGC that ES/GS is conditionally recommended over multi‐gene panels for individuals with unexplained epilepsy 26 . In addition, ES and GS have greater impact because these technologies include newly‐discovered epilepsy‐associated genes.…”

“…This analysis is consistent with recommendations made by NSGC that ES/GS is conditionally recommended over multi-gene panels for individuals with unexplained epilepsy. 26 In addition, ES and GS have greater impact because these technologies include newly-discovered epilepsy-associated genes. For instance, in our cohort, two probands were found to have pathogenic variants and one proband was found to have a variant of uncertain significance in CSNK2B, which was newly associated with disease at the time of analysis.…”

“…Although many studies have found that NGS results have impacted clinical care, and recent evidence‐based clinical guidelines put forth by the National Society of Genetic Counselors (NSGC) state that NGS is strongly recommended for all individuals with unexplained epilepsy, this testing is not consistently covered by payors 5,8,10,16–26 . Research in the field is limited and few studies examine the implications of ES results in epilepsy populations.…”

The current landscape of epilepsy genetics: where are we, and where are we going?

“…Through international collaboration between clinicians, scientists and family advocacy, knowledge of the genetic epilepsies continues to grow exponentially. In the clinic, genetic testing for individuals with any unexplained epilepsy has been officially set as standard of care by the National Society of Genetic Counselors (NSGC) [3 ▪▪ ]. Gene discovery continues at a steady pace, and we have a better understanding than ever of the natural history of genetic epilepsies, gained through gold-standard and innovative methods.…”

NAPB and developmental and epileptic encephalopathy: Description of the electroclinical profile associated with a novel pathogenic variant

“…An extended study of the βSnap-KO mice and in vitro analyses of induced pluripotent stem-derived neurons 18 would help to better understand the pathophysiological mechanism involved in NAPB-related DEE. Because multigene panels are still often used as first-tier testing, 19,20 we suggest including NAPB but strongly recommend using exome and genome sequencing to identify and describe more NAPB patients and better understand the associated phenotypes.…”