ARHGEF9 was first reported in relation to an X-linked complex neurodevelopmental disorder in 2004 in a child with hyperekplexia, severe intellectual disability (ID), and severe epilepsy (Harvey et al., PMID:15215304). Since that time, more than 30 probands have been reported in over 12 publications with a variable neurological phenotype consisting of intellectual disability, hyperekplexia, seizures, hypertonia, impaired psychomotor development (PMIDs: 34851771, 35638461, 35169261). The majority of variants are de novo for male probands; however, there are some familial cases of mildly affected mothers. The molecular spectrum of ARHGEF9 variants include missense, copy number variants, frameshift/nonsense, and structural X-chromosome abnormalities (PMIDs: 15215304, 17893116, 21633362, 22612257, 26834553, 28589176, 29130122, 25678704, 25898924, 30914922, 35638461, 35169261, 3485177, 33600053). Thirteen variants (missense and nonsense) reported in 14 probands, from 11 publications (PMIDs: 15215304, 21633362, 22612257, 26834553, 28589176, 29130122, 30914922, 35638461, 35169261, 34851771, 33600053) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached.
ARHGEF9 encodes a protein known as collybistin, a guanine nucleotide exchange factor, known to be an important organizer at synapses controlled by the neurotransmitter GABA and glycine (PMID: 35169261). As first reported in 2004 by Harvey et al. functional studies suggested the missense variant (G55A) disrupted critical domains in the protein, preventing appropriate translocation of the synaptic scaffold, gephyrin, to the cell membrane (PMID: 15215304). Subsequent functional studies (patient and non-patient cells) demonstrated ARHGEF9 variants affect collybistin to mediate gephyrin clustering (PMID: 25898924, 25678704). Additional experimental evidence is available to illustrate a generated Gabra2-1 phenocopy mice as a model to study targeted drug therapy (PMID: 35169261).
This gene-disease pair was originally evaluated by the Intellectual Disability and Autism GCEP on November 29, 2021. It was reevaluated on May 23, 2024. As a result of this reevaluation, the classification increased from moderate to definitive based on additional genetic evidence. Experimental evidence of two points remained unchanged from prior curation.
In summary, there is definitive evidence to support the relationship between ARHGEF9 and X-linked complex neurodevelopmental disorder. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on May 23, 2024 (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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