ARHGEF9

protein-coding

Cdc42 guanine nucleotide exchange factor 9, the group of Pleckstrin homology domain containing|Dbl family Rho GEFs

Gene summary

The protein encoded by this gene is a Rho-like GTPase that switches between the active (GTP-bound) state and inactive (GDP-bound) state to regulate CDC42 and other genes. This brain-specific protein also acts as an adaptor protein for the recruitment of gephyrin and together these proteins facilitate receceptor recruitement in GABAnergic and glycinergic synapses. Defects in this gene are the cause of startle disease with epilepsy (STHEE), also known as hyperekplexia with epilepsy, as well as several other types of cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

MANE transcript

NM_001353921.2

Inheritance

ClinVar variants

P:56U:263B:139

Top phenotype

Developmental and epileptic encephalopathy 8

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chrX:63,634,967-63,809,274

External References & Databases

Ensembl (ENSG00000131089)

Transcript & Mutation Effects

hg38 • Region Span ~174.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy, 8STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010375

Submitter: G2P

developmental and epileptic encephalopathy, 8STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010375

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 8STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010375

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 8SUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010375

Submitter: Orphanet

developmental and epileptic encephalopathy, 8DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010375

Submitter: Ambry Genetics

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*ARHGEF9* was first reported in relation to an X-linked complex neurodevelopmental disorder in 2004 in a child with hyperekplexia, severe intellectual disability, 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 impaired psychomotor development, intellectual disability, hyperekplexia, seizures, and hypertonia (PMIDs: 34851771, 35169261, 35638461). The majority of variants in male probands are de novo; 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, 25678704, 25898924, 26834553, 28589176, 29130122, 30914922, 33600053, 3485177, 35169261, 35638461). Thirteen variants (missense, nonsense and frameshift) that have been reported in 14 probands in 11 publications (PMIDs: 15215304, 21633362, 22612257, 26834553, 28589176, 29130122, 30914922, 33600053, 34851771, 35169261, 35638461) 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 (PMIDs: 25678704, 25898924). In summary, there is definitive evidence to support the relationship between *ARHGEF9* and X-linked complex neurodevelopmental disorder. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 29, 2021. It was reevaluated on May 23, 2024 (SOP version 10). As a result of this reevaluation, the classification increased from moderate to definitive based on additional genetic evidence.

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 8XL

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

Refs: 15215304; 21633362; 22612257

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARHGEF9 variants in ClinVar

16 Conditions Cataloged

Developmental and epileptic encephalopathy, 8Total: 398

not providedTotal: 156

not specifiedTotal: 59

Inborn genetic diseasesTotal: 58

ARHGEF9-related disorderTotal: 19

EpilepsyTotal: 3

Autism spectrum disorderTotal: 3

Intellectual disabilityTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001353921.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar	1 clinvar	12 clinvar	104 clinvar	4 clinvar	122
missense	2 clinvar	12 clinvar	227 clinvar	30 clinvar	1 clinvar	272
nonsense	16 clinvar	3 clinvar	7 clinvar			26
start loss			1 clinvar			1
frameshift	8 clinvar	4 clinvar	3 clinvar			15
splice donor/acceptor (+/-2bp)	2 clinvar	7 clinvar	13 clinvar			22
Total	29	27	263	134	5	458

Highest pathogenic variant AF is 0.0000018263756

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 80 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001353921.2	RefSeq	NP_001340850.1	10	MANE Select
ENST00000671741.2	Ensembl	ENSP00000500715.1	10	MANE Select
NM_001173479.2	RefSeq	NP_001166950.1	9	Standard
NM_001173480.2	RefSeq	NP_001166951.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
arhgef9b	Danio rerio	Structure: caudal vein plexus Quality: malformed abnormal

Gene / Model

Organism

Observed Phenotype

arhgef9b

Danio rerio

Structure: caudal vein plexus

Quality: malformed

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ectoderm Differentiation
Signaling by GPCR
Signal Transduction
GABA A receptor activation
Rho GTPase cycle

Biological Process

G protein-coupled receptor signaling pathway
regulation of Rho protein signal transduction
positive regulation of apoptotic process
regulation of small GTPase mediated signal transduction
regulation of postsynaptic specialization assembly

Molecular Function

guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity

Cellular Component

cytosol
postsynaptic density
cell junction
postsynaptic membrane
GABA-ergic synapse

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000253401
Coding exons: 10
Length: 150580
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.04	86	210	0.409	0.0000170	3481
Missense (PolyPhen)		11	74.501	0.14765		1188
Synonymous	0.192	77	79.2	0.973	0.00000673	877
Loss of Function	4.12	0	19.8	0.00	0.00000140	323

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as guanine nucleotide exchange factor (GEF) for CDC42. Promotes formation of GPHN clusters (By similarity). {ECO:0000250|UniProtKB:Q9QX73, ECO:0000269|PubMed:10559246}.;

Recessive Scores

pRec: 0.115

Intolerance Scores

LoFtool: 0.0652
RVIS EVS: -0.12
RVIS percentile EVS: 44.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.538

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium