ATRX

Summary

ATRX (ATRX chromatin remodeler, HGNC:886) is a protein-coding gene on chromosome Xq21.1, encoding Transcriptional regulator ATRX (P46100). Involved in transcriptional regulation and chromatin remodeling. In precision oncology, ATRX Underexpression confers sensitivity to Temozolomide + PCV Regimen in Malignant Astrocytoma (CIViC Level B); 2 further curated variant–drug associations are listed below. It is a selective cancer dependency (DepMap: 10.5% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene contains an ATPase/helicase domain, and thus it belongs to the SWI/SNF family of chromatin remodeling proteins. This protein is found to undergo cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and chromosomal segregation in mitosis. Mutations in this gene are associated with X-linked syndromes exhibiting cognitive disabilities as well as alpha-thalassemia (ATRX) syndrome. These mutations have been shown to cause diverse changes in the pattern of DNA methylation, which may provide a link between chromatin remodeling, DNA methylation, and gene expression in developmental processes. Multiple alternatively spliced transcript variants encoding distinct isoforms have been reported.

Source: NCBI Gene 546 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ATR-X-related syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 2,802 total — 70 pathogenic, 74 likely-pathogenic
• Phenotypes (HPO): 240
• Precision-oncology evidence (CIViC): 3 curated variant–drug associations
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 14 cancer types
• Cancer dependency (DepMap): dependent in 10.5% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000489

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:886
Approved symbol	ATRX
Name	ATRX chromatin remodeler
Location	Xq21.1
Locus type	gene with protein product
Status	Approved
Aliases	XH2, XNP
Ensembl gene	ENSG00000085224
Ensembl biotype	protein_coding
OMIM	300032
Entrez	546

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 11 protein_coding, 5 retained_intron, 5 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay

ENST00000373344, ENST00000395603, ENST00000400866, ENST00000460639, ENST00000479487, ENST00000480283, ENST00000493470, ENST00000622960, ENST00000623242, ENST00000623316, ENST00000623321, ENST00000623706, ENST00000624032, ENST00000624166, ENST00000624193, ENST00000624668, ENST00000624766, ENST00000625063, ENST00000635865, ENST00000636152, ENST00000636868, ENST00000637175, ENST00000637959, ENST00000675732, ENST00000675908

RefSeq mRNA: 2 — MANE Select: NM_000489 NM_000489, NM_138270

CCDS: CCDS14434, CCDS14435

Canonical transcript exons

ENST00000373344 — 35 exons

Exon	Start	End
ENSE00003361560	77504880	77508629
ENSE00003478884	77593696	77593849
ENSE00003485723	77633566	77633712
ENSE00003495888	77618806	77618981
ENSE00003516677	77684939	77685006
ENSE00003517230	77600434	77600564
ENSE00003519307	77681520	77684593
ENSE00003529715	77634594	77634703
ENSE00003538209	77522263	77522388
ENSE00003540435	77523252	77523401
ENSE00003545330	77656560	77656653
ENSE00003560400	77652114	77652353
ENSE00003571138	77574250	77574358
ENSE00003574843	77620395	77620532
ENSE00003586055	77654098	77654200
ENSE00003589340	77633207	77633384
ENSE00003596441	77599411	77599580
ENSE00003596469	77589834	77589940
ENSE00003603368	77676226	77676298
ENSE00003606635	77521403	77521498
ENSE00003613691	77664645	77664778
ENSE00003626230	77599732	77599820
ENSE00003636288	77688818	77688927
ENSE00003658687	77635915	77636056
ENSE00003664334	77616613	77616730
ENSE00003682636	77558669	77558846
ENSE00003691580	77557451	77557645
ENSE00003693770	77663382	77663558
ENSE00003694020	77520788	77520916
ENSE00003712557	77697583	77697635
ENSE00003713901	77696577	77696704
ENSE00003726390	77717131	77717243
ENSE00003730261	77698574	77698629
ENSE00003734946	77785982	77786216
ENSE00003736076	77693824	77693937

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 98.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.1146 / max 1248.3055, expressed in 1793 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199796	28.3460	1790
199787	3.0404	864
199795	1.2414	776
199793	0.8542	403
199792	0.8418	306
199794	0.5500	226
199791	0.2409	70

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.75	gold quality
calcaneal tendon	UBERON:0003701	98.03	gold quality
colonic epithelium	UBERON:0000397	97.29	gold quality
cortical plate	UBERON:0005343	97.27	gold quality
tendon	UBERON:0000043	97.04	gold quality
cerebellar vermis	UBERON:0004720	96.86	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.59	gold quality
choroid plexus epithelium	UBERON:0003911	96.33	gold quality
pylorus	UBERON:0001166	96.25	gold quality
tibia	UBERON:0000979	96.13	gold quality
sural nerve	UBERON:0015488	95.94	gold quality
CA1 field of hippocampus	UBERON:0003881	95.76	gold quality
ganglionic eminence	UBERON:0004023	95.72	gold quality
adrenal tissue	UBERON:0018303	95.62	gold quality
corpus callosum	UBERON:0002336	95.49	gold quality
tendon of biceps brachii	UBERON:0008188	95.49	gold quality
blood vessel layer	UBERON:0004797	95.30	gold quality
renal medulla	UBERON:0000362	95.28	gold quality
mucosa of stomach	UBERON:0001199	95.09	gold quality
ventricular zone	UBERON:0003053	95.03	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.98	gold quality
visceral pleura	UBERON:0002401	94.93	gold quality
postcentral gyrus	UBERON:0002581	94.74	gold quality
medial globus pallidus	UBERON:0002477	94.71	gold quality
parietal lobe	UBERON:0001872	94.69	gold quality
cardia of stomach	UBERON:0001162	94.52	gold quality
entorhinal cortex	UBERON:0002728	94.41	gold quality
globus pallidus	UBERON:0001875	94.37	gold quality
superior frontal gyrus	UBERON:0002661	94.31	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.30	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	6.71
E-MTAB-7052	no	269.32
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
ATRX
EPPIN
GATA4	Repression
H3-3A
HBA1	Repression
HBA2	Repression

Upstream regulators (CollecTRI, top): ATRX, CDX2

miRNA regulators (miRDB)

293 targeting ATRX, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-32-5P	99.98	75.21	1964

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 10.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• findings indicate that ATRX dosage is crucial for normal development and organization of the cortex, and emphasize the relevance of our model for the study of ATRX function and disease pathogenesis (PMID:11823444)
• involved in homologous DNA pairing (PMID:12205100)
• in individuals with myelodysplasia associated with alpha-thalassemia, somatic mutations of the gene ATRX cause an unexpectedly severe hematological phenotype compared with the wide spectrum of inherited mutations affecting this gene (PMID:12858175)
• forms a chromatin-remodeling complex with Daxx and localizes in promyelocytic leukemia nuclear bodies (PMID:12953102)
• series of novel point mutations in ATRX detected in archival DNA samples from marrow and/or blood of patients with myelodysplastic syndrome associated with alpha-thalassemia (PMID:14592816)
• the ATRX.Daxx complex is a novel ATP-dependent chromatin-remodeling complex, with ATRX being the core ATPase subunit and Daxx being the targeting subunit (PMID:14990586)
• ATRX as a chromatin remodeling protein, and its role in mammalian sex differentiation–REVIEW (PMID:15350606)
• Rad54 protein serves as a dsDNA gateway for the Rad51-ssDNA filament, promoting binding and an ATP hydrolysis-dependent translocation of dsDNA during the search for homologous sequences (PMID:15466868)
• genetic mechanisms responsible for the phenotype of patients carrying a premature stop mutation in the ATRX gene (PMID:15591283)
• report on two brothers with the ATR-X phenotype without HbH disease; both had a mutation in the 5’ upstream region of the ADD domain of the ATRX gene. (PMID:16376512)
• REVIEW: ATRX encodes a trans-acting factor capable of influencing the expression of alpha-globin and other genes, and involved in alpha-thalassemia associated with mental retardation and acquired alpha-thalassemia associated with myelodysplastic syndrome (PMID:16537041)
• Disruption of the MeCP2-ATRX interaction leads to pathological changes that contribute to mental retardation. (PMID:17296936)
• some of the patients suspected of ATR-X carry large intragenic duplications in the ATRX gene, leading to an absence of ATRX mRNA and of the protein (PMID:17579672)
• The effects of individual point mutations on the folding state and stability of the ADD domain correlate well with the levels of mutant ATRX protein in patients, providing insights into the molecular pathophysiology of ATR-X syndrome. (PMID:17609377)
• Mutations represent functional hypomorphs and suggest that loss of proper targeting to promyelocytic leukemia nuclear bodies is an important contributor to the pathogenesis of the ATR-X syndrome. (PMID:17957225)
• Study finds that ATRX is required for normal mitotic progression in human cultured cells and in neuroprogenitors. (PMID:18227278)
• Mutations in ATRX have been shown to perturb gene expression and DNA methylation; this is a report of 127 mutations including 32 reported here for the first time. (PMID:18409179)
• ATRX has a role in repressing immediate-early transcription (PMID:18922870)
• results demonstrate a link between branch migration activity of hRad54 and structure-specific endonuclease activity of hMus81-Eme1, suggesting that the Rad54 and Mus81-Eme1 proteins may cooperate in the processing of Holliday junction-like intermediates (PMID:19017809)
• Atrx plays role in interneuron survival and differentiation. (PMID:19088125)
• ATRX is present in adult human and rat testis and is expressed in the somatic cells; Sertoli, Leydig, and peritubular myoid cells, and also in germ cells; spermatogonia and early meiotic spermatocytes. (PMID:19444003)
• The N-terminal 1-212 amino acids of BLM of or an ATPase-dead mutant enhanced the ATPase and chromatin-remodeling activities of RAD54. (PMID:19671661)
• Partial ATRX gene duplication causes ATR-X syndrome. (PMID:19764021)
• proXNP is a good marker of cardiac output following pediatric cardiac surgery and might be a useful tool in the recognition of a low output state (PMID:19919584)
• ATRX interacts with histones in maintaining telomere structural integrity in pluripotent embryonic stem cells. (PMID:20110566)
• These results suggest that ATRX and hDaxx act as a complex that contributes to intrinsic antiviral resistance to HSV-1 infection, which is counteracted by HSV-1 ICP0. (PMID:20147399)
• Study shows that ATRX binds G4 DNA in vitro, suggesting a common mechanism by which ATRX may influence a wide range of nuclear processes in the telomeric, subtelomeric, and interstitial regions of mammalian chromosomes. (PMID:21029860)
• These results indicate that hRad54 can facilitate hRad51-promoted strand exchange through various degrees of mismatching. (PMID:21056573)
• this study suggested that aberrant CaMKII activation likely mediates abnormal spine formation in the prefrontal cortex. (PMID:21209221)
• identification of mutations in pancreatic neuroendocrine tumors; 44% had somatic inactivating mutations in MEN1; 43% had mutations in genes encoding DAXX and ATRX; clinically, mutations in MEN1 and DAXX/ATRX genes were associated with better prognosis (PMID:21252315)
• Evidence for a functional involvement of the four mutations affecting ATRX (p.1761M4T), PQBP1 (p.155R4X), and SLC6A8 (p.390P4L and p.477S4L), in the etiology of intellectual disability. (PMID:21267006)
• The experiments demonstrate that ATRX can act as a cellular intrinsic antiviral defense in U2OS cells by blocking gene expression from incoming HCMV genomes and did not affect the replication of herpes simplex virus type 1. (PMID:21310198)
• Disruption of H3K9me3 binding may be a general pathogenicity pathway of ATRX mutations in the ADD domain. (PMID:21421568)
• RAD51 may function as a universal factor during HR, whereas RAD54 mainly functions in other types of homologous recombination (gene targeting or intra-chromosomal HR), which involves interaction with chromosomal DNA (PMID:21501635)
• these mutant ATRX proteins are defective in translocating along DNA while one mutant, uniquely for a human disease-causing mutation, partially uncouples adenosine triphosphate (ATP) hydrolysis from DNA binding (PMID:21505078)
• The ADD domain of ATRX engages the N-terminal tail of histone H3 through two rigidly oriented binding pockets, one for unmodified Lys4 and the other for di- or trimethylated Lys9. (PMID:21666677)
• The ADD cysteine-rich domain of ATRX is a histone H3-binding module. (PMID:21666679)
• found 61% of pancreatic neuroendocrine tumors had abnormal telomeres; all of the tumors with abnormal telomeres had ATRX or DAXX mutations or loss of nuclear ATRX or DAXX protein; ATRX mutations also correlate with abnormal telomeres in CNS tumors (PMID:21719641)
• Role in chromatin assembly and genome structure. Its dysfunction or absence leads to devastating consequences in embryonic development and to human disease. (PMID:21851155)
• our data reveal RAD54-dependent and -independent contributions of HR to the cellular sensitivity to UV-light, and they uncover that RAD54 can compensate for the loss of TLS polymerase eta with regard to UV-light sensitivity. (PMID:21885354)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	atrx	ENSDARG00000042236
danio_rerio	atrxl	ENSDARG00000099449
mus_musculus	Atrx	ENSMUSG00000031229
rattus_norvegicus	Atrx	ENSRNOG00000056703
drosophila_melanogaster	XNP	FBGN0039338
caenorhabditis_elegans	xnp-1	WBGENE00006961

Paralogs (30): HLTF (ENSG00000071794), SMARCA2 (ENSG00000080503), SRCAP (ENSG00000080603), RAD54L (ENSG00000085999), BTAF1 (ENSG00000095564), CHD8 (ENSG00000100888), SMARCA1 (ENSG00000102038), CHD4 (ENSG00000111642), CHD5 (ENSG00000116254), TTF2 (ENSG00000116830), HELLS (ENSG00000119969), ZRANB3 (ENSG00000121988), CHD6 (ENSG00000124177), SMARCA4 (ENSG00000127616), INO80 (ENSG00000128908), CHD1L (ENSG00000131778), SMARCAL1 (ENSG00000138375), SHPRH (ENSG00000146414), SMARCA5 (ENSG00000153147), CHD1 (ENSG00000153922), SMARCAD1 (ENSG00000163104), RAD54L2 (ENSG00000164080), CHD3 (ENSG00000170004), CHD7 (ENSG00000171316), CHD2 (ENSG00000173575), CHD9 (ENSG00000177200), EP400 (ENSG00000183495), ERCC6L (ENSG00000186871), RAD54B (ENSG00000197275), ERCC6 (ENSG00000225830)

Protein

Protein identifiers

Transcriptional regulator ATRX — P46100 (reviewed: P46100)

Alternative names: ATP-dependent helicase ATRX, X-linked helicase II, X-linked nuclear protein, Znf-HX

All UniProt accessions (14): P46100, A0A087WWG0, A0A096LNL6, A0A096LNL7, A0A096LNL9, A0A096LNN3, A0A096LNR8, A0A096LNW1, A0A096LNX6, A0A096LP59, A0A096LPG6, A0A6Q8PHA4, A4LAA3, H0Y3T0

UniProt curated annotations — full annotation on UniProt →

Function. Involved in transcriptional regulation and chromatin remodeling. Facilitates DNA replication in multiple cellular environments and is required for efficient replication of a subset of genomic loci. Binds to DNA tandem repeat sequences in both telomeres and euchromatin and in vitro binds DNA quadruplex structures. May help stabilizing G-rich regions into regular chromatin structures by remodeling G4 DNA and incorporating H3.3-containing nucleosomes. Catalytic component of the chromatin remodeling complex ATRX:DAXX which has ATP-dependent DNA translocase activity and catalyzes the replication-independent deposition of histone H3.3 in pericentric DNA repeats outside S-phase and telomeres, and the in vitro remodeling of H3.3-containing nucleosomes. Its heterochromatin targeting is proposed to involve a combinatorial readout of histone H3 modifications (specifically methylation states of H3K9 and H3K4) and association with CBX5. Involved in maintaining telomere structural integrity in embryonic stem cells which probably implies recruitment of CBX5 to telomeres. Reports on the involvement in transcriptional regulation of telomeric repeat-containing RNA (TERRA) are conflicting; according to a report, it is not sufficient to decrease chromatin condensation at telomeres nor to increase expression of telomeric RNA in fibroblasts. May be involved in telomere maintenance via recombination in ALT (alternative lengthening of telomeres) cell lines. Acts as a negative regulator of chromatin incorporation of transcriptionally repressive histone MACROH2A1, particularily at telomeres and the alpha-globin cluster in erythroleukemic cells. Participates in the allele-specific gene expression at the imprinted IGF2/H19 gene locus. On the maternal allele, required for the chromatin occupancy of SMC1 and CTCF within the H19 imprinting control region (ICR) and involved in esatblishment of histone tails modifications in the ICR. May be involved in brain development and facial morphogenesis. Binds to zinc-finger coding genes with atypical chromatin signatures and regulates its H3K9me3 levels. Forms a complex with ZNF274, TRIM28 and SETDB1 to facilitate the deposition and maintenance of H3K9me3 at the 3’ exons of zinc-finger genes.

Subunit / interactions. Interacts with DAXX to form the chromatin remodeling complex ATRX:DAXX. Probably binds EZH2. Binds annexin V in a calcium and phosphatidylcholine/phosphatidylserine-dependent manner. Interacts directly with CBX5 via the PxVxL motif. Interacts with RAD50, MRE11 and NBN; indicative for an association with the MRN complex. Interacts with histone MACROH2A1. Interacts with histone H3 peptides methylated at ‘Lys-10’ with preferences H3K9me3 > H3K9me2 > H3K9me1. Interacts with histone H3 peptides unmethylated at ‘Lys-5’ (H3K4me0). Interacts with MECP2, SMC1 and SMC3. Interacts with SETDB1, TRIM28 and ZNF274.

Subcellular location. Nucleus. Chromosome. Telomere. PML body.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylated at serine residues during mitose. Phosphorylation may promote the release from the nuclear matrix and progression to mitosis.

Disease relevance. Alpha-thalassemia/impaired intellectual development syndrome, X-linked (ATRX) [MIM:301040] A disorder characterized by severe psychomotor retardation, facial dysmorphism, urogenital abnormalities, and alpha-thalassemia. An essential phenotypic trait are hemoglobin H erythrocyte inclusions. The disease is caused by variants affecting the gene represented in this entry. Intellectual disability-hypotonic facies syndrome, X-linked, 1 (MRXHF1) [MIM:309580] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSHF1 features include severe intellectual disability, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women. Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects. The disease is caused by variants affecting the gene represented in this entry. Alpha-thalassemia myelodysplasia syndrome (ATMDS) [MIM:300448] A disorder characterized by hypochromic, microcytic red blood cells, hemoglobin H detected in peripheral blood, and multilineage myelodysplasia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ADD domain predominantly interacts with histone H3 trimethylated at ‘Lys-10’(H3K9me3) (and to a lesser extent H3 mono- or dimethylated at ‘Lys-10’) and simultaneously to histone H3 unmethylated at ‘Lys-5’ (H3K4me0). The interaction with H3K9me3 is disrupted by the presence of H3K4me3 suggesting a readout of the combined histone H3 methylation state. Contains one Pro-Xaa-Val-Xaa-Leu (PxVxL) motif, which is required for interaction with chromoshadow domains. This motif requires additional residues -7, -6, +4 and +5 of the central Val which contact the chromoshadow domain.

Similarity. Belongs to the SNF2/RAD54 helicase family.

Isoforms (6)

UniProt ID	Names	Canonical?
P46100-1	4	yes
P46100-2	1
P46100-3	2
P46100-4	3
P46100-5	5
P46100-6	6

RefSeq proteins (2): NP_000480, NP_612114 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000330	SNF2_N	Domain
IPR001650	Helicase_C-like	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR014001	Helicase_ATP-bd	Domain
IPR025766	ADD	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR038718	SNF2-like_sf	Homologous_superfamily
IPR041430	ADD_ATRX	Domain
IPR049730	SNF2/RAD54-like_C	Domain
IPR052131	ATRX_domain-containing	Family
IPR058901	ATRX_C	Domain

Pfam: PF00176, PF00271, PF17981, PF26143

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (198 total): modified residue 49, sequence variant 40, compositionally biased region 32, cross-link 12, region of interest 10, mutagenesis site 10, strand 9, sequence conflict 8, turn 7, splice variant 6, helix 6, domain 3, short sequence motif 2, zinc finger region 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
3QL9	X-RAY DIFFRACTION	0.93
6G0O	X-RAY DIFFRACTION	1.4
5GRQ	X-RAY DIFFRACTION	1.58
3QLA	X-RAY DIFFRACTION	1.6
3QLN	X-RAY DIFFRACTION	1.9
5Y18	X-RAY DIFFRACTION	2.2
3QLC	X-RAY DIFFRACTION	2.5
4W5A	X-RAY DIFFRACTION	2.6
5Y6O	X-RAY DIFFRACTION	3.1
2JM1	SOLUTION NMR
2LBM	SOLUTION NMR
2LD1	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46100-F1	52.40	0.06

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (1): 1594–1601

Post-translational modifications (61): 10, 138, 142, 299, 438, 623, 623, 1004, 1488, 1982, 1982, 1987, 25, 34, 89, 92, 112, 213, 316, 591 …

Mutagenesis-validated functional residues (10):

Position	Phenotype
189	impairs interaction with histone h3 peptides and reduces localization to pericentromeric heterochromatin foci.
203	impairs interaction with histone h3 peptides trimethylated at ’lys-10’ (h3k9me3); loss of heterochromatic localization.
204	impairs interaction with histone h3 peptides trimethylated at ’lys-10’ (h3k9me3) and reduces localization to pericentrom
207	impairs interaction with histone h3 peptides trimethylated at ’lys-10’ (h3k9me3) and reduces localization to pericentrom
209	impairs interaction with histone h3 peptides trimethylated at ’lys-10’ (h3k9me3).
214	impairs interaction with histone h3 peptides trimethylated at ’lys-10’ (h3k9me3).
217	impairs interaction with histone h3 peptides trimethylated at ’lys-10’ (h3k9me3); loss of heterochromatic localization.
218	impairs interaction with histone h3 peptides unmethylated at ’lys-5’ (h3k4me0); reduces pericentromeric localization.
252	impairs interaction with histone h3 peptides and reduces localization to pericentromeric heterochromatin foci.
1600	abolishes atpase activity, no effect on pericentromeric heterochromatin localization.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-9670095	Inhibition of DNA recombination at telomere
R-HSA-9670613	Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations
R-HSA-9670615	Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations
R-HSA-157579	Telomere Maintenance
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-73886	Chromosome Maintenance
R-HSA-9006821	Alternative Lengthening of Telomeres (ALT)
R-HSA-9670621	Defective Inhibition of DNA Recombination at Telomere
R-HSA-9673013	Diseases of Telomere Maintenance
R-HSA-9675126	Diseases of mitotic cell cycle

MSigDB gene sets: 907 (showing top): GOBP_DNA_TEMPLATED_DNA_REPLICATION_MAINTENANCE_OF_FIDELITY, GOBP_CHROMOSOME_ORGANIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EPITHELIUM_DEVELOPMENT, MULLIGHAN_NPM1_SIGNATURE_3_UP, MORF_MSH3, GOBP_REGULATION_OF_DNA_TEMPLATED_DNA_REPLICATION, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_CELL_CYCLE_DNA_REPLICATION, MORF_BRCA1, MORF_ATRX, GOBP_SERTOLI_CELL_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (28): meiotic spindle organization (GO:0000212), DNA repair (GO:0006281), chromatin organization (GO:0006325), nucleosome assembly (GO:0006334), chromatin remodeling (GO:0006338), regulation of DNA-templated transcription (GO:0006355), transcription by RNA polymerase II (GO:0006366), spermatogenesis (GO:0007283), positive regulation of nuclear cell cycle DNA replication (GO:0010571), DNA damage response, signal transduction by p53 class mediator (GO:0030330), forebrain development (GO:0030900), replication fork processing (GO:0031297), subtelomeric heterochromatin formation (GO:0031509), positive regulation of telomere maintenance (GO:0032206), post-embryonic forelimb morphogenesis (GO:0035128), multicellular organism growth (GO:0035264), positive regulation of transcription by RNA polymerase II (GO:0045944), Sertoli cell development (GO:0060009), chromosome organization involved in meiotic cell cycle (GO:0070192), protein localization to chromosome, telomeric region (GO:0070198), seminiferous tubule development (GO:0072520), cellular response to hydroxyurea (GO:0072711), negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric (GO:1904908), DNA damage response (GO:0006974), regulation of gene expression (GO:0010468), negative regulation of macromolecule biosynthetic process (GO:0010558), regulation of cell cycle process (GO:0010564), regulation of chromosome organization (GO:0033044)

GO Molecular Function (16): DNA helicase activity (GO:0003678), chromatin binding (GO:0003682), ATP binding (GO:0005524), zinc ion binding (GO:0008270), DNA translocase activity (GO:0015616), ATP hydrolysis activity (GO:0016887), chromatin DNA binding (GO:0031490), histone binding (GO:0042393), histone H3K9me2/3 reader activity (GO:0062072), chromo shadow domain binding (GO:0070087), nucleotide binding (GO:0000166), DNA binding (GO:0003677), helicase activity (GO:0004386), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (11): nuclear chromosome (GO:0000228), condensed chromosome, centromeric region (GO:0000779), chromosome, telomeric region (GO:0000781), heterochromatin (GO:0000792), nucleus (GO:0005634), nucleoplasm (GO:0005654), pericentric heterochromatin (GO:0005721), nuclear body (GO:0016604), PML body (GO:0016605), chromosome, subtelomeric region (GO:0099115), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Defective Inhibition of DNA Recombination at Telomere	2
Telomere Maintenance	1
Chromosome Maintenance	1
Cell Cycle	1
Diseases of Telomere Maintenance	1
Alternative Lengthening of Telomeres (ALT)	1
Diseases of mitotic cell cycle	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
meiotic cell cycle	2
meiotic cell cycle process	2
chromatin organization	2
DNA-templated transcription	2
developmental process involved in reproduction	2
chromosome, telomeric region	2
ATP-dependent activity, acting on DNA	2
binding	2
DNA binding	2
ATP-dependent activity	2
nuclear lumen	2
chromosome, centromeric region	2
intracellular membraneless organelle	2
spindle organization	1
DNA metabolic process	1
DNA damage response	1
cellular component organization	1
nucleosome organization	1
protein-DNA complex assembly	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
male gamete generation	1
nuclear DNA replication	1
regulation of nuclear cell cycle DNA replication	1
positive regulation of cell cycle process	1
positive regulation of DNA-templated DNA replication	1
signal transduction in response to DNA damage	1
signal transduction by p53 class mediator	1
brain development	1
anatomical structure development	1
DNA-templated DNA replication maintenance of fidelity	1
constitutive heterochromatin formation	1
telomere maintenance	1
regulation of telomere maintenance	1
positive regulation of DNA metabolic process	1
positive regulation of chromosome organization	1
post-embryonic limb morphogenesis	1
forelimb morphogenesis	1
multicellular organismal process	1
developmental growth	1

Protein interactions and networks

STRING

5224 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATRX	DAXX	Q9UER7	998
ATRX	RAD51	Q06609	998
ATRX	RAD52	P43351	993
ATRX	SP100	P23497	991
ATRX	H3-3A	P06351	982
ATRX	RAD54B	Q9Y620	979
ATRX	DNMT3L	Q9UJW3	978
ATRX	MECP2	P51608	970
ATRX	TP53	P04637	963
ATRX	H3C1	P02295	946
ATRX	H3C14	Q71DI3	913
ATRX	H3-5	Q6NXT2	913
ATRX	H3-4	Q16695	913
ATRX	H3-7	Q5TEC6	912
ATRX	BRCA2	P51587	888

IntAct

120 interactions, top by confidence:

A	B	Type	Score
DAXX	ATRX	psi-mi:“MI:0915”(physical association)	0.870
ATRX	DAXX	psi-mi:“MI:0915”(physical association)	0.870
DAXX	ATRX	psi-mi:“MI:0403”(colocalization)	0.870
CSNK2A1	EIF3J	psi-mi:“MI:0914”(association)	0.810
IMP3	MPHOSPH10	psi-mi:“MI:0914”(association)	0.670
Mecp2	ATRX	psi-mi:“MI:0915”(physical association)	0.610
H3-3A	ATRX	psi-mi:“MI:0915”(physical association)	0.560
ATRX	RAD50	psi-mi:“MI:0915”(physical association)	0.540
RAD50	ATRX	psi-mi:“MI:0915”(physical association)	0.540
ATRX	RAD50	psi-mi:“MI:0403”(colocalization)	0.540
MACROH2A1	PARP1	psi-mi:“MI:0914”(association)	0.530
EPB41L3	AP3B1	psi-mi:“MI:0914”(association)	0.530
DAXX	TNRC18	psi-mi:“MI:0914”(association)	0.530
ATRX	EZH2	psi-mi:“MI:0915”(physical association)	0.520
ATRX	MRE11	psi-mi:“MI:0403”(colocalization)	0.430
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
MACROH2A1	ATRX	psi-mi:“MI:0915”(physical association)	0.400
ATRX	COX4I1	psi-mi:“MI:0915”(physical association)	0.400
ATRX	HNRNPD	psi-mi:“MI:0915”(physical association)	0.400
ATRX	NOMO1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (452): ATRX (Biochemical Activity), ATRX (Reconstituted Complex), ATRX (Affinity Capture-MS), ATRX (Affinity Capture-MS), ATRX (Affinity Capture-MS), ATRX (Affinity Capture-MS), ATRX (Affinity Capture-MS), ATRX (Affinity Capture-MS), ATRX (Affinity Capture-MS), ATRX (Affinity Capture-MS), ATRX (Affinity Capture-MS), ATRX (Affinity Capture-MS), ATRX (Affinity Capture-Western), ATRX (Co-crystal Structure), ATRX (Affinity Capture-Western)

ESM2 similar proteins: A0A3Q2UEI8, A0JM80, A0JNH9, A6QNQ6, A8MT70, B1WC58, E7FAP1, F1R983, F6SNN2, P23497, P46100, P49452, Q09003, Q0IIM1, Q0P5X5, Q2M2Z5, Q3UHX0, Q4R731, Q5FBB7, Q5QJC4, Q5RD97, Q5REF4, Q5W0B1, Q5ZLE9, Q61687, Q62394, Q6GNV6, Q6KAQ7, Q6P0N0, Q6P9P0, Q6PJP8, Q76FK4, Q7YQM3, Q7YQM4, Q80WQ8, Q80XJ2, Q80YR6, Q8BRH4, Q8IW19, Q8IYH5

Diamond homologs: A0A0P0WGX7, A1C9W6, A1CZE5, A2BGR3, A2R9H9, A4H7G5, A4HVU6, A4IHD2, A4PBL4, A4R227, A5E0W5, A6QQR4, A6ZL17, A6ZU34, A7EQA8, A7TJI3, A7Z019, B3LN76, B4F769, B5VE38, B6EU02, C0H4W3, C7GQI8, E7F1C4, F4HW51, O13682, O14148, P0CO16, P0CO17, P0CO18, P0CO19, P32863, P34739, P36607, P38086, P41410, P43610, P46100, P51532, P53115

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
ATRX	“up-regulates activity”	“Polycomb repressive complex 2”	binding
ATRX	down-regulates	Immortality
ATRX	“up-regulates activity”	ZBED1	binding
ATRX	“down-regulates quantity by repression”	GATA4	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Meiosis	5	16.8×	1e-03
Regulation of TP53 Activity through Phosphorylation	9	12.5×	2e-05
Reproduction	5	11.2×	4e-03
HDR through Homologous Recombination (HRR)	5	11.2×	4e-03
CHD1 and CHD2 subfamily	8	10.2×	2e-04
DNA Damage/Telomere Stress Induced Senescence	5	9.6×	6e-03
Meiotic recombination	6	9.2×	4e-03
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	5	8.6×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein localization to chromatin	5	27.1×	2e-04
heterochromatin formation	8	19.1×	5e-06
double-strand break repair	8	15.2×	2e-05
nucleosome assembly	10	13.1×	5e-06
DNA repair	12	7.2×	3e-05
mRNA splicing, via spliceosome	7	6.0×	1e-02
DNA damage response	9	4.5×	1e-02

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 14 cancer types — ACC, CLLSLL, GB, GBM, HGGNOS, LGGNOS, LMS, NBL, OS, OVT, PANET, PAST…(+2 more).

Clinical variants and AI predictions

ClinVar

2802 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	70
Likely pathogenic	74
Uncertain significance	904
Likely benign	1190
Benign	188

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012663	NM_000489.6(ATRX):c.7201-3_7201-2del	Pathogenic
1072204	NM_000489.6(ATRX):c.158del (p.Asn53fs)	Pathogenic
1072394	NC_000023.10:g.(?76759356)(77042755_?)del	Pathogenic
1072395	NC_000023.10:g.(?76937002)(76940508_?)del	Pathogenic
1073930	NM_000489.6(ATRX):c.1960C>T (p.Arg654Ter)	Pathogenic
11722	NM_000489.6(ATRX):c.4840T>C (p.Cys1614Arg)	Pathogenic
11723	NM_000489.6(ATRX):c.4950G>T (p.Lys1650Asn)	Pathogenic
11725	NM_000489.6(ATRX):c.6104A>T (p.Asp2035Val)	Pathogenic
11726	NM_000489.6(ATRX):c.6250T>C (p.Tyr2084His)	Pathogenic
11727	NM_000489.6(ATRX):c.6488A>G (p.Tyr2163Cys)	Pathogenic
11728	NM_000489.6(ATRX):c.7156C>T (p.Arg2386Ter)	Pathogenic
11729	NM_000489.6(ATRX):c.7162G>T (p.Glu2388Ter)	Pathogenic
11730	NM_000489.6(ATRX):c.5273-10T>A	Pathogenic
11732	NM_000489.6(ATRX):c.5131C>T (p.Pro1711Ser)	Pathogenic
11733	NM_000489.6(ATRX):c.751A>G (p.Lys251Glu)	Pathogenic
11736	NM_000489.6(ATRX):c.5225G>A (p.Arg1742Lys)	Pathogenic
11737	NM_000489.6(ATRX):c.7201-2A>G	Pathogenic
11740	NM_000489.6(ATRX):c.20+1G>A	Pathogenic
11741	NM_000489.6(ATRX):c.236C>G (p.Ser79Ter)	Pathogenic
11743	NM_000489.6(ATRX):c.1226T>C (p.Leu409Ser)	Pathogenic
11746	NM_000489.6(ATRX):c.6811A>G (p.Arg2271Gly)	Pathogenic
1332803	NM_000489.6(ATRX):c.809C>T (p.Pro270Leu)	Pathogenic
1334885	NM_000489.6(ATRX):c.6235C>T (p.Arg2079Ter)	Pathogenic
1441584	NM_000489.6(ATRX):c.2678dup (p.Thr894fs)	Pathogenic
1452479	NC_000023.10:g.(?76763809)(77041507_?)del	Pathogenic
1683919	NM_000489.6(ATRX):c.3943+3G>T	Pathogenic
1710155	NM_000489.6(ATRX):c.134-4884_242+41del	Pathogenic
1802595	NM_000489.6(ATRX):c.7366dup (p.Met2456fs)	Pathogenic
2024014	NM_000489.6(ATRX):c.161_162del (p.Asn53_Ser54insTer)	Pathogenic
2423152	NC_000023.10:g.(?76763829)(76776414_?)del	Pathogenic

SpliceAI

6355 predictions. Top by Δscore:

Variant	Effect	Δscore
X:77508630:C:CC	acceptor_gain	1.0000
X:77520787:CCAT:C	donor_gain	1.0000
X:77520914:CCA:C	acceptor_gain	1.0000
X:77520915:CAC:C	acceptor_gain	1.0000
X:77520917:C:CC	acceptor_gain	1.0000
X:77521397:G:C	donor_gain	1.0000
X:77521401:A:AC	donor_gain	1.0000
X:77521402:C:CC	donor_gain	1.0000
X:77521402:CTA:C	donor_gain	1.0000
X:77521402:CTACA:C	donor_gain	1.0000
X:77521405:CAG:C	donor_gain	1.0000
X:77521416:ATAT:A	donor_gain	1.0000
X:77521418:AT:A	donor_gain	1.0000
X:77521419:T:TA	donor_gain	1.0000
X:77521440:A:AC	donor_gain	1.0000
X:77521441:C:CC	donor_gain	1.0000
X:77521441:CTG:C	donor_gain	1.0000
X:77521495:GGTCC:G	acceptor_loss	1.0000
X:77521496:GTCC:G	acceptor_loss	1.0000
X:77521497:TCC:T	acceptor_loss	1.0000
X:77521498:CCTAG:C	acceptor_loss	1.0000
X:77521499:C:CC	acceptor_gain	1.0000
X:77521499:CT:C	acceptor_loss	1.0000
X:77521500:T:G	acceptor_loss	1.0000
X:77522258:CTCA:C	donor_loss	1.0000
X:77522259:TCA:T	donor_loss	1.0000
X:77522260:CACCT:C	donor_loss	1.0000
X:77522261:A:AC	donor_gain	1.0000
X:77522261:ACCT:A	donor_gain	1.0000
X:77522262:C:CC	donor_gain	1.0000

AlphaMissense

16645 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:77508616:A:T	V2405D	1.000
X:77520871:C:G	A2373P	1.000
X:77521462:C:G	A2338P	1.000
X:77521470:A:T	V2335D	1.000
X:77521483:C:G	G2331R	1.000
X:77521483:C:T	G2331R	1.000
X:77521494:A:G	L2327P	1.000
X:77522267:A:G	L2324P	1.000
X:77523263:C:G	A2280P	1.000
X:77523268:T:C	Y2278C	1.000
X:77523268:T:G	Y2278S	1.000
X:77523269:A:C	Y2278D	1.000
X:77523269:A:G	Y2278H	1.000
X:77523269:A:T	Y2278N	1.000
X:77523275:C:G	A2276P	1.000
X:77523276:C:A	W2275C	1.000
X:77523276:C:G	W2275C	1.000
X:77523277:C:G	W2275S	1.000
X:77523278:A:G	W2275R	1.000
X:77523278:A:T	W2275R	1.000
X:77523280:G:T	A2274D	1.000
X:77523281:C:G	A2274P	1.000
X:77523284:C:G	A2273P	1.000
X:77523288:T:A	R2271S	1.000
X:77523288:T:G	R2271S	1.000
X:77523304:A:G	L2266S	1.000
X:77523328:A:G	L2258S	1.000
X:77523331:A:G	L2257P	1.000
X:77523331:A:T	L2257H	1.000
X:77523350:A:C	Y2251D	1.000

dbSNP variants (sampled 300 via entrez): RS1000007753 (X:77704641 T>C), RS1000042499 (X:77725223 A>C), RS1000064618 (X:77661158 T>C), RS1000079203 (X:77586555 A>G), RS1000099890 (X:77717940 T>C), RS1000131460 (X:77586059 A>T), RS1000131896 (X:77650878 G>A), RS1000166463 (X:77755475 C>A), RS1000172496 (X:77718363 C>T), RS1000210792 (X:77627659 C>T), RS1000218714 (X:77777693 A>C), RS1000241097 (X:77642182 A>G), RS1000281639 (X:77512157 G>A), RS1000303909 (X:77540863 A>G), RS1000355905 (X:77631910 G>C)

Disease associations

OMIM: gene MIM:300032 | disease phenotypes: MIM:301040, MIM:309580, MIM:300448, MIM:181500, MIM:300853, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
alpha thalassemia-X-linked intellectual disability syndrome	Definitive	X-linked
ATR-X-related syndrome	Strong	X-linked
intellectual disability-hypotonic facies syndrome, X-linked, 1	Moderate	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
ATR-X-related syndrome	Definitive	XL

Mondo (13): alpha thalassemia-X-linked intellectual disability syndrome (MONDO:0010519), intellectual disability (MONDO:0001071), intellectual disability-hypotonic facies syndrome, X-linked, 1 (MONDO:0010663), alpha-thalassemia-myelodysplastic syndrome (MONDO:0010328), ATR-X-related syndrome (MONDO:0016980), anaplastic astrocytoma (MONDO:0016684), atypical teratoid rhabdoid tumor (MONDO:0020560), congenital nervous system disorder (MONDO:0002320), neurodevelopmental disorder (MONDO:0700092), schizophrenia (MONDO:0005090), X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection and neoplasia (MONDO:0010455), microcephaly (MONDO:0001149), genetic developmental and epileptic encephalopathy (MONDO:0100062)

Orphanet (16): X-linked alpha-thalassemia-intellectual disability syndrome (Orphanet:847), X-linked intellectual disability-hypotonic face syndrome (Orphanet:73220), Holmes-Gang syndrome (Orphanet:93970), Chudley-Lowry-Hoar syndrome (Orphanet:93971), Juberg-Marsidi syndrome (Orphanet:93972), Carpenter-Waziri syndrome (Orphanet:93973), Smith-Fineman-Myers syndrome (Orphanet:93974), OBSOLETE: Renier-Gabreels-Jasper syndrome (Orphanet:93975), Alpha-thalassemia-myelodysplastic syndrome (Orphanet:231401), Anaplastic astrocytoma (Orphanet:251589), Atypical teratoid rhabdoid tumor (Orphanet:99966), XMEN (Orphanet:317476), Male infertility with azoospermia or oligozoospermia due to single gene mutation (Orphanet:399805), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), OBSOLETE: ATR-X-related syndrome (Orphanet:263355)

HPO phenotypes

240 total (30 of 240 shown, HPO-id order):

HPO	Term
HP:0000010	Recurrent urinary tract infections
HP:0000028	Cryptorchidism
HP:0000037	Male pseudohermaphroditism
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000049	Shawl scrotum
HP:0000054	Micropenis
HP:0000062	Ambiguous genitalia
HP:0000076	Vesicoureteral reflux
HP:0000077	Abnormality of the kidney
HP:0000089	Renal hypoplasia
HP:0000104	Renal agenesis
HP:0000126	Hydronephrosis
HP:0000135	Hypogonadism
HP:0000141	Amenorrhea
HP:0000154	Wide mouth
HP:0000158	Macroglossia
HP:0000164	Abnormality of the dentition
HP:0000179	Thick lower lip vermilion
HP:0000188	Short upper lip
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000232	Everted lower lip vermilion
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000271	Abnormality of the face
HP:0000272	Malar flattening
HP:0000280	Coarse facial features
HP:0000286	Epicanthus

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST90002400_4	Plateletcrit	7.000000e-09
GCST90002402_517	Platelet count	3.000000e-17

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007985	platelet crit
EFO:0004309	platelet count

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
C538258	ATR-X syndrome (supp.)
C563023	Alpha-Thalassemia Myelodysplasia Syndrome (supp.)
C537445	Mental retardation Smith Fineman Myers type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

Clinical evidence (CIViC)

Drug × variant × indication: 3 predictive associations from 3 curated evidence items; also 2 prognostic, 2 diagnostic.

Variant	Therapy	Indication	Effect	Level	CIViC
ATRX Underexpression	Temozolomide + PCV Regimen	Malignant Astrocytoma	Sensitivity/Response	CIViC B	EID1647
ATRX Deletion	Cisplatin + Fluorouracil	Cancer	Sensitivity/Response	CIViC D	EID9239
ATRX Underexpression	VE-821 + AZ20	Osteosarcoma	Sensitivity/Response	CIViC D	EID5832

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

78 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	4
trichostatin A	affects cotreatment, decreases expression	3
Doxorubicin	decreases expression, increases expression, affects reaction, affects expression, affects response to substance (+1 more)	3
bisphenol A	increases expression, affects methylation, affects cotreatment, increases methylation	2
sodium arsenite	affects binding, increases reaction, decreases expression	2
perfluorooctane sulfonic acid	decreases expression	2
Resveratrol	increases expression, decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Tretinoin	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
pradimicin-IRD	increases expression, affects expression, affects response to substance	1
geldanamycin	increases expression	1
testosterone enanthate	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects expression, affects response to substance	1
terbufos	increases methylation	1
methylparaben	increases expression	1
butyraldehyde	decreases expression	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	decreases expression	1
aflatoxin B2	increases methylation	1
coumarin	affects phosphorylation	1
cupric oxide	decreases expression	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
tamibarotene	decreases expression	1

Cellosaurus cell lines

24 cell lines: 18 cancer cell line, 3 spontaneously immortalized cell line, 1 transformed cell line, 1 telomerase immortalized cell line, 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_5058	SNU-407	Cancer cell line	Male
CVCL_6610	CHLA-90	Cancer cell line	Male
CVCL_B8BN	Abcam HCT 116 ATRX KO	Cancer cell line	Male
CVCL_B8SN	Abcam MCF-7 ATRX KO	Cancer cell line	Female
CVCL_B9DS	Abcam A-549 ATRX KO	Cancer cell line	Male
CVCL_C0M2	GM28392	Transformed cell line	Male
CVCL_C0ZP	MCF10A_ATRX_718	Spontaneously immortalized cell line	Female
CVCL_C0ZQ	MCF10A_ATRX_722	Spontaneously immortalized cell line	Female
CVCL_C0ZR	MCF10A_ATRX_734	Spontaneously immortalized cell line	Female
CVCL_C1BQ	RPTEC_ATRX_932	Telomerase immortalized cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT03975829	PHASE4	RECRUITING	Pediatric Long-Term Follow-up and Rollover Study
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00430911	PHASE3	COMPLETED	Radiotherapy for Malignant Astrocytomas in the Elderly
NCT00717210	PHASE3	COMPLETED	Randomized Phase III Study of Sequential Radiochemotherapy of Anaplastic Glioma With PCV or Temozolomide
NCT00761280	PHASE3	TERMINATED	Efficacy and Safety of AP 12009 in Patients With Recurrent or Refractory Anaplastic Astrocytoma or Secondary Glioblastoma
NCT01502241	PHASE3	COMPLETED	Phase III Trial of Primary Radio- or Chemotherapy in Malignant Astrocytoma of the Elderly
NCT01656980	PHASE3	UNKNOWN	Safety and Efficacy Study of Intracranially Implanted Carmustine to Treat Newly Diagnosed Malignant Glioma
NCT01765088	PHASE3	UNKNOWN	A Phase III Trial on Adjuvant Temozolomide With or Without Interferon-alpha in Newly Diagnosed High-grade Gliomas
NCT02629757	PHASE3	UNKNOWN	A Study on β-elemene as Maintain Treatment for Newly Diagnosed Malignant Gliomas
NCT02796261	PHASE3	UNKNOWN	Study to Evaluate Eflornithine + Lomustine vs Lomustine in Recurrent Anaplastic Astrocytoma (AA) Patients
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00003470	PHASE2	COMPLETED	Antineoplaston Therapy in Treating Patients With Anaplastic Astrocytoma
NCT00004688	PHASE2	COMPLETED	Phase II Study of Carmustine, Streptozocin, and Mercaptopurine for Refractory or Recurrent Brain Neoplasms
NCT00062504	PHASE2	TERMINATED	Phase 2 Trial Using Talampanel in Patients With Recurrent High Grade Gliomas
NCT00100802	PHASE2	COMPLETED	Radiation Therapy, Temozolomide, and Lomustine in Treating Young Patients With Newly Diagnosed Gliomas
NCT00114309	PHASE2	UNKNOWN	131-I-TM-601 Study in Adults With Recurrent High-Grade Glioma
NCT00243490	PHASE2	WITHDRAWN	Photodynamic Therapy in the Treatment of Malignant Intracranial Tumors
NCT00409214	PHASE2	COMPLETED	Phase IIa Safety and Light Dose-escalation Study in Patients With Primary or Recurrent/High-grade Glioma Using the Litx™ System to Confirm the Zone of Tumor Destruction During the Intraoperative Treatment of Glioma
NCT00431561	PHASE2	COMPLETED	Phase IIb Clinical Trial With TGF-β2 Antisense Compound AP 12009 for Recurrent or Refractory High-grade Glioma
NCT00589875	PHASE2	COMPLETED	Phase 2a Study of CAN-2409 With Standard Radiation Therapy for Malignant Glioma
NCT00606008	PHASE2	COMPLETED	A Phase II Trial of Sutent (Sunitinib; SU011248) for Recurrent Anaplastic Astrocytoma and Glioblastoma
NCT00667394	PHASE2	COMPLETED	Tandutinib Plus Bevacizumab to Treat Recurrent Brain Tumors
NCT00879437	PHASE2	COMPLETED	Valproic Acid, Radiation, and Bevacizumab in Children With High Grade Gliomas or Diffuse Intrinsic Pontine Glioma
NCT00995007	PHASE2	COMPLETED	A Randomized Phase II Trial of Vandetanib (ZD6474) in Combination With Carboplatin Versus Carboplatin Alone Followed by Vandetanib Alone in Adults With Recurrent High-Grade Gliomas
NCT01095094	PHASE2	TERMINATED	Ritonavir and Lopinavir in Treating Patients With Progressive or Recurrent High-Grade Glioma
NCT01204684	PHASE2	COMPLETED	Dendritic Cell Vaccine for Patients With Brain Tumors
NCT01227434	PHASE2	TERMINATED	A Study of PD 0332991 in Patients With Recurrent Rb Positive Glioblastoma
NCT01380782	PHASE2	COMPLETED	BIBF 1120 for Recurrent High-Grade Gliomas
NCT01663012	PHASE2	COMPLETED	Phase II NKTR-102 In Bevacizumab-Resistant High Grade Glioma
NCT01836549	PHASE2	TERMINATED	Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors
NCT02372409	PHASE2	TERMINATED	Using MRI-Guided Laser Heat Ablation to Induce Disruption of the Peritumoral Blood Brain Barrier to Enhance Delivery and Efficacy of Treatment of Pediatric Brain Tumors
NCT02684058	PHASE2	COMPLETED	Study of Efficacy and Safety of Dabrafenib in Combination With Trametinib in Pediatric Patients With BRAF V600 Mutation Positive LGG or Relapsed or Refractory HGG Tumors
NCT02758366	PHASE2	TERMINATED	Prolonged Exposure to Doxorubicin in Patients With Glioblastoma Multiforme and Diffuse Intrinsic Pontine Glioma