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).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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