Introduction To identity the rare causative genes and analysis of genotype-phenotype correlations in Chinese Dravet syndrome (DS) patients who did not detect SCN1A mutation.

Methods DS patients were collected from February 2005 to June 2017. SCN1A and PCDH19 mutations were screened by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Next generation sequencing (NGS) for epilepsy-related panel was applied to SCN1A or PCDH19 mutation-negative patients.

Results Seven hundred and fifty DS patients were collected. 620 patients (620/750, 82.7%) carried SCN1A mutations and 130 were without SCN1A mutation. 20 patients were identified with 7 other causative genes, PCDH19 mutations in 7 cases, GABRG2 mutations in 2 cases, SCN2A mutation in 1 case, GABRA1 mutations in 3 and GABRB2 mutations in 3, TBC1D24 mutations in 2 and ALDH7A1 in 2 cases. Seven patients with PCDH19 mutations were featured by clustering of repeated seizures with short periods of times, only one had an episode of status epilepticus. Patients with GABRB2 mutations had a relatively better outcome of seizure control. Myoclonic status was emerging as hallmark features in patients with TBC1D24 mutations. Pyridoxine had a dramatic therapeutic effect in patients with ALDH7A1 mutations.

Conclusions The rare causative genes in DS patients include PCDH19, GABRG2, SCN2A, GABRA1, GABRB2, TBC1D24 and ALDH7A1. The finding of causative genes GABRB2 and TBC1D24 enrich the gene spectrum of DS. Patients with PCDH19, GABRB2 or TBC1D24 mutations have their own clinical characteristics. Our findings are helpful for a better and more comprehensive understanding of Dravet syndrome.