ARX
protein-codingaristaless related homeobox, the group of PRD class homeoboxes and pseudogenes
Gene summary
This gene is a homeobox-containing gene expressed during development. The expressed protein contains two conserved domains, a C-peptide (or aristaless domain) and the prd-like class homeobox domain. It is a member of the group-II aristaless-related protein family whose members are expressed primarily in the central and/or peripheral nervous system. This gene is thought to be involved in CNS development. Expansion of a polyalanine tract and other mutations in this gene cause X-linked cognitive disability and epilepsy. [provided by RefSeq, Jul 2016]
- MRXS1
- PRTS
- MRX76
- MRX54
- MRX43
- MRX36
- MRX29
- MRX32
- MRX33
- MRX38
- MRX87
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~12.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0100062
Submitter: ClinGen
ARX was reported in relation to Early Infantile Epileptic Encephalopathy in 2002 (Stromme et al. 2002). It is also reported in relation to intellectual disability (syndromic and nonsyndromic), hydranencephaly with abnormal genitalia, X-linked Lissencephaly, Partington syndrome, and Proud syndrome. Evidence included in this curation focuses on individuals with seizure onset prior to 6 months of age and excludes individuals with syndromic diagnoses and/or intellectual disability. At least 18 unique variants (missense, in-frame indel, nonsense, frameshift and polyalanine repeat, etc.) have been reported in humans. Evidence supporting this gene-disease pair includes case-level data and experimental data. In summary, ARX is definitively associated with X-linked Early Infantile Epileptic Encephalopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel on 6/4/19 (SOP version 6). As of 7/9/25, this record underwent administrative updates to provide additional information regarding the lumping and splitting of this gene. No new evidence has been reviewed or added.
Inheritance Pattern: XL
Disease ID:MONDO:0017856
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0019181
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010224
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010268
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0010632
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0700092
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010268
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0100148
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010268
Submitter: Genomics England PanelApp
Inheritance Pattern: XL
Disease ID:MONDO:0010268
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0018226
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010654
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010317
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0100148
Submitter: ClinGen
ARX has been reported in association with multiple X-linked recessive neurodevelopmental disorders including: intellectual disability, epilepsy, and Partington syndrome (PMIDs: 29659809, 30945278, 26029707, 12177367, 32383243, 17641262). ARX has previously been evaluated for its relationship with early-onset infantile encephalopathy by the ClinGen Epilepsy Gene Curation Expert Panel, focusing on individuals with seizure onset prior to three months of age. That gene-disease relationship was determined to be definitive on 6/21/19. This curation, specifically evaluating evidence to support a role for ARX in X-linked complex neurodevelopmental disorder, focuses on individuals with intellectual disability with or without seizures occurring later than 3 months of age, as well as individuals diagnosed with Partington syndrome, which is characterized by focal dystonia in addition to neurodevelopmental presentations. Notably, ARX has also been associated with X-linked lissencephaly, hydranencephaly with abnormal genitalia and Proud syndrome, all of which are outside the scope of work for this group and therefore were not included. Case-level, segregation and experimental data support this gene-disease relationship. At least 32 variants (missense, nonsense, duplication, deletion, etc.) have been reported in patients (PMID:16650978). To date no definitive genotypic-phenotypic correlation has been established, however, truncating variants have been associated with more severe phenotypes such as lissencephaly and missense variants have been associated with milder phenotypes such as non-syndromic intellectual disability (PMID: 16650978). The 24 polyalanine expansion, c.428_451dup, has been identified in approximately 40% of all ARX-related cases; the patients often present with intellectual disability (PMID: 16650978). Of the probands scored in this curation, 8 had a global developmental delay, 4 had intellectual disability, and 3 had epilepsy with seizure onset ranging from infancy to 3 years. Two probands were diagnosed with Partington syndrome. Relevant experimental data includes two mouse models and expression studies (PMIDs: 29659809, 19605412, 12359145). In summary, ARX is definitively associated with X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on 12/1/2020.
Inheritance Pattern: AD
Disease ID:MONDO:0100062
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Genitourinary; Musculoskeletal; 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: Monitoring for ophthalmologic complications during systemic steroid therapy has been advised; As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ARX variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_139058.3. 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 | 7 | 308 | 4 | 319 | ||
| missense | 12 | 22 | 311 | 49 | 5 | 399 |
| nonsense | 20 | 5 | 3 | 28 | ||
| start loss | 3 | 2 | 5 | |||
| frameshift | 60 | 14 | 1 | 75 | ||
| splice donor/acceptor (+/-2bp) | 5 | 1 | 6 | |||
| Total | 100 | 43 | 323 | 357 | 9 | 832 |
Highest pathogenic variant AF is 0.000018869681
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_620689.1 | 5 | MANE Select | |
| Ensembl | ENSP00000368332.4 | 5 | MANE Select | |
| Ensembl | ENSP00000490122.1 | 2 | Standard | |
| Ensembl | ENSP00000810958.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| arxa | Danio rerio | Structure: pancreatic A cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Ectoderm Differentiation
- Olfactory bulb development and olfactory learning
Biological Process
- negative regulation of transcription by RNA polymerase II
- axon guidance
- positive regulation of gene expression
- globus pallidus development
- cerebral cortex tangential migration
Molecular Function
- RNA polymerase II regulatory region sequence-specific DNA binding
- RNA polymerase II distal enhancer sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- chromatin binding
Cellular Component
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000379044
- Coding exons
- 5
- Length
- 12255
- 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 | 2.05 | 82 | 154 | 0.534 | 0.0000102 | 3508 |
| Missense (PolyPhen) | 11 | 36.283 | 0.30317 | 678 | ||
| Synonymous | -0.657 | 79 | 71.9 | 1.10 | 0.00000513 | 1253 |
| Loss of Function | 2.57 | 0 | 7.70 | 0.00 | 4.88e-7 | 174 |
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:
- Function
- FUNCTION: Transcription factor required for normal brain development. May be important for maintenance of specific neuronal subtypes in the cerebral cortex and axonal guidance in the floor plate.;
- Disease
- DISEASE: Epileptic encephalopathy, early infantile, 1 (EIEE1) [MIM:308350]: A severe form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high- voltage bursts alternating with almost flat suppression phases. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. {ECO:0000269|PubMed:11889467, ECO:0000269|PubMed:12376946, ECO:0000269|PubMed:27864847}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Partington syndrome (PRTS) [MIM:309510]: Characterized by mental retardation, episodic dystonic hand movements, and dysarthria. {ECO:0000269|PubMed:11889467}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Mental retardation, X-linked, ARX-related (MRXARX) [MIM:300419]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. {ECO:0000269|PubMed:11971879}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Agenesis of the corpus callosum, with abnormal genitalia (ACCAG) [MIM:300004]: A X-linked syndrome with variable expression in females. It is characterized by agenesis of corpus callosum, mental retardation and seizures. Manifestations in surviving males include severe acquired micrencephaly, mental retardation, limb contractures, scoliosis, tapered fingers with hyperconvex nails, a characteristic face with large eyes, prominent supraorbital ridges, synophrys, optic atrophy, broad alveolar ridges, and seizures. Urologic anomalies include renal dysplasia, cryptorchidism, and hypospadias. {ECO:0000269|PubMed:14722918}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.147
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.283
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |