Genotypic spectrum in 1215 patients with Dravet syndrome or Dravet syndrome-like phenotype

Dravet syndrome (DS) is a developmental and epileptic encephalopathy caused mainly by SCN1A variants, several other genes have been implicated in DS-like phenotype.

DS and DS-like patients were collected from February 2005 to December 2023. Clinical data and genetic results were collected and analyzed.

1215 patients were enrolled. SCN1A variants were identified in 1061 patients (87.3%), Thirty-one DS-like patients(2.6%) harbored variants in nine genes: PCDH19 (9), GABRA1 (6), GABRB2 (4), GABRG2 (3), GABRB3 (1), HCN1 (3), SCN2A (1), TBC1D24 (2). ALDH7A1 (2). DS-like patients with PCDH19 variants often exhibited clustered seizures with less frequent status epilepticus. Variants in GABA_A receptor genes were associated with a relatively better response to anti-seizure medications. Oxcarbazepine exacerbated seizures in patients GABRG2, GABRB2 or GABRA1 variants. ALDH7A1 patients achieved seizure control with pyridoxine, while TBC1D24-related cases exhibited distinct focal myoclonic features. SCN2A gain-of-function variants responded favorably to oxcarbazepine.

This study confirms SCN1A as the predominant genetic cause of DS, while identifying nine additional genes (PCDH19, GABRA1, GABRB2, GABRG2, GABRB3, HCN1, SCN2A, TBC1D24, and ALDH7A1) associated with DS-like phenotypes. This study highlights the significance of identifying the underlying genetic cause in guiding appropriate treatment strategies in DS or DS-like patients.

SCN1A variants were detected in 87% of 1,215 Chinese patients with Dravet syndrome. Nine genes including PCDH19, GABRA1, GABRB2, GABRG2, GABRB3, HCN1, SCN2A, TBC1D24 and ALDH7A1 were linked to DS-like phenotype in 31 patients. Sodium channel blockers may worsen seizures in patients with GABA_A receptor gene variants. Genetic testing improves etiological diagnosis, enabling targeted and individualized patient care in Dravet or Dravet-like syndrome.