intellectual disability-hypotonic facies syndrome, X-linked, 1

Summary

intellectual disability-hypotonic facies syndrome, X-linked, 1 (MONDO:0010663) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 118

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability-hypotonic facies syndrome, X-linked, 1
Mondo ID	MONDO:0010663
MeSH	C537445
OMIM	309580
Orphanet	73220, 93970, 93971, 93972, 93973, 93974
DOID	DOID:0080982
SNOMED CT	717763008, 719212004
UMLS	C4759781
MedGen	1676827
GARD	0003521
Is cancer (heuristic)	no

Also known as: Carpenter-Waziri syndrome · Chudley intellectual disability syndrome · Chudley Lowry Hoar syndrome · Chudley mental retardation syndrome · Chudley syndrome 1 · Chudley-Lowry syndrome · Chudley-Lowry-Hoar syndrome · Holmes-Gang syndrome · intellectual disability Smith Fineman Myers type · intellectual disability-hypotonic facies syndrome X-linked, 1 · intellectual disability-hypotonic facies syndrome, X-linked, 1 · intellectual disability-hypotonic facies syndrome, X-linked, type 1 · JMS · Juberg Marsidi syndrome · Juberg-Marsidi mental retardation syndrome · Juberg-Marsidi syndrome · mental retardation Smith Fineman Myers type · mental retardation, X-linked, with growth retardation, deafness, and microgenitalism · mental retardation-hypotonic facies syndrome X-linked, 1 · mental retardation-hypotonic facies syndrome, X-linked, 1 (+12 more)

Data availability: 118 ClinVar variants · 1 GenCC gene-disease record.

Disease family

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 › intellectual disability-hypotonic facies syndrome, X-linked, 1

Related subtypes (1): alpha thalassemia-X-linked intellectual disability syndrome

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

118 retrieved; paginated sample, class counts are floors:

49 uncertain significance, 27 conflicting classifications of pathogenicity, 17 likely pathogenic, 8 pathogenic, 7 pathogenic/likely pathogenic, 5 benign/likely benign, 2 likely benign, 2 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
11728	NM_000489.6(ATRX):c.7156C>T (p.Arg2386Ter)	ATRX	Pathogenic	criteria provided, multiple submitters, no conflicts
11731	NM_000489.6(ATRX):c.6392G>A (p.Arg2131Gln)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11735	NM_000489.6(ATRX):c.736C>T (p.Arg246Cys)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11739	NM_000489.6(ATRX):c.4862C>T (p.Thr1621Met)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11742	NM_000489.6(ATRX):c.109C>T (p.Arg37Ter)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332803	NM_000489.6(ATRX):c.809C>T (p.Pro270Leu)	ATRX	Pathogenic	criteria provided, single submitter
1710155	NM_000489.6(ATRX):c.134-4884_242+41del	ATRX	Pathogenic	no assertion criteria provided
1802595	NM_000489.6(ATRX):c.7366dup (p.Met2456fs)	ATRX	Pathogenic	criteria provided, single submitter
2506580	NM_000489.6(ATRX):c.399_400dup (p.Leu134fs)	ATRX	Pathogenic	no assertion criteria provided
3233402	NM_000489.6(ATRX):c.371-1201G>A	ATRX	Pathogenic	criteria provided, single submitter
372309	NM_000489.6(ATRX):c.6532C>T (p.Arg2178Trp)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372728	NM_000489.6(ATRX):c.6254G>A (p.Arg2085His)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4532784	NM_000489.6(ATRX):c.567C>A (p.His189Gln)	ATRX	Pathogenic	criteria provided, single submitter
689744	NM_000489.6(ATRX):c.477del (p.Lys159fs)	ATRX	Pathogenic	criteria provided, single submitter
93141	NM_000489.6(ATRX):c.536A>G (p.Asn179Ser)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1028792	NM_000489.6(ATRX):c.5449-7A>G	ATRX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172655	NM_000489.6(ATRX):c.5540A>G (p.Tyr1847Cys)	ATRX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
11734	NM_000489.6(ATRX):c.568C>G (p.Pro190Ala)	ATRX	Likely pathogenic	criteria provided, single submitter
1343274	NM_000489.6(ATRX):c.5281A>G (p.Met1761Val)	ATRX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1992338	NM_000489.6(ATRX):c.6127T>C (p.Ser2043Pro)	ATRX	Likely pathogenic	criteria provided, single submitter
2442228	NM_000489.6(ATRX):c.758T>C (p.Leu253Ser)	ATRX	Likely pathogenic	criteria provided, single submitter
3066026	NM_000489.6(ATRX):c.667T>C (p.Cys223Arg)	ATRX	Likely pathogenic	no assertion criteria provided
3258091	NM_000489.6(ATRX):c.4967T>C (p.Leu1656Ser)	ATRX	Likely pathogenic	criteria provided, single submitter
3383180	NM_000489.6(ATRX):c.559T>G (p.Tyr187Asp)	ATRX	Likely pathogenic	criteria provided, single submitter
3598429	NM_000489.6(ATRX):c.7096G>T (p.Glu2366Ter)	ATRX	Likely pathogenic	criteria provided, single submitter
3598430	NM_000489.6(ATRX):c.3010A>T (p.Lys1004Ter)	ATRX	Likely pathogenic	criteria provided, single submitter
3598433	NM_000489.6(ATRX):c.798C>G (p.Tyr266Ter)	ATRX	Likely pathogenic	criteria provided, single submitter
4294308	NM_000489.6(ATRX):c.5651C>T (p.Thr1884Ile)	ATRX	Likely pathogenic	criteria provided, single submitter
4532781	NM_000489.6(ATRX):c.809C>G (p.Pro270Arg)	ATRX	Likely pathogenic	criteria provided, single submitter
635054	NM_000489.6(ATRX):c.6254G>T (p.Arg2085Leu)	ATRX	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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	Definitive	X-linked	alpha thalassemia-X-linked intellectual disability 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
HUWE1	Orphanet:528084	Non-specific syndromic intellectual disability
EPOR	Orphanet:90042	Primary familial polycythemia

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
HUWE1	HGNC:30892	ENSG00000086758	Q7Z6Z7	E3 ubiquitin-protein ligase HUWE1	clinvar
EPOR	HGNC:3416	ENSG00000187266	P19235	Erythropoietin receptor	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.
HUWE1	E3 ubiquitin-protein ligase HUWE1	E3 ubiquitin-protein ligase which mediates ubiquitination and subsequent proteasomal degradation of target proteins.
EPOR	Erythropoietin receptor	Receptor for erythropoietin, which mediates erythropoietin-induced erythroblast proliferation and differentiation.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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
Antibody/Immunoglobulin	1	9.7×	0.298
Enzyme (other)	1	4.0×	0.321
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATRX	Transcription factor	no		SNF2_N, Helicase_C-like, Znf_FYVE_PHD
HUWE1	Enzyme (other)	yes	2.3.2.26	HECT_dom, WWE_dom, UBA-like_sf
EPOR	Antibody/Immunoglobulin	yes		Long_hematopoietin_rcpt_CS, FN3_dom, Erythropoietin_rcpt

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
right lobe of thyroid gland	1
skin of abdomen	1
skin of leg	1
left lobe of thyroid gland	1
olfactory bulb	1
type B pancreatic cell	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
HUWE1	300	ubiquitous	marker	skin of leg, skin of abdomen, right lobe of thyroid gland
EPOR	268	ubiquitous	marker	type B pancreatic cell, olfactory bulb, left lobe of thyroid gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATRX	5,796
HUWE1	5,793
EPOR	1,563

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPOR	P19235	22
HUWE1	Q7Z6Z7	19
ATRX	P46100	12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. 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×	0.002	ATRX
Defective Inhibition of DNA Recombination at Telomere	1	3806.7×	0.002	ATRX
Diseases of Telomere Maintenance	1	3806.7×	0.002	ATRX
Defective Inhibition of DNA Recombination at Telomere Due to DAXX Mutations	1	1903.3×	0.002	ATRX
Defective Inhibition of DNA Recombination at Telomere Due to ATRX Mutations	1	1903.3×	0.002	ATRX
Erythropoietin activates Phospholipase C gamma (PLCG)	1	543.8×	0.005	EPOR
Erythropoietin activates STAT5	1	543.8×	0.005	EPOR
Signaling by Erythropoietin	1	346.1×	0.006	EPOR
Erythropoietin activates Phosphoinositide-3-kinase (PI3K)	1	317.2×	0.006	EPOR
Erythropoietin activates RAS	1	253.8×	0.007	EPOR
Diseases of mitotic cell cycle	1	131.3×	0.012	ATRX
Telomere Maintenance	1	122.8×	0.012	ATRX
Chromosome Maintenance	1	70.5×	0.020	ATRX
Inhibition of DNA recombination at telomere	1	56.0×	0.023	ATRX
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.091	HUWE1
Cell Cycle	1	12.0×	0.091	ATRX
Neutrophil degranulation	1	7.7×	0.132	HUWE1
Disease	1	4.4×	0.212	ATRX

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
post-embryonic forelimb morphogenesis	1	2808.7×	0.008	ATRX
negative regulation of maintenance of mitotic sister chromatid cohesion, telomeric	1	2808.7×	0.008	ATRX
chromosome organization involved in meiotic cell cycle	1	1123.5×	0.008	ATRX
positive regulation of nuclear cell cycle DNA replication	1	936.2×	0.008	ATRX
negative regulation of peroxisome proliferator activated receptor signaling pathway	1	936.2×	0.008	HUWE1
erythropoietin-mediated signaling pathway	1	936.2×	0.008	EPOR
meiotic spindle organization	1	802.5×	0.008	ATRX
negative regulation of mitochondrial fusion	1	702.2×	0.008	HUWE1
subtelomeric heterochromatin formation	1	510.7×	0.008	ATRX
protein localization to chromosome, telomeric region	1	510.7×	0.008	ATRX
positive regulation of type 2 mitophagy	1	510.7×	0.008	HUWE1
cellular response to hydroxyurea	1	468.1×	0.008	ATRX
Sertoli cell development	1	374.5×	0.009	ATRX
protein branched polyubiquitination	1	280.9×	0.011	HUWE1
seminiferous tubule development	1	255.3×	0.012	ATRX
decidualization	1	224.7×	0.012	EPOR
membrane fusion	1	208.1×	0.013	HUWE1
positive regulation of telomere maintenance	1	170.2×	0.014	ATRX
obsolete positive regulation of protein targeting to mitochondrion	1	165.2×	0.014	HUWE1
base-excision repair	1	156.0×	0.014	HUWE1
replication fork processing	1	140.4×	0.015	ATRX
DNA damage response, signal transduction by p53 class mediator	1	119.5×	0.016	ATRX
forebrain development	1	117.0×	0.016	ATRX
protein monoubiquitination	1	114.6×	0.016	HUWE1
circadian regulation of gene expression	1	78.0×	0.023	HUWE1
positive regulation of protein ubiquitination	1	71.1×	0.024	HUWE1
protein K48-linked ubiquitination	1	56.2×	0.029	HUWE1
nucleosome assembly	1	46.8×	0.033	ATRX
multicellular organism growth	1	45.7×	0.033	ATRX
Golgi organization	1	44.6×	0.033	HUWE1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATRX	0	0
HUWE1	0	0
EPOR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
EPOR	9	Binding:9
HUWE1	4	Binding:3, Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HUWE1	2.3.2.26	HECT-type E3 ubiquitin transferase

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

0 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.

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	0
C	Druggable family + PDB, no drug	2	HUWE1, EPOR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ATRX

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATRX	0	—
HUWE1	4	—
EPOR	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.