Introduction: Rolandic epilepsy (RE) is one of the most common idiopathic childhood epilepsies. Together with more atypical and severe variants (such as epilepsy-aphasia disorders and epileptic encephalopathy with continuous spike-and-waves during slow wave sleep) it forms the spectrum of idiopathic focal childhood epilepsies with a presumably shared genetic etiology. In the majority of typical and atypical rolandic epilepsy patients a predominantly complex mode of inheritance is suggested, the underlying genetics, however, still remain elusive. In the present study I aimed to identify genetic risk factors contributing to the predisposition of typical and atypical rolandic epilepsy. Methods and Patients: We performed whole exome sequencing and SNP-array based genotyping in a large cohort of 290 patients with typical and atypical rolandic epilepsy. We primarily focused on the screening of common and rare single nucleotide variants and copy number variations in regions previously implicated in related diseases. We were particularly interested in the genes GRIN2A and DEPDC5 and in six recurrent copy number variations, 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.2, and 22q11.2, which have been associated with a range of neurodevelopmental diseases. In addition to the aim of identifying new genetic risk factors we comprehensively reanalyzed two typical and atypical rolandic epilepsy associated genes, ELP4 and SRPX2, in our large cohort of affected individuals. We further evaluated the burden of rare variants in GRIN2A, DEPDC5, SRPX2, ELP4 and SRPX2/ELP4-interaction genes in the affected individuals compared with controls. We systematically assessed the frequency of the six recurrent rearrangements and additionally screened genome-wide for further large novel copy number variations. For each risk variant we evaluated clinical correlations and family segregation whenever possible. Results:
In the present study, we successfully identified GRIN2A, DEPDC5 and 16p11.2 duplications as significant genetic risk factors for typical and atypical rolandic epilepsy. These risk factors were observed in about 7.5%, 1.2% and 1.5% of patients respectively. Mutations in GRIN2A, DEPDC5 and duplications on chromosome 16p11.2 displayed incomplete penetrance and intra- and interfamilial phenotypic variability. Three families demonstrated in addition to the primary genetic lesion a second risk factor mirroring the concept of the multiple hit hypothesis in complex diseases. Our re-examination analysis of ELP4 and SRPX2 and their functional interacting genes failed to identify any likely pathogenic variation. Conclusion: In summary we identified three novel genetic risk factors for the whole spectrum of typical and atypical rolandic epilepsy and strongly emphasize the complex genetic etiology in these syndromes and their close relationship to each other. Our re- examination analysis of ELP4 and SRPX2 considerably argues against these genes as risk factors for typical and atypical rolandic epilepsy.