Developmental and Epileptic Encephalopathy Due to a Novel ARHGEF9 Deletion Variant: Case Series of Two Siblings.

INTRODUCTION

Developmental and epileptic encephalopathy (DEE) is a group of severe neurological disorders characterized by early-onset epilepsy and developmental delay, often caused by genetic variants. Cdc42 Guanine Nucleotide Exchange Factor 9 (ARHGEF9) gene variants have been linked to DEE, yet novel variants and their phenotypic presentations remain incompletely characterized.

CLINICAL CASES: Herein, we describe two siblings with DEE caused by a novel deletion variant in the ARHGEF9 gene. Both patients presented with early-onset epilepsy and developmental delay. Whole-exome sequencing identified a hemizygous c.1037_1045del variant in the ARHGEF9 gene (NM_015185.2) in both brothers, which is reported here for the first time. Notably, the two siblings exhibited a marked difference in outcomes: the elder brother achieved good seizure control with anti-epileptic drugs, while the proband, despite multidrug therapy and vagus nerve stimulation (VNS), exhibited a limited response and continued to experience frequent seizures.

CONCLUSIONS

These cases expand the genotypic spectrum of ARHGEF9-related disorders and underscore the intrafamilial phenotypic variability associated with this gene. These findings emphasize the significance of early genetic testing for establishing a diagnosis, assessing prognosis, and facilitating genetic counseling.