Submission Details

Autosomal dominant

09/10/2020

The RAC1 gene is located on chromosome 7 at 7p22.1 and encodes the Rac family small GTPase 1 protein, a plasma membrane bound GTPase which is a modulator of the cytoskeleton, involved in the growth and differentiation of many cell types. The RAC1 gene was first reported in relation to autosomal dominant RAC1-related intellectual disability in 2017 (28886345; Reijnders et al. 2017). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven missense variants, which occurred de novo, in seven affected individuals were reported by Reijnders et al. 2017. This gene-disease association is supported by experimental data; RAC1 interacts with and is activated by the guanine exchange factor TRIO, variants in TRIO, located within its GEF domain are also associated with an intellectual disability syndrome (28928363: Sadybekov et al. 2017). Similarly, to some pathogenic TRIO variants, the RAC1 Cys18Tyr variant, associated with a severe clinical phenotype, has an inhibitory effect on AMPAR-mediated synaptic transmission and consequently suppresses LTP induction in a rat organotypic hippocampal slice culture model (30042656: Tian et al. 2018). Data from animal models also support the gene disease association; zebrafish overexpressing pathogenic RAC1 variants showed altered neuronal proliferation and head size compared to wildtype and conditional forebrain-specific Rac1-knockout mice (homozygous) recapitulate some key features of the disease including impaired neuronal migration, reduced neuronal proliferation and microcephaly (28886345; Reijnders et al. 2017); 19007770; Chen et al. 2009). In summary, there is strong evidence to support the relationship between RAC1 and RAC1 related intellectual disability (autosomal dominant). Additional clinical reports are needed to reach a definitive classification.

28886345 28928363 19007770 30042656