Utility of Exome Sequencing for Diagnosis in Unexplained Pediatric-Onset Epilepsy.

Importance: Genomic advances inform our understanding of epilepsy and can be translated to patients as precision diagnoses that influence clinical treatment, prognosis, and counseling. Objective: To delineate the genetic landscape of pediatric epilepsy and clinical utility of genetic diagnoses for patients with epilepsy. Design, Setting, and Participants: This cohort study used phenotypic data from medical records and treating clinicians at a pediatric hospital to identify patients with unexplained pediatric-onset epilepsy. Exome sequencing was performed for 522 patients and available biological parents, and sequencing data were analyzed for single nucleotide variants (SNVs) and copy number variants (CNVs). Variant pathogenicity was assessed, patients were provided with their diagnostic results, and clinical utility was evaluated. Patients were enrolled from August 2018 to October 2021, and data were analyzed through December 2022. Exposures: Phenotypic features associated with diagnostic genetic results. Main Outcomes and Measures: Main outcomes included diagnostic yield and clinical utility. Diagnostic findings included variants curated as pathogenic, likely pathogenic (PLP), or diagnostic variants of uncertain significance (VUS) with clinical features consistent with the involved gene's associated phenotype. The proportion of the cohort with diagnostic findings, the genes involved, and their clinical utility, defined as impact on clinical treatment, prognosis, or surveillance, are reported. Results: A total of 522 children (269 [51.5%] male; mean [SD] age at seizure onset, 1.2 [1.4] years) were enrolled, including 142 children (27%) with developmental epileptic encephalopathy and 263 children (50.4%) with intellectual disability. Of these, 100 participants (19.2%) had identifiable genetic explanations for their seizures: 89 participants had SNVs (87 germline, 2 somatic mosaic) involving 69 genes, and 11 participants had CNVs. The likelihood of identifying a genetic diagnosis was highest in patients with intellectual disability (adjusted odds ratio [aOR], 2.44; 95% CI, 1.40-4.26), early onset seizures (aOR, 0.93; 95% CI, 0.88-0.98), and motor impairment (aOR, 2.19; 95% CI 1.34-3.58). Among 43 patients with apparently de novo variants, 2 were subsequently determined to have asymptomatic parents harboring mosaic variants. Of 71 patients who received diagnostic results and were followed clinically, 29 (41%) had documented clinical utility resulting from their genetic diagnoses. Conclusions and Relevance: These findings suggest that pediatric-onset epilepsy is genetically heterogeneous and that some patients with previously unexplained pediatric-onset epilepsy had genetic diagnoses with direct clinical implications.

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

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.

Mutations in NRXN1 and NRXN2 in a patient with early-onset epileptic encephalopathy and respiratory depression.

Early infantile epileptic encephalopathy (EIEE) is a severe disorder associated with epilepsy, developmental delay and intellectual disability, and in some cases premature mortality. We report the case of a female infant with EIEE and strikingly suppressed respiratory dysfunction that led to death. Postmortem research evaluation revealed hypoplasia of the arcuate nucleus of the medulla, a candidate region for respiratory regulation. Genetic evaluation revealed heterozygous variants in the related genes NRXN1 (c.2686C>T, p.Arg896Trp) and NRXN2 (c.3176G>A, p.Arg1059Gln), one inherited from the mother with family history of sudden infant death syndrome (SIDS) and one from the father with family history of febrile seizures. Although there are no previous reports with the digenic combination of NRXN1 and NRXN2 variants, patients with biallelic loss of NRXN1 in humans and double neurexin 1α/2α knockout mice have severe breathing abnormalities, corresponding to the respiratory phenotype of our patient. These observations and the known interaction between the NRXN1 and NRXN2 proteins lead us to hypothesize that digenic variants in NRXN1 and NRXN2 contributed to the phenotype of EIEE, arcuate nucleus hypoplasia, respiratory failure, and death.

Diagnostic yield of genetic tests in epilepsy: A meta-analysis and cost-effectiveness study.

OBJECTIVE: To compare the cost-effectiveness of genetic testing strategies in patients with epilepsy of unknown etiology. METHODS: This meta-analysis and cost-effectiveness study compared strategies involving 3 genetic tests: chromosomal microarray (CMA), epilepsy panel (EP) with deletion/duplication testing, and whole-exome sequencing (WES) in a cost-effectiveness model, using "no genetic testing" as a point of comparison. RESULTS: Twenty studies provided information on the diagnostic yield of CMA (8 studies), EP (9 studies), and WES (6 studies). The diagnostic yield was highest for WES: 0.45 (95% confidence interval [CI]: 0.33-0.57) (0.32 [95% CI: 0.22-0.44] adjusting for potential publication bias), followed by EP: 0.23 (95% CI: 0.18-0.29), and CMA: 0.08 (95% CI: 0.06-0.12). The most cost-effective test was WES with an incremental cost-effectiveness ratio (ICER) of $15,000/diagnosis. However, after adjusting for potential publication bias, the most cost-effective test was EP (ICER: $15,848/diagnosis) followed by WES (ICER: $34,500/diagnosis). Among combination strategies, the most cost-effective strategy was WES, then if nondiagnostic, EP, then if nondiagnostic, CMA (ICER: $15,336/diagnosis), although adjusting for potential publication bias, the most cost-effective strategy was EP ± CMA ± WES (ICER: $18,385/diagnosis). While the cost-effectiveness of individual tests and testing strategies overlapped, CMA was consistently less cost-effective than WES and EP. CONCLUSION: WES and EP are the most cost-effective genetic tests for epilepsy. Our analyses support, for a broad population of patients with unexplained epilepsy, starting with these tests. Although less expensive, CMA has lower yield, and its use as the first-tier test is thus not supported from a cost-effectiveness perspective.

Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression.

OBJECTIVE: We sought to identify genetic causes of early onset epileptic encephalopathies with burst suppression (Ohtahara syndrome and early myoclonic encephalopathy) and evaluate genotype-phenotype correlations. METHODS: We enrolled 33 patients with a referral diagnosis of Ohtahara syndrome or early myoclonic encephalopathy without malformations of cortical development. We performed detailed phenotypic assessment including seizure presentation, electroencephalography, and magnetic resonance imaging. We confirmed burst suppression in 28 of 33 patients. Research-based exome sequencing was performed for patients without a previously identified molecular diagnosis from clinical evaluation or a research-based epilepsy gene panel. RESULTS: In 17 of 28 (61%) patients with confirmed early burst suppression, we identified variants predicted to be pathogenic in KCNQ2 (n = 10), STXBP1 (n = 2), SCN2A (n = 2), PNPO (n = 1), PIGA (n = 1), and SEPSECS (n = 1). In 3 of 5 (60%) patients without confirmed early burst suppression, we identified variants predicted to be pathogenic in STXBP1 (n = 2) and SCN2A (n = 1). The patient with the homozygous PNPO variant had a low cerebrospinal fluid pyridoxal-5-phosphate level. Otherwise, no early laboratory or clinical features distinguished the cases associated with pathogenic variants in specific genes from each other or from those with no prior genetic cause identified. INTERPRETATION: We characterize the genetic landscape of epileptic encephalopathy with burst suppression, without brain malformations, and demonstrate feasibility of genetic diagnosis with clinically available testing in >60% of our cohort, with KCNQ2 implicated in one-third. This electroclinical syndrome is associated with pathogenic variation in SEPSECS. Ann Neurol 2017;81:419-429.

Genetic testing in the epilepsies-developments and dilemmas.

In the past two decades, the number of genes recognized to have a role in the epilepsies has dramatically increased. The availability of testing for epilepsy-related genes is potentially helpful for clarification of the diagnosis and prognosis, selection of optimal treatments, and provision of information for family planning. For some patients, identification of a specific genetic cause of their epilepsy has important personal value, even in the absence of clear clinical utility. The availability of genetic testing also raises new issues that have only begun to be considered. These issues include the growing importance of educating physicians about when and how to test patients, the need to ensure that affected individuals and their families can make informed choices about testing and receive support after receiving the results, and the question of what the positive and negative consequences of genetic testing will be for affected individuals, their family members, and society.