Abstracts

Rationale: Micro-chromosomal imbalances are increasingly recognized in neurological disorders with a complex genetic inheritance such as epilepsy, schizophrenia, intellectual disability and autism. They can be both inherited and de novo. Certain genomic areas (‘hotspots’) appear to be susceptible to copy number variation (CNV). This study looks at the rate of common CNVs in people with drug resistant juvenile myoclonic epilepsy (JME).Methods: 80 JME cases were recruited through clinics. Drug resistance was defined as continued seizures despite treatment with adequate doses of appropriate antiepileptic drugs including 1000mg/day or more of sodium valproate. The cases were submitted for high-resolution SNP genotyping (Affymetrix CytoScan HD platform). Data were analysed using Affymetrix’s Chromosome Analysis Suite and data filtered on 50 consecutive probes. Each CNV was confirmed using qualitative PCR (qPCR). Inheritance status was confirmed, where possible, using breakpoint junctional PCR on parental samples.Results: 13 hotspot CNVs were predicted at 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 17p11.2 and 8 were confirmed using qPCR. There were also two cases with 1q31.1 deletions. A further 14 confirmed CNVs (in 11 patients) were identified disrupting genes associated with epilepsy, autism, intellectual disability or schizophrenia. This included three NRXN1 deletions and three NLGN1 duplications.Conclusions: The novel finding that people with drug resistant JME have a 10% chance of having a common CNV is important for accurate genetic counselling. Furthermore this study demonstrates that drug-resistance enriches a clinical cohort for common copy number variation, to the same extent that intellectual disability does. The enigma of how these and other genomic variations may contribute to disease may be aided by mapping smaller recurrent CNVs such as NRXN1 and NLGN1 and demands further molecular biology studies.