Abstracts

Rationale: Determining the genetic etiology of epilepsy can have important implications for treatment and management. However, primary and syndromic forms of epilepsy are genetically heterogeneous, which creates challenges for diagnostic testing. This study describes the utility of a comprehensive multi-gene testing panel for identifying mutations in genes causing epilepsy. Methods: A targeted testing panel combining Next Generation sequencing and deletion/duplication testing by exon-level array CGH of 53 genes associated with epilepsy was designed and validated. Results: In 176 consecutive clinical cases with different forms of epilepsy, 20% were positive for a known or predicted disease-causing mutation that accounted for the patient's phenotype. In the largest subgroup of 51 patients with infantile epileptic encephalopathy, a mutation or likely disease-causing variant was reported in 25% (13 cases). As expected, approximately half of the identified mutations were found in genes common for infantile epileptic encephalopathy. One patient had the two most common POLG mutations causing Alpers Syndrome. Three other patients had mutations in the SLC2A1 gene causing glucose transporter deficiency; two of these patients had mutations identified by sequence analysis while another had a partial gene deletion only detectable by exon-level array CGH. Knowledge of mutations in POLG and SLC2A1 can alter the clinical treatment and prognosis for these patients. The remaining mutations were identified in genes that are less commonly described in infantile epilepsy. Three novel mutations in the STXBP1 gene were found. Two patients had a small deletion or duplication resulting in a premature stop codon. In the other patient, a partial STXBP1 gene deletion was identified by exon-level array CGH, which likely would have been missed by whole genome array CGH. A de novo mutation in KCNQ2 was found in a patient with infantile spasms. Lastly, a single patient was homozygous for a novel missense mutation in PNPO. Although this mutation has not been published thus far, the amino acid is part of a highly conserved substrate-binding domain of PNPO. This finding was of interest not only because PNPO deficiency is extremely rare and clinical testing is relatively uncommon, but also because there is available treatment. The patient had an improvement in his seizures and overall responsiveness upon treatment with pyridoxal 5' phosphate. Conclusions: These data demonstrate the clinical utility of a broad but targeted epilepsy panel that utilizes both Next generation sequencing and exon-level array CGH to analyze both common and rare genetic causes of epilepsy.