<h3>Background</h3> We sought to investigate the diagnostic yield and mutation spectrum in previously reported genes for early-onset epilepsy and disorders of severe developmental delay. <h3>Methods</h3> In 400 patients with these disorders with no known underlying aetiology and no major structural brain anomaly, we analysed 46 genes using a combination of targeted sequencing on an Illumina MiSeq platform and targeted, exon-level microarray copy number analysis. <h3>Results</h3> We identified causative mutations in 71/400 patients (18%). The diagnostic rate was highest among those with seizure onset within the first two months of life (39%), although overall it was similar in those with and without seizures. The most frequently mutated gene was <i>SCN2A</i> (11 patients, 3%). Other recurrently mutated genes included <i>CDKL5, KCNQ2</i>, <i>SCN8A</i> (six patients each), <i>FOXG1, MECP2, SCN1A, STXBP1</i> (five patients each), <i>KCNT1, PCDH19, TCF4</i> (three patients each) and <i>ATP1A3, PRRT2</i> and <i>SLC9A6</i> (two patients each). Mutations in <i>EHMT1, GABRB3, LGI1, MBD5, PIGA, UBE3A</i> and <i>ZEB2</i> were each found in single patients. We found mutations in a number of genes in patients where either the electroclinical features or dysmorphic phenotypes were atypical for the identified gene. In only 11 cases (15%) had the clinician sufficient certainty to specify the mutated gene as the likely cause before testing. <h3>Conclusions</h3> Our data demonstrate the considerable utility of a gene panel approach in the diagnosis of patients with early-onset epilepsy and severe developmental delay disorders., They provide further insights into the phenotypic spectrum and genotype–phenotype correlations for a number of the causative genes and emphasise the value of exon-level copy number testing in their analysis.

Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis