FGD1 was first reported in relation to X-linked Aarskog-Scott syndrome in 1994 (Pasteris et al., PMID: 7954831). FGD1 encodes a guanine nucleotide exchange factor that activates the Rho GTPase CDC42. CDC42 participates in multiple cellular processes, including cell growth, actin cytoskeleton remodeling, and nuclear signaling. Features seen in affected males include short stature, short and broad hands and feet, genital malformations, and distinctive facial features, including hypertelorism, ptosis, long philtrum, and short nose with anteverted nares. Some individuals have mild intellectual disability or, more commonly, learning difficulties. Female carriers are usually unaffected but may sometimes present with subtle features.
Eight variants (nonsense, frameshift, missense, exonic deletion) that have been reported in 11 probands in 8 publications (PMIDs: 7954831, 10930571, 11093277, 14560308, 16353258, 17152066, 20082460, 21739585) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function.
In summary, there is definitive evidence supporting the relationship between FGD1 and X-linked Aarskog-Scott syndrome. 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 December 6, 2017 (SOP Version 5). As of July 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
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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