ARX

aristaless related homeobox, the group of PRD class homeoboxes and pseudogenes

Basic information

Region (hg38): X:25003694-25016420

Previous symbols: [ "MRXS1", "PRTS", "MRX76", "MRX54", "MRX43", "MRX36", "MRX29", "MRX32", "MRX33", "MRX38", "MRX87" ]

Links

ENSG00000004848 ∙ NCBI:170302 ∙ OMIM:300382 ∙ HGNC:18060 ∙ Uniprot:Q96QS3 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• intellectual disability, X-linked, with or without seizures, arx-related (Definitive), mode of inheritance: XLR
• Partington syndrome (Definitive), mode of inheritance: XLR
• X-linked lissencephaly with abnormal genitalia (Moderate), mode of inheritance: XL
• X-linked lissencephaly with abnormal genitalia (Strong), mode of inheritance: XL
• intellectual disability, X-linked, with or without seizures, arx-related (Moderate), mode of inheritance: XL
• developmental and epileptic encephalopathy (Supportive), mode of inheritance: AD
• West syndrome (Supportive), mode of inheritance: AD
• corpus callosum agenesis-abnormal genitalia syndrome (Supportive), mode of inheritance: XL
• X-linked spasticity-intellectual disability-epilepsy syndrome (Supportive), mode of inheritance: XL
• non-syndromic X-linked intellectual disability (Supportive), mode of inheritance: XL
• X-linked lissencephaly with abnormal genitalia (Supportive), mode of inheritance: XL
• Partington syndrome (Supportive), mode of inheritance: XL
• infantile epileptic-dyskinetic encephalopathy (Supportive), mode of inheritance: XL
• intellectual disability, X-linked, with or without seizures, arx-related (Definitive), mode of inheritance: XL
• Partington syndrome (Definitive), mode of inheritance: XL
• X-linked lissencephaly with abnormal genitalia (Strong), mode of inheritance: XL
• developmental and epileptic encephalopathy (Definitive), mode of inheritance: XL
• X-linked complex neurodevelopmental disorder (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Partington syndrome; Developmental and epileptic encephalopathy 1; Lissencephaly, X-linked 2; Proud syndrome; Intellectual developmental disorder, X-linked, with or without seizures, ARX-related; Intellectual developmental disorder, X-linked 29	XL	General	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	Craniofacial; Genitourinary; Musculoskeletal; Neurologic	3177452; 1605226; 8826464; 9001795; 8826462; 9307258; 10334471; 10398246; 10398242; 10398243; 10353782; 11971879; 11891829; 12485186; 12379852; 12116222; 12177367; 11889467; 12689911;14722918; 15200506; 15850492; 17082467; 17664401; 17668384; 18462864; 19439424; 19738637; 21108397; 21426321; 22490986; 22585566; 22922607; 23039062; 23072184; 26029707; 31400578
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

This is a list of variants' phenotypes submitted to ClinVar and linked to the ARX gene.

• X-linked lissencephaly with abnormal genitalia (22 variants)
• not provided (19 variants)
• Developmental and epileptic encephalopathy, 1;Intellectual disability, X-linked, with or without seizures, arx-related (18 variants)
• Developmental and epileptic encephalopathy, 1 (10 variants)
• Intellectual disability, X-linked, with or without seizures, arx-related;Developmental and epileptic encephalopathy, 1 (9 variants)
• Corpus callosum agenesis-abnormal genitalia syndrome (4 variants)
• epileptic encephalopathy, early infanitle, 1 (3 variants)
• Inborn genetic diseases (2 variants)
• Partington syndrome (1 variants)
• ARX-associated condition (1 variants)
• X-linked spasticity-intellectual disability-epilepsy syndrome (1 variants)
• Developmental and epileptic encephalopathy, 1;Partington syndrome;Corpus callosum agenesis-abnormal genitalia syndrome;X-linked lissencephaly with abnormal genitalia;Intellectual disability, X-linked, with or without seizures, arx-related (1 variants)
• Intellectual disability (1 variants)
• Aicardi syndrome (1 variants)
• Hydranencephaly with abnormal genitalia (1 variants)
• Intellectual disability, X-linked, with or without seizures, arx-related (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ARX gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	262	4	271
missense	7	14	241	23	3	288
nonsense	14	2	1			17
start loss	1	1				2
frameshift	46	8	1			55
inframe indel	7	4	26	18	2	57
splice donor/acceptor (+/-2bp)	3		1			4
splice region			6	12	1	19
non coding				35	6	41
Total	78	29	275	338	15

Highest pathogenic variant AF is 0.00000955

Variants in ARX

This is a list of pathogenic ClinVar variants found in the ARX region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-25004209-CACGCTGGGGCCCTCGCTGGGGAGATCAACTTCGAGCGCCAAAATGCTATTTAAAAAAAAAAAAGAAAGAAAGAAAGAAAGAAAAGAAAGGCTAAGTGGGGTGTCAGGAGGAAGAGGTTGGGCTTTTTAAATTTTTTACTTCAATATCAGGCGTCTGGGGGAGAAAACCTCCCCGATATTTTCAGGAAAGTAAGAACAAGAGAGAGTGGATGTTGGAGTTGGAGCGAGGTTGGCAGTAGCAGGGGCAGGGGCAGGGGCGGGTGGACAGCCAGCCGAGGAGGTGCCACGTCCCGGAGCGCCGAGGGCTGCCATGCCCGCATCCAGACTGCTGTGAAGGCGGCTGCGCTCTCTCAGTGCCGTCTCGGGAGTGTGCTGGTCCTCTGTTTCCATTTGGTCTTGAGTGGTGCTGAGTGAGGTGACCTTTCGGGGCGCGCGCGGGGCGCGGGTGTGGAGGGCAGCCTTTAGCACACCTCCTTGCCCGTGCTGGTGCCCGGCAGGATGTTGAGCTGCGTGAGCTGCGCCGCGTGCTCCTTGGCCTTGAGCCTCAGCGCGGCTATGCTAGAGGCGCGTCTGTCTGCGGCCGCCGTGGCCGGGTCGGCCAGGGCGCCCGATGCCACTGCGCCCTCCACGGCGGGTGTGGGCTGTCTCAGGAGCGCGGCCGCGGTCGACGCGCTGGTCAGGGGGGCCATTGTGGAAAAGAGCCTGCAGGGAGAGCAAACAGCGCGGTCATGGCCTCGGGAGCTGTGCGCGGCGCCTCGGGCAGCGTCTCCCGCCGCTTGTCGCCGGGGCAGCTGAGGGGCGCGGTACCCACGGGACCCGGATGGGCCGCGGCGGGGAAGTGGGCAGAGGGCGCGGGCGGAAGCTGGACCCCGCAGAGAGGGCTTTCCTGGGGCAGGGAACCGACTGGGGGGAAAAGACCGAGTCCAGATATTCCCCGAGGGGCCGGGCCGGGCCGGGGTCCACAGGCCGGCGTGGAGACCTCAAGCCCCACGGCCCAGTGGCGTGGATTCGGTGGTTTCGCTTAAACGGACGGTTTATTCCAAGGCCAGGGGCTGCAATGACACTATCTCCCAGGAGAGAATGCGGAAGGAGAAAAGGAGAGGAGAGCAAAAGAAGGGAAGGTGGAGGGTGGGAGGGGGGAGGAAAAAAAAGACGGAGAAGGTGGGATTCCAGCTGCCCGGACGCACGCCGCAGGCTCTGAGATCTCCCTCCGGCTCCTTGGCCCGGGACTTTCTGCGCCCTGAAGAAACAGGCCTAGCTCGCCGGCCTCCCGGGCCACCCGCGCCGCCGCGGCCGCCCTTCCGCGCGGGACTCAGCTACCCGCGTCTGGCCAGCGCCTGCGGGTGAGAGTGAAGGGCGACCGCCTGTTGATTTCGGCTCCACGGGCGGGTGTCACCTGCCAGCAGCCCCACATCCTGGCGCGGCGACCCCAGCTGTCTTCCCCGCGCCCCTGTAGCCTCTGGCCTCAGGGAGCCCCCGACCCACGACCCTGGCGCGCGGCGCAAGGCGATGCCCAAG-C		Developmental and epileptic encephalopathy, 1	Pathogenic (Apr 01, 2002)
X-25004650-G-A		not specified	Likely benign (Mar 11, 2016)
X-25004665-A-C		ARX-related disorder	Likely benign (Aug 20, 2020)
X-25004668-C-G		not specified	Likely benign (May 04, 2016)
X-25004675-A-G		Developmental and epileptic encephalopathy, 1	Uncertain significance (Jan 01, 2019)
X-25004682-C-T		Intellectual disability, X-linked, with or without seizures, arx-related;Developmental and epileptic encephalopathy, 1	Likely benign (Sep 01, 2022)
X-25004683-T-A			Uncertain significance (Sep 16, 2022)
X-25004685-G-T		Intellectual disability, X-linked, with or without seizures, arx-related;Developmental and epileptic encephalopathy, 1	Likely benign (May 22, 2023)
X-25004688-C-T		not specified • Developmental and epileptic encephalopathy, 1;Intellectual disability, X-linked, with or without seizures, arx-related • Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 31, 2024)
X-25004689-G-C		Developmental and epileptic encephalopathy, 1;Intellectual disability, X-linked, with or without seizures, arx-related	Uncertain significance (May 16, 2023)
X-25004691-G-A		Developmental and epileptic encephalopathy, 1;Intellectual disability, X-linked, with or without seizures, arx-related	Likely benign (Sep 02, 2022)
X-25004700-C-T		Developmental and epileptic encephalopathy, 1;Intellectual disability, X-linked, with or without seizures, arx-related	Likely benign (Nov 04, 2023)
X-25004718-C-T		Intellectual disability, X-linked, with or without seizures, arx-related;Developmental and epileptic encephalopathy, 1	Likely benign (Dec 27, 2023)
X-25004721-G-A		Developmental and epileptic encephalopathy, 1;Intellectual disability, X-linked, with or without seizures, arx-related	Likely benign (Oct 09, 2023)
X-25004721-G-C		Intellectual disability, X-linked, with or without seizures, arx-related;Developmental and epileptic encephalopathy, 1	Likely benign (Nov 17, 2022)
X-25004730-C-T		Intellectual disability, X-linked, with or without seizures, arx-related;Developmental and epileptic encephalopathy, 1	Likely benign (Jun 20, 2023)
X-25004735-G-T		Inborn genetic diseases	Uncertain significance (Jul 08, 2014)
X-25004736-C-G			Uncertain significance (Dec 22, 2020)
X-25004738-C-A		Developmental and epileptic encephalopathy, 1;Intellectual disability, X-linked, with or without seizures, arx-related	Uncertain significance (Jun 13, 2022)
X-25004738-CCTTGGCCTTGAGCCTCAGCGCGGCTATG-C		Corpus callosum agenesis-abnormal genitalia syndrome	Likely pathogenic (May 04, 2022)
X-25004741-T-C		Developmental and epileptic encephalopathy, 1;Intellectual disability, X-linked, with or without seizures, arx-related	Uncertain significance (Nov 27, 2023)
X-25004743-G-A		Developmental and epileptic encephalopathy, 1;Intellectual disability, X-linked, with or without seizures, arx-related	Uncertain significance (Aug 24, 2021)
X-25004744-C-T		Developmental and epileptic encephalopathy, 1;Intellectual disability, X-linked, with or without seizures, arx-related	Likely pathogenic (Aug 09, 2021)
X-25004747-T-C		Corpus callosum agenesis-abnormal genitalia syndrome	Pathogenic/Likely pathogenic (May 04, 2022)
X-25004748-G-C		Intellectual disability, X-linked, with or without seizures, arx-related;Developmental and epileptic encephalopathy, 1	Likely benign (Jan 04, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ARX	protein_coding	protein_coding	ENST00000379044	5	12255

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.908	0.0912	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.05	82	154	0.534	0.0000102	3508
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Ectoderm Differentiation;Olfactory bulb development and olfactory learning (Consensus)

Recessive Scores

• pRec: 0.147

Haploinsufficiency Scores

• pHI: 0.826
• hipred: Y
• hipred_score: 0.756
• ghis: 0.566

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.283

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Arx
• Phenotype: growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); endocrine/exocrine gland phenotype; homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; reproductive system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: arxa
• Affected structure: pancreatic A cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;axon guidance;positive regulation of gene expression;globus pallidus development;cerebral cortex tangential migration;embryonic olfactory bulb interneuron precursor migration;cell proliferation in forebrain;cerebral cortex GABAergic interneuron migration;regulation of cell population proliferation;lipid digestion;positive regulation of organ growth;neuron development;epithelial cell fate commitment
• Cellular component: nucleus
• 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