Exome Sequencing of 963 Chinese Families Identifies Novel Epilepsy Candidate Genes

Epilepsy, a prevalent neurodevelopmental disorder in children, is often accompanied by detrimental psychological consequences and other comorbidities. We performed exome sequencing on 963 patient-parent trios, revealing differences in genetic epidemiology between Chinese and European epilepsy cohorts. The diagnostic yield for known epilepsy genes was 40%. Pathogenic variants were most commonly found in SCN1A, KCNQ2, and DEPDC5. Additionally, we identified 15 novel monogenic epilepsy candidates in at least two patients diagnosed with developmental and epileptic encephalopathy, non-acquired focal epilepsy, or genetic generalized epilepsy, including ADCY2, BCAR3, CDC45, CHRNG, CRTC2, CSMD1, CSMD2, KDM6B, KIF1B, PLEKHM3, PPP4R1, RASGRP2, SGSM2, SYNE1, and ZFHX3. Aside from ADCY2, which was implicated in the GABAergic synapse pathway based on KEGG analysis, these candidates do not belong to known epilepsy pathways. Local field potential recordings in zebrafish and calcium imaging experiments validated associations for 11 of these genes, excluding those unsuitable for functional analyses. Furthermore, we found that CRTC2 overexpression leads to hippocampal neuronal hyperactivity using multi-electrode arrays and electrophysiology. We have documented the first-line medications prescribed for patients harboring variants in the novel candidate genes. This study expands our understanding of the genetic underpinnings of epilepsy and provides opportunities for early diagnosis and personalized medicine approaches.