Abstracts

Rationale: Epilepsy is a common neurological disorder but highly heterogeneous clinically and genetically. Paroxysmal dyskinesia (PxD) is a group of diseases characterized by episodic involuntary movements triggered by various factors. However, patients with PxD frequently have different types of epileptic seizures and vise versa. Mutations in many genes have been identified to be the common causes of PxD and epilepsy. The genetic and clinical overlaps between PxD and epilepsy have pointed out there are common pathomechanisms underlying the two groups of diseases. A correct genetic diagnosis is essential for further understanding of the mechanisms and identifying potential therapies. This study was aimed to evaluate the contribution of the next-generation sequencing (NGS) in the efficiency of genetic diagnosis and to explore the impacts on diagnostic strategy and pharmacotherapy in clinical practicing. Methods: In 193 unrelated Han Taiwanese patients, we have screened rare variants (global minor allelic frequency < 0.001) leading to altered amino acid sequences in 203 disease genes reported to be causative genes of epilepsy or PxD by targeted sequencing. Among them, 129 had the clinical diagnosis of suspicious genetic epilepsy and 64 fulfilled the diagnostic criteria of primary PxD (Erro et al., 2014). For all recruited patients, there was no obvious lesion on brain MRIs except for mesial temporal sclerosis. For those of PxD, a PRRT2 pathogenic variant should be excluded before targeted sequencing. Results: Non-benign rare variants (including pathogenic, likely pathogenic, variant of uncertain significance, or novel variants) were identified in 41 patients with epilepsy (the hit rate: 31.8%) and 12 cases with PxD (the hit rate: 18.8%). There are 6 genes in which the non-benign rare variants were detected in both epilepsy and PD groups: PRRT2, CACNA1A, KCNJ10, SCN8A, SLC2A1, and KATNB1. Variants in these genes were distributed in 22 patients, accounting 11.5% of our cohort. Conclusions: Our results documented there are significant genetic overlaps between non-lesional epilepsy and PxD. The high-throughput NGS could rapidly screen possible causative variants in the shared genes and greatly enhance the diagnostic efficiency. The genetic findings may also guide the selection of drugs. The functions of these pathogenic genes reflected the critical roles of channelopathies, synaptic dysfunction and molecular transporter defects in the pathophysiological framework of the two paroxysmal neurological diseases. Funding: No funding