ARHGEF28 encodes a multidomain protein with guanine nucleotide exchange factor (GEF) activity. Its normal function and the potential mechanism of pathogenicity are so far unclear. ARHGEF28 was first reported in relation to amyotrophic lateral sclerosis in 2013 (Droppelmann et al., PMID: 23286752). The gene was curated under a semidominant inheritance model due to limited genetic evidence and the presence of both autosomal dominant and autosomal recessive inheritance classifications in GenCC.
Ten variants that have been reported in 13 probands in four publications (PMIDs: 23286752, 24712971, 27154192, 31060816) are included in this curation. For nine of these variants, lack of information on testing for variants in other potentially disease-causing genes or the presence of such variants led to a score of 0 points. A predicted splice donor site variant in two probands was scored 0.5 points each due to very limited prior testing.
This gene-disease relationship is also supported by expression and protein-protein interaction evidence. ARHGEF28 is expressed in the brain and spinal cord (PMID: 19488899) and forms cytoplasmic inclusions in motor neurons of fALS and sALS patients, but not in normal controls (PMID: 22835604). A split-ubiquitin assay in yeast showed that ARHGEF28 interacts directly with TARDBP (PMID: 32764283).
In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen ALS GCEP on March 28, 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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