OP81 – 2242: Genetic diagnosis in early infantile epileptic encephalopathy and severe neurodevelopmental delay using a gene panel: Our experience and results so far

Abstract

Objective The early infantile epileptic encephalopathy (EIEE) syndromes are a heterogeneous group of conditions characterised by intractable seizures and developmental delay or regression. The results of a pilot study (presented at the EPNS congress, 2013) demonstrated the diagnostic utility of a gene panel. We describe the successful implementation of a gene panel into diagnostic service, our experience so far and the results from 400 patients. Methods Two different custom enrichments (SureSelect, Agilent and TSCA, Illumina) were used to target 45 genes associated with EIEE and developmental delay followed by sequencing on the Illumina MiSeq. We tested 400 children with severe developmental delay and/or early onset seizures who were referred to the Regional Genetics Laboratory (250 SureSelect, 100 TSCA, 50 Pilot Study). Results The results of the TSCA enrichment were poorer than expected with ∼85% coverage of target bases ≥30 × sequence depth. The SureSelect panel performed significantly better, generating data with ∼99.8% of target bases covered ≥30 ×. Mutations in 21 different genes were identified in 67 patients giving a detection rate of 17%. The most frequently mutated genes were SCN2A (11 patients), CDKL5 and KCNQ2 (6 patients each). We found mutations in a number of genes in patients with electroclinical phenotypes not typical for the gene. Conclusion We report on the introduction of a targeted 45 gene panel for EIEE and severe developmental delay disorders. The custom SureSelect panel performed significantly better than TSCA and is now our chosen platform for this panel which has now been expanded to 66 genes. Given genetic heterogeneity and phenotypic pleiotropy in EIEE, the panel is proving a useful and popular diagnostic tool for Neurologists and Clinical Geneticists, thereby allowing better disease prognostication and genetic counselling for these families, as well as reducing the number and cost of conventional diagnostic tests.