Targeted gene panel and genotype-phenotype correlation in children with developmental and epileptic encephalopathy

We performed targeted gene-panel sequencing for children with developmental and epileptic encephalopathy (DEE) and evaluated the clinical implications of genotype-phenotype correlations.

We assessed 278 children with DEE using a customized gene panel that included 172 genes, and extensively reviewed their clinical characteristics, including therapeutic efficacy, according to genotype.

In 103 (37.1%) of the 278 patients with DEE, 35 different disease-causing monogenic mutations were identified. The diagnostic yield was higher among patients who were younger at seizure onset, especially those whose seizures started during the neonatal period, and in patients with drug-resistant epilepsy. According to epilepsy syndromes, the diagnostic yield was the highest among patients with West syndrome (WS) with a history of neonatal seizures and mutations in KCNQ2 and STXBP1 were most frequently identified. On the basis of genotypes, we evaluated the clinical progression and seizure outcomes with specific therapeutic regimens; these were similar to those reported previously. In particular, sodium channel blockers were effective in patients with mutations in KCNQ2 and SCN2A in infancy, as well as SCN8A, and interestingly, the ketogenic diet also showed diverse efficacy for patients with SCN1A, CDKL5, KCNQ2, STXBP1, and SCN2A mutations. Unfortunately, quinidine was not effective in 2 patients with migrating focal epilepsy in infancy related to KCNT1 mutations.

Targeted gene-panel sequencing is a useful diagnostic tool for DEE in children, and genotype-phenotype correlations are helpful in anticipating the clinical progression and treatment efficacy among these patients.