Radioulnar synostosis with amegakaryocytic thrombocytopenia 1

Summary

Radioulnar synostosis with amegakaryocytic thrombocytopenia 1 (MONDO:0024558) is a disease caused by HOXA11 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: HOXA11 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	radioulnar synostosis with amegakaryocytic thrombocytopenia 1
Mondo ID	MONDO:0024558
OMIM	605432
UMLS	C4551975
MedGen	1637913
GARD	0018068
Is cancer (heuristic)	no

Also known as: HOXA11 radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome · radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome caused by mutation in HOXA11 · radioulnar synostosis with amegakaryocytic thrombocytopenia 1 · RUSAT1

Data availability: 14 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › hematologic disorder › congenital hematological disorder › radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome › radioulnar synostosis with amegakaryocytic thrombocytopenia 1

Related subtypes (1): radioulnar synostosis with amegakaryocytic thrombocytopenia 2

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

14 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 1 pathogenic, 1 conflicting classifications of pathogenicity, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
14897	NM_005523.6(HOXA11):c.872del (p.Asn291fs)	HOXA11	Pathogenic	no assertion criteria provided
1675087	NM_005523.6(HOXA11):c.396G>C (p.Arg132Ser)	HOXA11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306559	NM_005523.6(HOXA11):c.152T>A (p.Leu51Gln)	HOXA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
2671724	NM_005523.6(HOXA11):c.451C>A (p.Pro151Thr)	HOXA11	Uncertain significance	criteria provided, single submitter
3106549	NM_005523.6(HOXA11):c.10G>C (p.Asp4His)	HOXA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
3379742	NM_005523.6(HOXA11):c.644G>T (p.Arg215Leu)	HOXA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
3379743	NM_005523.6(HOXA11):c.531GGC[7] (p.Ala183_Thr184insAlaAla)	HOXA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
3526229	NM_005523.6(HOXA11):c.403G>A (p.Val135Ile)	HOXA11	Uncertain significance	criteria provided, multiple submitters, no conflicts
3766596	NM_005523.6(HOXA11):c.380A>G (p.Tyr127Cys)	HOXA11	Uncertain significance	criteria provided, single submitter
4277653	NM_005523.6(HOXA11):c.112_113dup (p.Ser39fs)	HOXA11	Uncertain significance	criteria provided, single submitter
3891341	NM_005523.6(HOXA11):c.328A>C (p.Ser110Arg)	LOC107126281	Uncertain significance	criteria provided, single submitter
3898018	NM_004991.4(MECOM):c.1123C>T (p.Pro375Ser)	MECOM	Uncertain significance	criteria provided, single submitter
4086168	NM_004991.4(MECOM):c.604G>C (p.Asp202His)	MECOM	Uncertain significance	criteria provided, single submitter
4685781	NM_005523.6(HOXA11):c.348C>T (p.His116=)	HOXA11	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 3 · 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
HOXA11	Strong	Autosomal dominant	radioulnar synostosis with amegakaryocytic thrombocytopenia 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HOXA11	Orphanet:71289	Radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome
MECOM	Orphanet:402020	Acute myeloid leukemia with inv(3)(q21q26.2) or t(3;3)(q21;q26.2)
MECOM	Orphanet:71289	Radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HOXA11	HGNC:5101	ENSG00000005073	P31270	Homeobox protein Hox-A11	gencc,clinvar
MECOM	HGNC:3498	ENSG00000085276	Q03112	Histone-lysine N-methyltransferase MECOM	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HOXA11	Homeobox protein Hox-A11	Sequence-specific transcription factor which is part of a developmental regulatory system that provides cells with specific positional identities on the anterior-posterior axis.
MECOM	Histone-lysine N-methyltransferase MECOM	Functions as a transcriptional regulator binding to DNA sequences in the promoter region of target genes and regulating positively or negatively their expression.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.0

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
Transcription factor	2	8.3×	0.015

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HOXA11	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
MECOM	Transcription factor	no		SET_dom, Znf_C2H2_type, Znf_C2H2_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of uterus	1
endocervix	1
myometrium	1
cardia of stomach	1
pylorus	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HOXA11	98	broad	marker	body of uterus, myometrium, endocervix
MECOM	276	ubiquitous	marker	cardia of stomach, renal medulla, pylorus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECOM	2,442
HOXA11	1,131

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MECOM	Q03112	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HOXA11	P31270	62.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Kidney development	1	407.9×	0.016	MECOM
Formation of the nephric duct	1	317.2×	0.016	MECOM
Formation of the ureteric bud	1	248.3×	0.016	HOXA11
PTEN Regulation	1	114.2×	0.025	MECOM
Regulation of PTEN gene transcription	1	89.2×	0.025	MECOM
PKMTs methylate histone lysines	1	80.4×	0.025	MECOM
Intracellular signaling by second messengers	1	45.7×	0.036	MECOM
Chromatin organization	1	40.8×	0.036	MECOM
Chromatin modifying enzymes	1	36.1×	0.036	MECOM
PIP3 activates AKT signaling	1	33.4×	0.036	MECOM
Developmental Biology	1	7.2×	0.146	MECOM
Signal Transduction	1	5.1×	0.187	MECOM

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of cell development	1	8426.0×	0.002	HOXA11
positive regulation of chondrocyte development	1	8426.0×	0.002	HOXA11
cartilage development involved in endochondral bone morphogenesis	1	1203.7×	0.007	HOXA11
mesodermal cell fate specification	1	1053.2×	0.007	HOXA11
embryonic skeletal joint morphogenesis	1	766.0×	0.007	HOXA11
prostate gland development	1	702.2×	0.007	HOXA11
heterochromatin organization	1	648.1×	0.007	MECOM
organ induction	1	601.9×	0.007	HOXA11
positive regulation of DNA-templated transcription	2	27.9×	0.007	HOXA11, MECOM
chondrocyte development	1	468.1×	0.007	HOXA11
positive regulation of chondrocyte differentiation	1	401.2×	0.007	HOXA11
uterus development	1	401.2×	0.007	HOXA11
negative regulation of programmed cell death	1	366.4×	0.007	MECOM
developmental growth	1	366.4×	0.007	HOXA11
proximal/distal pattern formation	1	324.1×	0.007	HOXA11
hematopoietic stem cell proliferation	1	324.1×	0.007	MECOM
negative regulation of JNK cascade	1	280.9×	0.008	MECOM
metanephros development	1	255.3×	0.008	HOXA11
embryonic forelimb morphogenesis	1	247.8×	0.008	HOXA11
response to testosterone	1	234.1×	0.008	HOXA11
dorsal/ventral pattern formation	1	210.7×	0.008	HOXA11
embryonic limb morphogenesis	1	200.6×	0.008	HOXA11
branching involved in ureteric bud morphogenesis	1	183.2×	0.009	HOXA11
response to estrogen	1	172.0×	0.009	HOXA11
embryonic digit morphogenesis	1	150.5×	0.010	HOXA11
regulation of transcription by RNA polymerase II	2	11.7×	0.010	HOXA11, MECOM
single fertilization	1	91.6×	0.015	HOXA11
anterior/posterior pattern specification	1	90.6×	0.015	HOXA11
methylation	1	85.1×	0.015	MECOM
protein maturation	1	81.8×	0.015	MECOM

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HOXA11	0	0
MECOM	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MECOM	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	HOXA11, MECOM

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)
HOXA11	0	—
MECOM	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.