Abstracts

Rationale: Severe myoclonic epilepsy of infancy (SMEI), severe idiopathic generalized epilepsy of infancy (SIGEI) and genetic epilepsy with febrile seizures plus (GEFS+) are associated with mutations in the SCN1A gene. However, SCN1A mutations only occur in a fraction of patients and therefore partially explain these disorders. Previous studies highlighted the importance of rare CNVs in the development of numerous epilepsy phenotypes, but CNV data for patients with SCN1A-related epilepsies is limited. In this study, we report rare CNVs in patients with diagnosed or suspected SMEI, SIGEI and GEFS+. We hypothesize that rare CNVs contain genes contributing to the etiology of SCN1A-related epilepsies. Methods: We selected 38 patients with SMEI, SIGEI, GEFS+ and unclassified generalized epilepsy of infancy with febrile, myoclonic and generalized tonic-clonic seizures; 14 subjects had previous negative SCN1A testing. SCN1A sequencing is in progress for all subjects. All patients were evaluated for rare CNVs using genome-wide array CGH. Arrays contained 180.000 probes covering the whole genome with an overall median probe spacing of 13kb. CNVs spanning at least 5 probes, containing RefSeq genes and with less than 50% overlap with a CNV detected in 4519 published controls were reported. The last criterium was not applied to established hotspot CNVs known to occur rarely in healthy controls. Results: We identified 13 rare CNVs in 8 of 38 patients, some of which contain promising candidate genes. Two individuals had hotspot CNVs: a SCN1A-mutation-negative SMEI patient presented with a duplication of 1q21.1, a locus associated with autism and intellectual disability (ID), and a GEFS+ patient carried a distal 16p11.2 deletion previously reported in patients with neurodevelopmental phenotypes. Additionally, we found a 1q44 deletion in a girl with an unclassified epilepsy of infancy, ID and short stature. This rearrangement is linked to the core phenotype of corpus callosum anomalies and microcephaly. However, these features were absent in the proband at the time of examination. Examples of novel CNVs are a 217kb duplication containing 5 zinc finger genes and a 191kb duplication partially including ELMO1 in a SMEI patient with negative SCN1A testing. ELMO1 is highly expressed throughout the brain and encodes for a protein involved in phagocytosis and cell motility. Furthermore, we identified two deletions, one deleting the complete SLC7A11 gene and one interrupting GPHN, in a GEFS+ patient. SLC7A11 encodes for a cysteine/glutamate transporter while mutations in GPHN are associated with hyperekplexia. Both genes could contribute to the proband's phenotype. Parental DNA is being evaluated when available. Conclusions: We report rare CNVs in 8 of 38 patients with diagnosed or suspected SMEI, SIGEI and GEFS+. Our observations illustrate the importance of rare CNVs for these epilepsies, though clinical interpretation is still difficult. Genes included in these CNV regions can be considered candidate genes. Evaluation of candidates in larger cohorts of patients with epilepsy may identify additional mutations in a subset of genes.