Clinical and Molecular Characterization of Three Novel ARHGEF9 Mutations in Patients with Developmental Delay and Epilepsy

Mutations in the rho guanine nucleotide exchange factor 9 gene ( ARHGEF9 ) are present in patients with heterogeneous phenotypes including psychomotor developmental delay and variable degrees of epilepsy. Malfunction of collybistin (CB) encoded by ARHGEF9 leading to impaired clustering of gephyrin-dependent glycine receptors and γ-aminobutyric acid type A (GABAα) receptors is a crucial pathogenic mechanism. Here, we report on three patients with epilepsy and mental retardation. We studied three male patients with epilepsy and mild to moderate mental retardation. We conducted targeted panel sequencing of genes known to cause inherited disorders. In vitro studies and transcriptional experiments were performed to evaluate the functional and splicing effects of these variants on CB. Two novel missense variants (p.I294T and p.R357I) and one novel splicing variant (c.381+3A>G) in ARHGEF9 were identified in the three patients, respectively. In vitro studies confirmed that the two missense variants disrupted CB-mediated accumulation of gephyrin in submembrane microclusters. Transcriptional experiments of the splicing variant revealed the presence of aberrant transcripts leading to truncated protein product. Significance: Our cases and functional studies enrich our understanding of the phenotypic and genotypic spectrum of ARHGEF9 .