A de novo deletion encompassing the ARHGEF9 gene was identified in a male patient presenting with mild-to-moderate autism, severe intellectual disability, and epilepsy; iPSC-derived neural progenitor cells from this patient showed a complete loss of CB expression and hyperactivation of mTORC1 signaling under basal conditions (Machado et al., 2016). A second de novo deletion involving the ARHGEF9 gene was identified in an 8-year-old female patient diagnosed with ASD and ADHD and presenting with mild intellectual disability, global developmental delay, and severe speech impairment (Bhat et al., 2016). A phenotypic review of 18 patients with ARHGEF9 variants (10 previously published, 8 novel; 13 males, 5 females with highly skewed X-chromosome inactivation) demonstrated that the majority of patients presented with intellectual disability, epilepsy, and dysmorphic facial features; 4 of the 18 patients described in this report presented with autistic features (Alber et al., 2017). Jung et al., 2025 reported novel rare missense variants in ARHGEF9 in male individuals with autism spectrum disorder that were experimentally shown to induce defective inhibitory synaptic transmission in cultured hippocampal neurons from Arhgef9 conditional knockout mice. Additional characterization of medial prefrontal cortex (mPFC)-specific Arhgef9 conditional knockout mice in Jung et al., 2025 found that these mice exhibited altered inhibitory synaptic density and transmission, impaired ultrasound vocalization, and reduced gephyrin phosphorylation levels, and that expression of a subset of ASD-associated ARHGEF9 variants failed to rescue impaired GABAergic synaptic transmission and reduced gephyrin phosphorylation levels in these mice.
Molecular Function
The protein encoded by this gene is a Rho-like GTPase that acts as a guanine nucleotide exchange factor (GEF) for CDC42 and other genes and promotes the formation of GPHN clusters. Variants in this gene are associated with a form of early infantile epileptic encephalopathy (EIEE8, OMIM 300607).
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism.
Phenotypic and genetic analysis of children with unexplained neurodevelopmental delay and neurodevelopmental comorbidities in a Chinese cohort using trio-based whole-exome sequencing
Comparison of first-tier whole-exome sequencing with a multi-step traditional approach for diagnosing paediatric outpatients: An Italian prospective study
