ATR-X-related syndrome

Summary

ATR-X-related syndrome (MONDO:0016980) is a disease caused by ATRX (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: ATRX (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 13

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ATR-X-related syndrome
Mondo ID	MONDO:0016980
Orphanet	263355
Is cancer (heuristic)	no

Also known as: ATR-X-related syndrome

Data availability: 13 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › syndromic intellectual disability › X-linked syndromic intellectual disability › ATR-X-related syndrome

Related subtypes (80): X-linked intellectual disability-psychosis-macroorchidism syndrome, X-linked intellectual disability-plagiocephaly syndrome, intellectual disability, X-linked 49, MEHMO syndrome, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability, Stocco dos Santos type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, corpus callosum agenesis-intellectual disability-coloboma-micrognathia syndrome, X-linked intellectual disability-cerebellar hypoplasia syndrome, Allan-Herndon-Dudley syndrome, syndromic X-linked intellectual disability Claes-Jensen type, X-linked intellectual disability-retinitis pigmentosa syndrome, syndromic X-linked intellectual disability 14, syndromic X-linked intellectual disability 94, intellectual disability, X-linked syndromic, Turner type, syndromic X-linked intellectual disability Shrimpton type, X-linked intellectual disability-craniofacioskeletal syndrome, syndromic X-linked intellectual disability Raymond type, syndromic X-linked intellectual disability 17, syndromic X-linked intellectual disability Nascimento type, syndromic X-linked intellectual disability Chudley-Schwartz type, X-linked intellectual disability-cardiomegaly-congestive heart failure syndrome, X-linked intellectual disability, Cantagrel type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, intellectual disability, X-linked 99, syndromic, female-restricted, intellectual disability, X-linked, syndromic, Bain type, Borjeson-Forssman-Lehmann syndrome, Coffin-Lowry syndrome, syndromic X-linked intellectual disability 5, X-linked intellectual disability-seizures-psoriasis syndrome, Renpenning syndrome, Partington syndrome, syndromic X-linked intellectual disability 12, severe X-linked intellectual disability, Gustavson type, syndromic X-linked intellectual disability Snyder type, Wilson-Turner syndrome, Prieto syndrome, skeletal dysplasia-intellectual disability syndrome, X-linked intellectual disability-spastic quadriparesis syndrome, early-onset parkinsonism-intellectual disability syndrome, X-linked intellectual disability, Schimke type, X-linked intellectual disability, Cilliers type, X-linked intellectual disability, van Esch type, X-linked intellectual disability-epilepsy syndrome, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, X-linked intellectual disability, Schutz type, X-linked intellectual disability-hypotonia-movement disorder syndrome, X-linked intellectual disability with isolated growth hormone deficiency, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-precocious puberty-obesity syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability-macrocephaly-macroorchidism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Seemanova type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, X-linked intellectual disability-acromegaly-hyperactivity syndrome, X-linked intellectual disability-corpus callosum agenesis-spastic quadriparesis syndrome, fried syndrome, X-linked intellectual disability-ataxia-apraxia syndrome, intellectual developmental disorder, X-linked, syndromic, Pilorge type, Paganini-Miozzo syndrome, intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type, intellectual disability, X-linked, syndromic, 35, intellectual disability, X-linked, syndromic, Houge type, MED12-related intellectual disability syndrome, NAA10-related syndrome, ATP6AP2-related disorder, X-linked intellectual disability with hypopituitarism, SOX3-related X-linked pituitary hormone deficiency with or without intellectual developmental disorder, intellectual developmental disorder, X-linked, syndromic, with pigmentary mosaicism and coarse facies, intellectual developmental disorder, X-linked, syndromic 37, CASK-related intellectual disability

Subtypes (2): alpha thalassemia-X-linked intellectual disability syndrome, intellectual disability-hypotonic facies syndrome, X-linked, 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

13 retrieved; paginated sample, class counts are floors:

7 uncertain significance, 2 pathogenic, 2 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073930	NM_000489.6(ATRX):c.1960C>T (p.Arg654Ter)	ATRX	Pathogenic	criteria provided, multiple submitters, no conflicts
4531355	NM_000489.6(ATRX):c.4510C>T (p.Arg1504Ter)	ATRX	Pathogenic	criteria provided, single submitter
3377337	NM_000489.6(ATRX):c.5786+1del	ATRX	Likely pathogenic	criteria provided, single submitter
1077999	NM_000489.6(ATRX):c.1615C>G (p.Gln539Glu)	ATRX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
589005	NM_000489.6(ATRX):c.1168C>T (p.Arg390Cys)	ATRX	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
587606	NM_001184.4(ATR):c.3152G>A (p.Arg1051His)	ATR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1896780	NM_000489.6(ATRX):c.346A>G (p.Ile116Val)	ATRX	Uncertain significance	criteria provided, multiple submitters, no conflicts
3377336	NM_000489.6(ATRX):c.5870T>C (p.Val1957Ala)	ATRX	Uncertain significance	criteria provided, single submitter
3780650	NM_000489.6(ATRX):c.3305G>T (p.Arg1102Met)	ATRX	Uncertain significance	criteria provided, single submitter
3780655	NM_000489.6(ATRX):c.3637C>G (p.Gln1213Glu)	ATRX	Uncertain significance	criteria provided, single submitter
4070910	Single allele	ATRX	Uncertain significance	criteria provided, single submitter
4531354	NM_000489.6(ATRX):c.5687A>C (p.Lys1896Thr)	ATRX	Uncertain significance	criteria provided, single submitter
696189	NM_000489.6(ATRX):c.1303A>G (p.Ile435Val)	ATRX	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ATRX	Strong	X-linked	ATR-X-related syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATRX	Orphanet:100075	Neuroendocrine tumor of stomach
ATRX	Orphanet:231401	Alpha-thalassemia-myelodysplastic syndrome
ATRX	Orphanet:847	X-linked alpha-thalassemia-intellectual disability syndrome
ATRX	Orphanet:96253	Cushing disease
ANTXR1	Orphanet:2067	GAPO syndrome
ATR	Orphanet:313846	Familial cutaneous telangiectasia and oropharyngeal cancer predisposition syndrome
ATR	Orphanet:808	Seckel syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATRX	HGNC:886	ENSG00000085224	P46100	Transcriptional regulator ATRX	gencc,clinvar
ANTXR1	HGNC:21014	ENSG00000169604	Q9H6X2	Anthrax toxin receptor 1	clinvar
ATR	HGNC:882	ENSG00000175054	Q13535	Serine/threonine-protein kinase ATR	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATRX	Transcriptional regulator ATRX	Involved in transcriptional regulation and chromatin remodeling.
ANTXR1	Anthrax toxin receptor 1	Plays a role in cell attachment and migration.
ATR	Serine/threonine-protein kinase ATR	Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	9.2×	0.313
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATRX	Transcription factor	no		SNF2_N, Helicase_C-like, Znf_FYVE_PHD
ANTXR1	Other/Unknown	no		VWF_A, Anthrax_toxin_rcpt_C, Anthrax_toxin_rcpt_extracel
ATR	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
colonic epithelium	1
endothelial cell	1
decidua	1
palpebral conjunctiva	1
stromal cell of endometrium	1
Brodmann (1909) area 23	1
adrenal tissue	1
epithelium of nasopharynx	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATRX	294	ubiquitous	marker	endothelial cell, calcaneal tendon, colonic epithelium
ANTXR1	270	ubiquitous	marker	stromal cell of endometrium, decidua, palpebral conjunctiva
ATR	289	ubiquitous	marker	Brodmann (1909) area 23, epithelium of nasopharynx, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATRX	5,796
ATR	3,541
ANTXR1	2,039

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATRX	P46100	12
ATR	Q13535	10
ANTXR1	Q9H6X2	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Alternative Lengthening of Telomeres (ALT)	1	3806.7×	0.004	ATRX
Defective Inhibition of DNA Recombination at Telomere	1	3806.7×	0.004	ATRX
Diseases of Telomere Maintenance	1	3806.7×	0.004	ATRX
Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations	1	1903.3×	0.005	ATRX
Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations	1	1903.3×	0.005	ATRX
Cell Cycle	2	24.0×	0.017	ATRX, ATR
Uptake and function of anthrax toxins	1	317.2×	0.018	ANTXR1
Diseases of DNA Double-Strand Break Repair	1	271.9×	0.018	ATR
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	271.9×	0.018	ATR
Diseases of DNA repair	1	190.3×	0.022	ATR
Cellular response to heat stress	1	131.3×	0.022	ATR
Diseases of mitotic cell cycle	1	131.3×	0.022	ATRX
Homologous DNA Pairing and Strand Exchange	1	126.9×	0.022	ATR
Telomere Maintenance	1	122.8×	0.022	ATRX
Homology Directed Repair	1	102.9×	0.022	ATR
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	102.9×	0.022	ATR
Impaired BRCA2 binding to RAD51	1	102.9×	0.022	ATR
Activation of ATR in response to replication stress	1	100.2×	0.022	ATR
HDR through Single Strand Annealing (SSA)	1	97.6×	0.022	ATR
Meiosis	1	95.2×	0.022	ATR
Fanconi Anemia Pathway	1	92.8×	0.022	ATR
Presynaptic phase of homologous DNA pairing and strand exchange	1	90.6×	0.022	ATR
DNA Double-Strand Break Repair	1	82.8×	0.023	ATR
Chromosome Maintenance	1	70.5×	0.026	ATRX
Reproduction	1	63.4×	0.026	ATR
HDR through Homologous Recombination (HRR)	1	63.4×	0.026	ATR
TP53 Regulates Transcription of DNA Repair Genes	1	60.4×	0.026	ATR
Disease	2	8.7×	0.026	ATRX, ATR
Inhibition of DNA recombination at telomere	1	56.0×	0.027	ATRX
Meiotic synapsis	1	47.0×	0.030	ATR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein localization to chromosome, telomeric region	2	1021.3×	6e-05	ATRX, ATR
replication fork processing	2	280.9×	4e-04	ATRX, ATR
post-embryonic forelimb morphogenesis	1	2808.7×	0.003	ATRX
establishment of RNA localization to telomere	1	2808.7×	0.003	ATR
establishment of protein-containing complex localization to telomere	1	2808.7×	0.003	ATR
positive regulation of telomerase catalytic core complex assembly	1	2808.7×	0.003	ATR
negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric	1	2808.7×	0.003	ATRX
nuclear membrane disassembly	1	1872.4×	0.003	ATR
negative regulation of extracellular matrix assembly	1	1404.3×	0.004	ANTXR1
DNA repair	2	42.6×	0.004	ATRX, ATR
chromosome organization involved in meiotic cell cycle	1	1123.5×	0.004	ATRX
positive regulation of nuclear cell cycle DNA replication	1	936.2×	0.005	ATRX
meiotic spindle organization	1	802.5×	0.005	ATRX
subtelomeric heterochromatin formation	1	510.7×	0.007	ATRX
cellular response to hydroxyurea	1	468.1×	0.007	ATRX
response to arsenic-containing substance	1	401.2×	0.008	ATR
Sertoli cell development	1	374.5×	0.008	ATRX
regulation of cellular response to heat	1	351.1×	0.008	ATR
positive regulation of DNA damage response, signal transduction by p53 class mediator	1	330.4×	0.008	ATR
replicative senescence	1	330.4×	0.008	ATR
negative regulation of DNA replication	1	295.6×	0.008	ATR
mitotic G2/M transition checkpoint	1	267.5×	0.009	ATR
seminiferous tubule development	1	255.3×	0.009	ATRX
positive regulation of telomere maintenance via telomerase	1	244.2×	0.009	ATR
cellular response to gamma radiation	1	200.6×	0.010	ATR
regulation of double-strand break repair	1	193.7×	0.010	ATR
nucleobase-containing compound metabolic process	1	175.5×	0.011	ATR
positive regulation of telomere maintenance	1	170.2×	0.011	ATRX
positive regulation of epidermal growth factor receptor signaling pathway	1	165.2×	0.011	ANTXR1
interstrand cross-link repair	1	144.0×	0.012	ATR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATR	8	3
ATRX	0	0
ANTXR1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERALASERTIB	3	ATR
DACTOLISIB	3	ATR
BERZOSERTIB	2	ATR
CAMONSERTIB	2	ATR
TUVUSERTIB	2	ATR
ELIMUSERTIB	1	ATR
M4344	1	ATR
AEW-541	1	ATR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ATR	231	Binding:226, Functional:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATR	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ATR	231

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

8 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CERALASERTIB	3	ATR
DACTOLISIB	3	ATR
BERZOSERTIB	2	ATR
CAMONSERTIB	2	ATR
TUVUSERTIB	2	ATR
ELIMUSERTIB	1	ATR
M4344	1	ATR
AEW-541	1	ATR

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	ATR
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ATRX, ANTXR1

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ATRX	0	—
ANTXR1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.