Clinical and genetic characteristics of PCDH19-related epilepsy syndromes：differences between East-Asians and European-Americans

Background: Protocadherin-19 (PCDH19) gene is the most common epileptic pathogenic gene after SCN1A. PCDH19-related epilepsy syndrome is an infantile onset disorder characterized by clusters of seizures. This study aims to compare the clinical and genetic differences of PCDH19-related epilepsy syndromes between East-Asians and European-Americans. Methods: We performed targeted next-generation sequencing in 931 patients with epilepsy. All previously reported epilepsy-related PCDH19 pathogenic variants were reviewed. The clinical and genetic differences between East Asians and European-Americans were analyzed. Results: This cohort was predominantly female (93.3%), with the median onset age of seizures was 12 months. Twelve PCDH19 variants in 15 patients with epilepsy were identified, which included five novel variants in the cohort. A total of 167 East-Asian cases and 358 European-American cases were enrolled in analyzing. In general, East-Asians were more commonly manifested as generalized tonic-clonic seizure (GTCS) at the disease onset (53.85% vs. 36.47%; P=0.001). Noteworthily, European-Americans showed higher incidence of psychiatric comorbidities (P＜0.05). However, anti-seizure medications (ASMs) of GABAergic regulators, like clobazam, clonazepam, levetiracetam, nitrazepam, topiramate, and sodium valproate, were indicated to be more effective on PCDH19-related epilepsy syndrome. In the aspect of phenotype-genotype correlation, significant difference was only found in nonsense variants distribution. Conclusion: Our findings expanded the genetic spectrum of PCDH19-related epilepsy syndrome. There were some differences of PCDH19-related epilepsy syndrome between races, especially in the seizure onset type and comorbidity incidence. The management of comorbidities will be another focus of attention in the future.