Diagnostic yield of genetic testing in epileptic encephalopathy in childhood

Abstract

Summary Objective Epilepsy is a common neurologic disorder of childhood. To determine the genetic diagnostic yield in epileptic encephalopathy, we performed a retrospective cohort study in a single epilepsy genetics clinic. Methods We included all patients with intractable epilepsy, global developmental delay, and cognitive dysfunction seen between January 2012 and June 2014 in the Epilepsy Genetics Clinic. Electronic patient charts were reviewed for clinical features, neuroimaging, biochemical investigations, and molecular genetic investigations including targeted next‐generation sequencing of epileptic encephalopathy genes. Results Genetic causes were identified in 28% of the 110 patients: 7% had inherited metabolic disorders including pyridoxine dependent epilepsy caused by ALDH7A1 mutation, Menkes disease, pyridox(am)ine‐5‐phosphate oxidase deficiency, cobalamin G deficiency, methylenetetrahydrofolate reductase deficiency, glucose transporter 1 deficiency, glycine encephalopathy, and pyruvate dehydrogenase complex deficiency; 21% had other genetic causes including genetic syndromes, pathogenic copy number variants on array comparative genomic hybridization, and epileptic encephalopathy related to mutations in the SCN1A, SCN2A, SCN8A, KCNQ2, STXBP1, PCDH19, and SLC9A6 genes. Forty‐five percent of patients obtained a genetic diagnosis by targeted next‐generation sequencing epileptic encephalopathy panels. It is notable that 4.5% of patients had a treatable inherited metabolic disease. Significance To the best of our knowledge, this is the first study to combine inherited metabolic disorders and other genetic causes of epileptic encephalopathy. Targeted next‐generation sequencing panels increased the genetic diagnostic yield from <10% to >25% in patients with epileptic encephalopathy.

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

“…In addition, in patients with epileptic encephalopathies with onset in the first year of life, the overall positive rate was 41.8%, which is in line with recent smaller studies examining the diagnostic yield of targeted NGS panels. 39 This finding suggests that the increased yield in patients with epilepsy is driven largely by patients with neonatal and infantile onset. Even though several genes, such as KCNQ2, are already established, this particular group has not been systematically investigated in existing studies.…”

Cardiac arrhythmia in a mouse model of sodium channel SCN8A epileptic encephalopathy

“…Since then, more than 140 patients with SCN8A mutations have been identified (8) (www.SCN8A.net/ Home.aspx). The combined incidence of de novo mutations of SCN8A in EIEE was 1% (19 of 1,957) in five large studies of several hundred individuals each (9)(10)(11)(12)(13). Common features of EIEE13 include seizure onset between birth and 18 mo of age, mild to severe cognitive and developmental delay, and mild to severe movement disorders that may result in immobility (8).…”

Whole Exome Sequencing in Neurogenetic Diagnostic Odysseys: An Argentinian Experience

“…Although a diagnostic yield of about 30% in neurogenetic disorders can be extrapolated from the results of large series that have included other medical conditions as well (Fogel et al, 2014;Gillissen et al, 2014;Bettencourt et al, 2014;Mercimek-Mahmutoglu et al, 2015), there are not specific reports assessing its utility in a setting such as ours: a neurogeneticist led academic group serving in a low-income country.…”