Discovery novel variations in Sleep-related Hypermotor Epilepsy (SHE) using Next Generation Sequencing approach

Sleep-related hypermotor epilepsy (SHE) is a rare form of focal epilepsy, with an estimated minimum prevalence of 1.8/100,000 individuals. SHE affects both sexes, and involves sleep-related seizures with various motor manifestations. Seizure onset may be at any age with a peak during childhood and adolescence. Seizure frequency may be very high, with occurrence either every night or almost every night, usually many times per night. Clustering is characteristic but not obligatory for diagnosis. Seizures occur predominantly during sleep, primarily in non- REM (NREM) sleep and rarely during REM sleep. Seizures during active wakefulness may also occasionally occur during the patient's lifetime. SHE is a genetically heterogeneous condition and the roles of CHRNA4, CHRNA2 and CHRNB2 genes have been clearly established in this disease. Mutations in the KCNT1 gene have been identified in families with severe SHE.In this study, we analyzed a familial case of SHE coming from the South of Italy using an amplicon based "Next Generation Sequencing" approach with a ready to use Neurological panel comprising the most relevant genes associated with neurological disease. DNA sample from the family's proband were screened for 766 genes by using the Personal Genome Machine (PGM)-Thermofisher Scientific and the alignement and the variant caller were carried out using the Ion Torrent suite vers.5.6. After the bioinformatic analisys, we have not highlighted patological variations in the most associated SHE genes (CHRNA4-CHRNA2-KCNT1).We are able to identify a missense variation (c1204 G>A p.Ala402Thr) in the proband DNA in the exon 5 of the acetylcholine receptor, neuronal nicotinic, beta-2 subunit gene (CHRNB2). The proband is affected by a SHE from the age of 26. The same variation was identified in the DNA of the proband's mother who is affected by a very severe form of the disease and in the DNA of the two proband's son: the 7-year-old daughter shows very slight nocturnal shocks and the 4-year-old son has not shown any sign of the disease so far.In conclusion, gene panels and NGS sequencing approach will improve the number and specificity of the studied genes, influencing the success of diagnosis in complex genetic phenotype like SHE.