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Relevance to Autism

A de novo deletion encompassing the ARHGEF9 gene was identified in a male patient presenting with mild-to-moderate autism, severe intellectual disability, and epilepsy; iPSC-derived neural progenitor cells from this patient showed a complete loss of CB expression and hyperactivation of mTORC1 signaling under basal conditions (Machado et al., 2016). A second de novo deletion involving the ARHGEF9 gene was identified in an 8-year-old female patient diagnosed with ASD and ADHD and presenting with mild intellectual disability, global developmental delay, and severe speech impairment (Bhat et al., 2016). A phenotypic review of 18 patients with ARHGEF9 variants (10 previously published, 8 novel; 13 males, 5 females with highly skewed X-chromosome inactivation) demonstrated that the majority of patients presented with intellectual disability, epilepsy, and dysmorphic facial features; 4 of the 18 patients described in this report presented with autistic features (Alber et al., 2017).

Molecular Function

The protein encoded by this gene is a Rho-like GTPase that acts as a guanine nucleotide exchange factor (GEF) for CDC42 and other genes and promotes the formation of GPHN clusters. Variants in this gene are associated with a form of early infantile epileptic encephalopathy (EIEE8, OMIM 300607).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Collybistin binds and inhibits mTORC1 signaling: a potential novel mechanism contributing to intellectual disability and autism.
ASD, ID, epilepsy/seizures
Support
A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders
DD, epilepsy/seizures
Support
Missense Mutation R338W in ARHGEF9 in a Family with X-linked Intellectual Disability with Variable Macrocephaly and Macro-Orchidism.
ID
Support
Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing.
Epilepsy/seizures
Support
The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering.
Epilepsy/seizures
Hyperekplexia
Support
Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.
ASD
ID, epilepsy/seizures
Support
Autism spectrum disorder in females with ARHGEF9 alterations and a random pattern of X chromosome inactivation.
ASD, DD/ID
Support
ARHGEF9 mutations in epileptic encephalopathy/intellectual disability: toward understanding the mechanism underlying phenotypic variation.
ID, epilepsy/seizures
Support
Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.
ID
Macrocephaly
Support
Xq11.1-11.2 deletion involving ARHGEF9 in a girl with autism spectrum disorder.
ASD, ADHD, ID, DD
Recent Recommendation
ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation.
ID, epilepsy/seizures
Autistic features

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN715R001 
 copy_number_loss 
  
  
 De novo 
 NA 
 Simplex 
 GEN715R002 
 missense_variant 
 c.164G>C 
 p.Gly55Ala 
 De novo 
 NA 
  
 GEN715R003 
 missense_variant 
 c.1012C>T 
 p.Arg338Trp 
 Familial 
 Maternal 
 Multi-generational 
 GEN715R004 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN715R005 
 translocation 
  
  
 De novo 
 NA 
  
 GEN715R006 
 translocation 
  
  
 De novo 
 NA 
  
 GEN715R007 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN715R008 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN715R009 
 inversion 
  
  
 De novo 
 NA 
  
 GEN715R010 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN715R011 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN715R012 
 stop_gained 
 c.4C>T 
 p.Gln2Ter 
 Familial 
 Maternal 
  
 GEN715R013 
 missense_variant 
 c.950C>G 
 p.Ser317Trp 
 Familial 
 Maternal 
 Multiplex 
 GEN715R014 
 missense_variant 
 c.530T>C 
 p.Leu177Pro 
 De novo 
 NA 
  
 GEN715R015 
 missense_variant 
 c.311G>A 
 p.Arg104Gln 
 De novo 
 NA 
  
 GEN715R016 
 missense_variant 
 c.869G>A 
 p.Arg290His 
 De novo 
 NA 
 Multiplex 
 GEN715R017 
 missense_variant 
 c.1198G>A 
 p.Glu400Lys 
 De novo 
 NA 
  
 GEN715R018 
 splice_site_variant 
 c.1141+2T>C 
  
 De novo 
 NA 
  
 GEN715R019 
 missense_variant 
 c.1067G>A 
 p.Arg356Gln 
 Familial 
 Maternal 
  
 GEN715R020 
 stop_gained 
 c.865C>T 
 p.Arg289Ter 
 Familial 
 Paternal 
  
 GEN715R021 
 missense_variant 
 c.868C>T 
 p.Arg290Cys 
 Familial 
 Maternal 
 Multiplex 
 GEN715R022 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN715R023 
 copy_number_loss 
  
  
 De novo 
 NA 
  
 GEN715R024 
 stop_gained 
 c.417G>A 
 p.Met139Ile 
 Familial 
 Maternal 
  
 GEN715R025 
 stop_gained 
 c.510T>A 
 p.Tyr170Ter 
 Familial 
 Maternal 
  
 GEN715R026 
 missense_variant 
 c.950C>T 
 p.Ser317Leu 
 Familial 
 Maternal 
  
 GEN715R027 
 inframe_insertion 
 c.882_883insATT 
 p.Thr294_Gln295insIle 
 Familial 
 Maternal 
 Simplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion
 1
 
X
Duplication
 1
 
X
Duplication
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 18
 
X
Deletion-Duplication
 8
 
X
Deletion
 2
 
X
Duplication
 2
 
X
Deletion
 2
 
X
Duplication
 1
 

No Animal Model Data Available


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
GPHN gephyrin 10243 Q9NQX3 IP/WB; Y2H
Kins S , et al. 1999
GPHN gephyrin 10243 Q9NQX3 Y2H
Um JW , et al. 2016
MTOR mechanistic target of rapamycin (serine/threonine kinase) 2475 P42345 IP/WB
Machado CO , et al. 2015

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