ClinGen Dosage Sensitivity Curation Page

ARHGEF9

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 2
  • Strength of Evidence (disclaimer): Some evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
21633362 Shimojima et al. (2011) report a boy with seizures, intellectual disability, right frontal polymicrogyria, and ataxic gait who had a nonsense mutation in exon 1a, which is transcribed only in variant transcript 2. This mutation was inherited from a normal mother. The authors confirmed that transcript 2 is expressed in the brain. They also report a boy with seizures, intellectual disability, and a hypoplastic frontal lobe who had a de novo 737 kb deletion that includes ARHGEF9 and two other transcripts of unknown function.
18615734 Kalscheuer et al (2009) report a female with intellectual disability, hypotonia, epilepsy, and dysmorphisms who had a de novo balanced t(X;18)(q11.1;q11.21) which resulted in a truncated ARHGEF9 fusion protein. The normal X and ARHGEF9 copy were inactive.

Haploinsufficiency phenotype comments:

Several other patients with cytogenetic anomalies involving ARHGEF9 have been reported: Marco et al (2008, PMID:17893116) report a female with intellectual disability, hypersensitivity, and hyperactivity who had a de novo apparently balanced inv(X)(q11.1q27.3) with a breakpoint determined by FISH mapping to disrupt ARHGEF9. Transcription was reduced to 9% and skewed X-inactivation toward the abnormal X was shown. Lesca et al (2011, PMID:21626670) report a 6 year old boy with intellectual disability, epilepsy, dysmorphisms, and macrocephaly who had a de novo 1.29 Mb deletion including ARHGEF9, 1 other gene of unknown function, 3 putative genes, and 1 gene for a non-coding RNA. Holmen et al. (2012, PMID:22670894) report females with osteophathic striata congenita due to deletions of the WTX gene and commented that two individuals with larger deletions including ARHGEF9 who had more severe neurologic presentations. Additionally, missense mutations in patients with epileptic encephalopathy (OMIM 300607) have been reported. Harvey et al (2004, PMID:15215304) report a male patient with hyperekplexia and epilepsy and a missense mutation in the SH3 domain, inheritance not reported. Functional studies indicate that the mutation causes mislocalization of gephyrin and GABA receptors, which is thought to be the ultimate cause of the phenotype. However, it isn't clear if this effect is due to loss of function or another mechanism. Marco et al (PMID: 17893116) also report one male patient with X-linked intellectual disability with a non-synonymous sequence change that was not found in controls, but inheritance and functional data are not provided. Two additional intronic variants were reported that may affect branch site affinity.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.