RAC1

Inheritance Pattern: AD

Disease ID:MONDO:0030913

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0030913

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0030913

Submitter: Orphanet

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

*RAC1* was first reported in relation to autosomal dominant syndromic intellectual disability (ID) in 2016 in a large cohort of ID patient-parent trios (Lelieveld et al., PMID: 27479843), and was subsequently described in detail in 7 individuals with syndromic ID in 2017 (Reijnders et al., PMID: 28886345). *RAC1* encodes a RHO GTPase that plays a role in the development and function of the nervous system, including regulation of neuronal morphology and migration. Affected individuals present with developmental delay, mild-to-severe ID, dysmorphic facial features, micro/macrocephaly, and abnormal brain MRI findings; more variable features include hypotonia, epilepsy, autism, congenital heart defects, and skin abnormalities (PMIDs: 28886345, 34725860, 35139179, 37059841). Fourteen unique *RAC1* missense variants reported in 14 probands in 5 publications (PMIDs: 28886345, 34725860, 35139179, 37059841, 37328543) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Most variants are *de novo*. The majority of variants have been found to cluster at residues Q61–R68 in the switch II region of *RAC1*, with 4 unrelated patients harboring the same *de novo* p.Y64D variant. Variants in the switch II region are reported to be constitutively active, whereas most variants outside the switch II region, including variants in the switch I region, are reported to exert a dominant negative effect; further functional characterization is needed to determine the effect of variants within each region (PMIDs: 28886345, 34725860, 35139179, 37059841). This gene-disease relationship is also supported by experimental evidence, including *in vitro* functional assays, biochemical function, protein interaction, and mouse, drosophila and zebrafish models (PMIDs: 28886345, 32109419, 34557485, 35139179, 37059841). In summary, there is definitive evidence to support the relationship between *RAC1* and autosomal dominant syndromic ID. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 20, 2023 (SOP Version 10).

Inheritance Pattern: AD

Disease ID:MONDO:0030913

Submitter: Illumina

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.

Inheritance Pattern: AD

Disease ID:MONDO:0030913

Submitter: G2P