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ARX

aristaless related homeobox

The *ARX* gene, or aristaless related homeobox, provides instructions for a protein that acts as a transcription factor, playing a crucial role in embryonic development, particularly in the brain, pancreas, and testes. The ARX protein is essential for regulating the activity of other genes during development, influencing cell migration and differentiation.

Chromosome Xp21.3 Various HGNC:18060 Tier C
ARX Xp21.3 p arm q arm X

ARX is located on the short (p) arm of chromosome X, at band Xp21.3. Arm ratio per GRCh38 - banding schematic.

Explore chromosome X in the library →

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Clinical tests that include this

Carrier Screening panel
ARX is 1 of 1,008 genes on this panel
Expanded carrier screening for recessive and X-linked conditions

Overview

The *ARX* gene (aristaless related homeobox) is fundamental for proper embryonic development, providing the genetic blueprint for a protein that functions as a transcription factor. This protein orchestrates the expression of numerous other genes, especially those involved in the formation and maturation of the brain, pancreas, and testes. Its precise control over genetic programmes ensures the correct development of these vital organs.

What the gene does

The ARX protein functions as a transcription factor, meaning it binds to specific DNA sequences to regulate the activity of other genes. During early embryonic development, this regulatory role is critical for the formation of various body structures. Specifically, the ARX protein is involved in the development of the brain, pancreas, and testes. In the pancreas, testes, and skeletal muscles, ARX assists in cell differentiation, the process where cells mature into specialised types. Within the developing brain, it plays a key role in the migration and communication of nerve cells, known as neurons. This includes regulating genes essential for the correct positioning of interneurons, which are nerve cells that relay signals between other neurons.

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Chromosome location

The *ARX* gene is situated on the short (p) arm of the X chromosome at position 21.3, a location denoted as Xp21.3. This chromosomal address means that conditions associated with *ARX* variants often exhibit an X-linked inheritance pattern.

Protein structure

The ARX protein consists of 562 amino acids and contains several distinct functional domains. It features multiple disordered regions, including one at amino acids 1-21, another from amino acids 50-81, and a larger region spanning amino acids 118-255. A crucial Homeobox domain, responsible for DNA binding, is located between amino acids 328-387. Additionally, an OAR motif is present from amino acids 530-543, which may be involved in protein-protein interactions.

Domain map · 562 amino acids
Homeobox (328–387)OAR (530–543)Homeobox328–387OAR530–5431~281562
Region - functional region
Motif - short conserved sequence
🧬 Explore 3D structure on AlphaFold
UniProt:Q96QS3Length:562 aaStructure:AlphaFold

Key variants

Variants within the *ARX* gene can lead to a diverse range of clinical presentations, primarily affecting neurological development. These genetic changes can include insertions, deletions, or substitutions of DNA building blocks, which may alter the structure or function of the ARX protein. The specific impact of a variant often depends on its type and location within the gene.

The table below shows the top 10 pathogenic or likely-pathogenic variants currently classified in ClinVar for ARX.
View all on ClinVar →

Sample of pathogenic variants

10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.1150C>T
single nucleotide variant
 p.Arg384Cys Pathogenic/Likely pathogenic ★★☆☆ Developmental and epileptic encephalopathy, 1
c.1223_1226dup
Microsatellite
 p.Leu410fs Pathogenic ★★☆☆ X-linked lissencephaly with abnormal genitalia
c.1471del
Deletion
 p.Pro490_Leu491insTer Pathogenic ★★☆☆ Developmental and epileptic encephalopathy, 1
c.1472del
Deletion
 p.Leu491fs Pathogenic ★★☆☆ Developmental and epileptic encephalopathy, 1
c.590del
Deletion
 p.Gly197fs Pathogenic/Likely pathogenic ★★☆☆ X-linked ARX-related disorders
c.880G>T
single nucleotide variant
 p.Glu294Ter Pathogenic ★★☆☆ Developmental and epileptic encephalopathy, 1
c.922G>T
single nucleotide variant
 p.Glu308Ter Pathogenic ★★☆☆ Inborn genetic diseases
c.956C>A
single nucleotide variant
 p.Ser319Ter Pathogenic/Likely pathogenic ★★☆☆ Intellectual disability, X-linked, with or without seizures, ARX-related
c.994C>G
single nucleotide variant
 p.Arg332Gly Pathogenic/Likely pathogenic ★★☆☆ Developmental and epileptic encephalopathy, 1
c.994C>T
single nucleotide variant
 p.Arg332Cys Pathogenic/Likely pathogenic ★★☆☆ Arachnoid cyst

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Pathogenic variants in the *ARX* gene are associated with a spectrum of neurodevelopmental disorders, reflecting its critical role in brain formation. These conditions include various forms of intellectual disability, often X-linked, and conditions characterised by epilepsy and movement disorders. For example, *ARX* variants are linked to West syndrome, Partington syndrome, and X-linked lissencephaly with abnormal genitalia.

UK clinical status

In the UK, the *ARX* gene is included in several NHS Genomic Medicine Service national test panels, indicating its recognised clinical significance. It is classified as 'green' in DDG2P, and is also present in panels for Differences in sex development, Dystonia, chorea or related movement disorder (childhood onset), Early onset dystonia, Early onset or syndromic epilepsy, Foetal anomalies, Intellectual disability, Intestinal failure or congenital diarrhoea, and Malformations of cortical development.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Differences in sex development · R146 NHS GMS → Dystonia, chorea or related movement disorder, childhood onset · R57 NHS GMS → Fetal anomalies · R21 NHS GMS → Intestinal failure or congenital diarrhoea · R331 NHS GMS → DDG2P NHS GMS → Early onset or syndromic epilepsy NHS GMS → Intellectual disability NHS GMS → Malformations of cortical development NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Frequently asked questions

What is the function of the ARX gene?

The *ARX* gene provides instructions for a protein that acts as a transcription factor, regulating the activity of other genes. It is crucial for the development and proper functioning of the brain, pancreas, and testes, influencing cell migration and differentiation.

What kind of health conditions are associated with ARX gene variants?

Variants in the *ARX* gene are associated with a range of neurodevelopmental disorders. These can include various forms of intellectual disability, epilepsy, and specific syndromes such as West syndrome, Partington syndrome, and X-linked lissencephaly with abnormal genitalia.

Why is the ARX gene located on the X chromosome important?

The location of the *ARX* gene on the X chromosome means that conditions caused by its variants often follow an X-linked inheritance pattern. This can result in different patterns of inheritance and disease expression between males and females.

References

  1. Cho IT, Lim Y, Golden JA. Aristaless Related Homeobox (ARX) Interacts with β-Catenin, BCL9, and P300 to Regulate Canonical Wnt Signaling. PloS one. 2017. PMID: 28103279
  2. Lee K, Ireland K, Bleeze M. ARX polyalanine expansion mutations lead to migration impediment in the rostral cortex coupled with a developmental deficit of calbindin-positive cortical GABAergic interneurons. Neuroscience. 2017. PMID: 28627419
  3. Marques I, Sá MJ, Soares G. Unraveling the pathogenesis of ARX polyalanine tract variants using a clinical and molecular interfacing approach. Molecular genetics & genomic medicine. 2015. PMID: 26029707
  4. Shoubridge C, Tan MH, Seiboth G. ARX homeodomain mutations abolish DNA binding and lead to a loss of transcriptional repression. Human molecular genetics. 2012. PMID: 22194193
  5. Olivetti PR, Noebels JL. Interneuron, interrupted: molecular pathogenesis of ARX mutations and X-linked infantile spasms. Current opinion in neurobiology. 2012. PMID: 22565167
  6. Abedini SS, Kahrizi K, Behjati F. Mutational screening of ARX gene in Iranian families with X-linked intellectual disability. Archives of Iranian medicine. 2012. PMID: 22642246
  7. Cossée M, Faivre L, Philippe C. ARX polyalanine expansions are highly implicated in familial cases of mental retardation with infantile epilepsy and/or hand dystonia. American journal of medical genetics. Part A. 2011. PMID: 21204215
  8. Shoubridge C, Fullston T, Gécz J. ARX spectrum disorders: making inroads into the molecular pathology. Human mutation. 2010. PMID: 20506206
  9. Itoh M, Takizawa Y, Hanai S. Partial loss of pancreas endocrine and exocrine cells of human ARX-null mutation: consideration of pancreas differentiation. Differentiation; research in biological diversity. 2010. PMID: 20538404
  10. Shoubridge C, Cloosterman D, Parkinson-Lawerence E. Molecular pathology of expanded polyalanine tract mutations in the Aristaless-related homeobox gene. Genomics. 2007. PMID: 17490853
  11. Guerrini R, Moro F, Kato M. Expansion of the first PolyA tract of ARX causes infantile spasms and status dystonicus. Neurology. 2007. PMID: 17664401
  12. Poirier K, Lacombe D, Gilbert-Dussardier B. Screening of ARX in mental retardation families: Consequences for the strategy of molecular diagnosis. Neurogenetics. 2006. PMID: 16235064
  13. Gécz J, Cloosterman D, Partington M. ARX: a gene for all seasons. Current opinion in genetics & development. 2006. PMID: 16650978
  14. Suri M. The phenotypic spectrum of ARX mutations. Developmental medicine and child neurology. 2005. PMID: 15707237
  15. Kato M, Dobyns WB. X-linked lissencephaly with abnormal genitalia as a tangential migration disorder causing intractable epilepsy: proposal for a new term, "interneuronopathy". Journal of child neurology. 2005. PMID: 15921244
  16. Partington MW, Turner G, Boyle J. Three new families with X-linked mental retardation caused by the 428-451dup(24bp) mutation in ARX. Clinical genetics. 2004. PMID: 15200506
  17. Nasrallah IM, Minarcik JC, Golden JA. A polyalanine tract expansion in Arx forms intranuclear inclusions and results in increased cell death. The Journal of cell biology. 2004. PMID: 15533998
  18. Uyanik G, Aigner L, Martin P. ARX mutations in X-linked lissencephaly with abnormal genitalia. Neurology. 2003. PMID: 12874405
  19. Sherr EH. The ARX story (epilepsy, mental retardation, autism, and cerebral malformations): one gene leads to many phenotypes. Current opinion in pediatrics. 2003. PMID: 14631200
  20. Strømme P, Mangelsdorf ME, Shaw MA. Mutations in the human ortholog of Aristaless cause X-linked mental retardation and epilepsy. Nature genetics. 2002. PMID: 11889467
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 13 September 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .