ARHGEF9

Gene Facts

• HGNC Symbol: ARHGEF9 (HGNC:14561)
• HGNC Name: Cdc42 guanine nucleotide exchange factor 9
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: KIAA0424, PEM-2
• %HI: 10.55
• pLI: 1
• LOEUF: 0.15
• Cytoband: Xq11.1
• Genomic Coordinates:

  GRCh37/hg19:	chrX:62854847-63005094
  GRCh38/hg38:	chrX:63634967-63785214

• MANE Select Transcript: NM_001353921.2 ENST00000671741.2
• Function: Acts as a guanine nucleotide exchange factor (GEF) for CDC42. Promotes formation of GPHN clusters (By similarity). {ECO:0000250|UniProtKB:Q9QX73, ECO:0000269|PubMed:10559246}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-13514
• ClinGen Curation ID: CCID:006686
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Sufficient Evidence for Haploinsufficiency (3)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 11/25/2021

Haploinsufficiency (HI) Score Details

• HI Score: 3
• HI Evidence Strength: Sufficient Evidence for Haploinsufficiency

HI Disease

• X-linked complex neurodevelopmental disorder

HI Evidence

• PUBMED: 18615734
  Kalscheuer et al (2009) reported a de novo balanced chromosomal translocation in a female patient with a disturbed sleep-wake cycle, late-onset epileptic seizures, increased anxiety, aggressive behavior, and intellectual disability, but not hyperekplexia. The t(X;18)(q11.1;q11.21), resulted in disruption of ARHGEF9 on Xq11, while the other breakpoint lies in a region of 18q11 did not involve any known or predicted genes. The authors verified that the chromosomal rearrangement led to inactivation of the normal X chromosome and normal ARHGEF9 was subject to X inactivation. Therefore, the translocation resulted in the production of functionally defective collybistin isoforms, lacking the PH domain and C-terminus.
• PUBMED: 21633362
  Shimojima et al (2011) identified a de novo 737 kb deletion Xq11.1 including ARHGEF9 and a maternally inherited nonsense variant of ARHGEF9 in exon 1a which is transcribed only in variant transcript 2 in two males with severe intellectual disability and epilepsy. The authors confirmed that transcript 2 is expressed in the brain.
• PUBMED: 25898924
  Machado et al (2016) reported a de novo 216.7 kb microdeletion of Xq11.1 including a single gene, ARHGEF9, in a male patient with severe intellectual disability, epilepsy, and mild to moderate autism.
• PUBMED: 28589176
  Alber et al (2017) reviewed 13 males (including two brothers) with sequence variants or chromosomal disruptions and 5 females with chromosomal disruptions affecting ARHGEF9 (de novo sequence variants (x6), maternally inherited sequence variants (x5); chromosomal disruptions including deletions, translocations, and a paracentric inversion (x7)). All affected females had strongly skewed X-inactivation in favor of the abnormal X-chromosome. The symptoms included delayed motor development alone or in combination with seizures in early childhood. Intellectual disability was severe in most and moderate in patients with milder variants. Males with severe intellectual disability had severe epilepsy and facial dysmorphism. Loss of only the protein’s PH domain function is associated with the absence of epilepsy. Mothers of the various male patients in this study did not have X-linked intellectual disability, indicating that random X-inactivation protects female carriers of ARHGEF9 variants. Summary of the reviewed cases: P1 (female) de novo balanced translocation 46,X, t(X;20)(q12;P13) (Alber et al (2017)) P2 (female) de novo balanced translocation 46,X, t(X;18)(q11.1;q11.21) (Kalscheuer et al (2009) PMID: 18615734) P3 (female) 27 kb de novo deletion of Xq11.1 chrX:62,838,630-62,865,334, last two exons (Alber et al (2017)) P4 (female), 7.5 kb de novo deletion of Xq11.1, chrX:62,856,764-62,864,305, last exon(Alber et al (2017)) P5 (female) de novo paracentric inversion 46,X,inv(X)(q11.1q27.3) (Marco et al (2008) PMID: 17893116) P6 (male), de novo 1.29 Mb deletion of Xq11.11, 2 protein coding genes: SPIN4 and ARHGEF9 (Lesca et al (2011) PMID: 21626670) P7 (male), de novo 737 kb deletion of Xq11.11 involving ARHGEF9 (Shimojima et al (2011)) P8 (male), maternally inherited stop codon (p.Q2*) (Shimojima et al (2011)) P9 (male), de novo missense variant (p.G55A) (Harvey et al (2014) PMID: 15215304) P10 (male), maternally inherited missense (brother of P11) (p.S317W) (Alber et al (2017)) P11 (male), maternally inherited missense (brother of P10) (p.S317W) (Alber et al (2017)) P12 (male), de novo missense variant (p.L177P) (Alber et al (2017)) P13 (male), de novo missense variant (p.R104Q) (Alber et al (2017)) P14 (male), de novo missense variant (p.R290H) (Lemke et al (2012) PMID: 22612257) P15 (male), maternally inherited missense variant (p.R338W) (Long et al (2015) PMID: 26834553) P16 (male), de novo missense variant (p.E400K) (de Ligt et al (2012) PMID: 23033978) P17 (male), de novo splice site variant (c.1300+2T>C) ) (de Ligt et al (2012) PMID: 23033978) P18 (male), maternally inherited missense variant (p.R356Q) (Alber et al (2017))
• PUBMED: 30048823
  Aarabi et al (2019) reported two unrelated females with autism and mild intellectual disability. No seizures or hyperekplexia were detected. High resolution X-chromosome microarray analysis revealed de novo intragenic deletions in ARHGEF9 of 24 kb and 56 kb involving exons 5-8 and exons 3-8 and leading to truncated forms of collybistin. Peripheral blood samples revealed random X-chromosome inactivation in both patients.
• PUBMED: 31942680
  Yao et al (2020) identified two maternally inherited novel missense variants (p.I294T and p.R357I) and one maternally inherited novel splicing variant (c.381+3A>G) of ARHGEF9 in three male patients with epilepsy of varying degrees and intellectual disability. In vitro studies confirmed that the two missense variants disrupted CB-mediated accumulation of gephyrin in submembrane microclusters. Transcriptional experiments of the splicing variant revealed the presence of aberrant transcripts leading to truncated protein product. The mother of patient with the splicing variant was also diagnosed with epilepsy, but in a substantially milder form compared with the proband.

• HI Evidence Comments: The ARHGEF9 gene encodes collybistin, a brain-specific guanine nucleotide exchange factor 9 (GEF) located on chromosome Xq11.1 that spans approximately 150 kb of genomic sequence. Collybistin (Cb) is a key protein in the inhibitory gamma-amino butyric acid (GABA)-ergic synapses which interacts with gephyrin to anchor neurotransmitter receptors in the postsynaptic compartment. Cb-/- deficient mice demonstrate impaired learning and increased anxiety. Hemizygous ARHGEF9 pathogenic sequence variants and chromosomal aberrations have been reported in males with autism spectrum disorders (ASD), severe intellectual disability (ID), developmental delay (DD), dysmorphic features and seizures. In females, the phenotype is variable ranging from unaffected mothers of affected males to females with ASD and mild intellectual disability (ID) to moderate ID and developmental delay (DD). In females with X-autosome translocations disrupting ARHGEF9, clinical manifestations included severe ID, DD and seizures, resembling phenotype in males. Several other patients with cytogenetic anomalies involving ARHGEF9 have been reported: Marco et al (2008, PMID:17893116) reported 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) identified a 1.3 Mb deletion of Xq11.11 including a single gene, ARHGEF9, in a male patient with severe intellectual disability, focal epilepsy, tall stature, macrocephaly, and dysmorphism. Holmen et al. (2012, PMID:22670894) reported 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. Bhat et al (2016, PMID 27238888) reported a de novo 82 kb deletion of chromosome Xq11.1-11.2 involving exon 1 of ARHGEF9 in a female with autism spectrum disorder, intellectual disability, and speech delay. Additionally, missense variants 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 variant in the SH3 domain, inheritance not reported. Functional studies indicate that the variant 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. Further, Ghesh et al (2021) (PMID 33600053) reported three novel loss-of-function variants in ARHGEF9: A de novo synonymous variant affecting splicing (NM_015185.2: c.1056G>A, p.(Lys352=)) in one female; a nonsense variant in another female (c.865C>T, p.(Arg289*)), that is, also present as a somatically mosaic variant in her father, and a de novo nonsense variant in a male with nonverbal severe intellectual disability and severe epilepsy (c.899G>A; p.(Trp300*)). Both females presenting with moderate intellectual disability showed a random XCI.

NOTE

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 (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: There is currently no reported evidence for triplosensitivity of ARHGEF9 in the literature.

NOTE

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.