The relationship between ARHGDIA (Rho-GDP dissociation inhibitor alpha) and AR Nephrotic syndrome type 8 was evaluated using the ClinGen Clinical Validity Framework. The ARHGDIA gene encodes a protein that regulates signalling through the Rho GTPases that are also critical for the functioning of the actin cytoskeleton. ARHGDIA inhibits the dissociation of the Rho family members from GDP and keeps them in an inactive state. It is expressed ubiquitously but at high levels in the kidney, lung, thymus, spleen and small intestine. ARHGDIA was first reported in relation to nephrotic syndrome by Gupta in 2013 (PMID: 23434736) and by Gee (PMID: 238675020) in 2013 independently. This is the only disease associated with pathogenic variants in this gene. The clinical presentation is with the nephrotic syndrome soon after birth. Only three pathogenic variants have been reported in ARHGDIA associated with human disease. These are a missense variant, an amino acid deletion and a truncating variant. The mechanism of pathogenicity is Gain of Function. However the gene-disease association is supported by experimental expression, protein interaction data, functional alterations in patient and non-patient cells and in non-human model organisms. In summary, ARHGDIA is moderately associated with AR nephrotic syndrome. This has been demonstrated in both the clinical diagnostic and research setting, and has been upheld over time. This assessment was performed according to the ClinGen Gene Clinical Validity SOP version 9 and was approved by the Cystic kidney disease and Ciliopathy Working Group on 24 May 2022.
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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