Radioulnar synostosis with amegakaryocytic thrombocytopenia 2

Summary

Radioulnar synostosis with amegakaryocytic thrombocytopenia 2 (MONDO:0014758) is a disease caused by MECOM (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: MECOM (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 36

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	radioulnar synostosis with amegakaryocytic thrombocytopenia 2
Mondo ID	MONDO:0014758
OMIM	616738
UMLS	C4225221
MedGen	901732
GARD	0018069
Is cancer (heuristic)	no

Also known as: MECOM radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome · radio-ulnar synostosis-amegakaryocytic thrombocytopenia syndrome caused by mutation in MECOM · radioulnar synostosis with amegakaryocytic thrombocytopenia 2 · radioulnar synostosis with amegakaryocytic thrombocytopenia 2; RUSAT2 · radioulnar synostosis with amegakaryocytic thrombocytopenia type 2 · RUSAT2

Data availability: 36 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 2

Related subtypes (1): radioulnar synostosis with amegakaryocytic thrombocytopenia 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

36 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 7 likely pathogenic, 5 pathogenic, 2 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1188840	NM_004991.4(MECOM):c.2849G>C (p.Arg950Thr)	MECOM	Pathogenic	no assertion criteria provided
218951	NM_004991.4(MECOM):c.2830A>G (p.Thr944Ala)	MECOM	Pathogenic	no assertion criteria provided
218952	NM_004991.4(MECOM):c.2816A>G (p.His939Arg)	MECOM	Pathogenic	no assertion criteria provided
218953	NM_004991.4(MECOM):c.2812C>T (p.Arg938Trp)	MECOM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3359122	NM_004991.4(MECOM):c.627T>A (p.Tyr209Ter)	MECOM	Pathogenic	criteria provided, single submitter
3768768	NM_004991.4(MECOM):c.2592_2598del (p.Asp864fs)	MECOM	Pathogenic	criteria provided, single submitter
1676728	NM_004991.4(MECOM):c.2398A>T (p.Lys800Ter)	MECOM	Likely pathogenic	criteria provided, single submitter
1703774	NM_004991.4(MECOM):c.739C>T (p.Gln247Ter)	MECOM	Likely pathogenic	criteria provided, single submitter
2500844	NM_004991.4(MECOM):c.2772-4A>G	MECOM	Likely pathogenic	criteria provided, single submitter
3602676	NM_004991.4(MECOM):c.2836G>A (p.Glu946Lys)	MECOM	Likely pathogenic	criteria provided, single submitter
3775584	NM_004991.4(MECOM):c.2842C>G (p.Pro948Ala)	MECOM	Likely pathogenic	criteria provided, single submitter
4814141	NM_004991.4(MECOM):c.2403del (p.Gly802fs)	MECOM	Likely pathogenic	criteria provided, single submitter
599157	NM_017807.4(OSGEP):c.892A>T (p.Met298Leu)	OSGEP	Likely pathogenic	criteria provided, single submitter
2066867	NM_004991.4(MECOM):c.3013A>G (p.Met1005Val)	MECOM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3124829	NM_004991.4(MECOM):c.1834T>G (p.Phe612Val)	MECOM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2663785	NM_001753.5(CAV1):c.284C>T (p.Thr95Met)	CAV1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1699003	NM_004991.4(MECOM):c.2873_2875del (p.Phe958_Ser959delinsCys)	MECOM	Uncertain significance	criteria provided, single submitter
1703773	NM_004991.4(MECOM):c.1256C>T (p.Ser419Phe)	MECOM	Uncertain significance	criteria provided, single submitter
1703775	NM_004991.4(MECOM):c.2315C>T (p.Pro772Leu)	MECOM	Uncertain significance	criteria provided, single submitter
1805470	NM_004991.4(MECOM):c.2889C>G (p.Asn963Lys)	MECOM	Uncertain significance	criteria provided, single submitter
1805733	NM_004991.4(MECOM):c.2577+4A>T	MECOM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2433683	NM_004991.4(MECOM):c.2327G>A (p.Ser776Asn)	MECOM	Uncertain significance	criteria provided, single submitter
2433684	NM_004991.4(MECOM):c.1384G>T (p.Ala462Ser)	MECOM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2582652	NM_004991.4(MECOM):c.1268A>C (p.His423Pro)	MECOM	Uncertain significance	criteria provided, single submitter
2616701	NM_004991.4(MECOM):c.405C>A (p.Phe135Leu)	MECOM	Uncertain significance	criteria provided, single submitter
2627761	NM_004991.4(MECOM):c.3065C>T (p.Ala1022Val)	MECOM	Uncertain significance	no assertion criteria provided
2731626	NM_004991.4(MECOM):c.1301C>T (p.Ala434Val)	MECOM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2791266	NM_004991.4(MECOM):c.2548C>A (p.Pro850Thr)	MECOM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2869374	NM_004991.4(MECOM):c.782C>T (p.Thr261Met)	MECOM	Uncertain significance	criteria provided, multiple submitters, no conflicts
3235918	NM_004991.4(MECOM):c.375+7162G>T	MECOM	Uncertain significance	criteria provided, single submitter

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
MECOM	Definitive	Autosomal dominant	radioulnar synostosis with amegakaryocytic thrombocytopenia 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
CAV1	Orphanet:220393	Diffuse cutaneous systemic sclerosis
CAV1	Orphanet:220402	Limited cutaneous systemic sclerosis
CAV1	Orphanet:275777	Heritable pulmonary arterial hypertension
CAV1	Orphanet:696206	Congenital generalized lipodystrophy type 3
OSGEP	Orphanet:2065	Galloway-Mowat 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
MECOM	HGNC:3498	ENSG00000085276	Q03112	Histone-lysine N-methyltransferase MECOM	gencc,clinvar
CAV1	HGNC:1527	ENSG00000105974	Q03135	Caveolin-1	clinvar
OSGEP	HGNC:18028	ENSG00000092094	Q9NPF4	tRNA N6-adenosine threonylcarbamoyltransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
CAV1	Caveolin-1	May act as a scaffolding protein within caveolar membranes.
OSGEP	tRNA N6-adenosine threonylcarbamoyltransferase	Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine.

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
Protease	1	12.2×	0.239
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MECOM	Transcription factor	no		SET_dom, Znf_C2H2_type, Znf_C2H2_sf
CAV1	Other/Unknown	no		Caveolin, Caveolin_CS
OSGEP	Protease	yes		Gcp-like_dom, Peptidase_M22_CS, KAE1/TsaD

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
cardia of stomach	1
pylorus	1
renal medulla	1
lower lobe of lung	1
parietal pleura	1
pleura	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MECOM	276	ubiquitous	marker	cardia of stomach, renal medulla, pylorus
CAV1	287	ubiquitous	marker	parietal pleura, lower lobe of lung, pleura
OSGEP	254	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CAV1	6,673
OSGEP	2,733
MECOM	2,442

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
OSGEP	Q9NPF4	2
MECOM	Q03112	1
CAV1	Q03135	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 67. 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
Metabolism of nitric oxide: NOS3 activation and regulation	1	761.3×	0.032	CAV1
NOSTRIN mediated eNOS trafficking	1	761.3×	0.032	CAV1
eNOS activation	1	292.8×	0.032	CAV1
SARS-CoV-2 targets host intracellular signalling and regulatory pathways	1	292.8×	0.032	CAV1
Thyroxine biosynthesis	1	271.9×	0.032	CAV1
Kidney development	1	271.9×	0.032	MECOM
Triglyceride metabolism	1	223.9×	0.032	CAV1
FOXO-mediated transcription of cell cycle genes	1	223.9×	0.032	CAV1
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	223.9×	0.032	CAV1
Formation of the nephric duct	1	211.5×	0.032	MECOM
Triglyceride catabolism	1	158.6×	0.037	CAV1
Basigin interactions	1	146.4×	0.037	CAV1
VEGFR2 mediated vascular permeability	1	135.9×	0.037	CAV1
Disassembly of the destruction complex and recruitment of AXIN to the membrane	1	119.0×	0.037	CAV1
FOXO-mediated transcription	1	112.0×	0.037	CAV1
RHOH GTPase cycle	1	102.9×	0.037	CAV1
tRNA modification in the nucleus and cytosol	1	97.6×	0.037	OSGEP
RND1 GTPase cycle	1	88.5×	0.037	CAV1
RHOF GTPase cycle	1	86.5×	0.037	CAV1
RND3 GTPase cycle	1	86.5×	0.037	CAV1
RND2 GTPase cycle	1	86.5×	0.037	CAV1
PTEN Regulation	1	76.1×	0.040	MECOM
Signaling by VEGF	1	73.2×	0.040	CAV1
RHOD GTPase cycle	1	68.0×	0.040	CAV1
RHOJ GTPase cycle	1	66.8×	0.040	CAV1
RHOQ GTPase cycle	1	60.4×	0.040	CAV1
Regulation of PTEN gene transcription	1	59.5×	0.040	MECOM
SARS-CoV-1-host interactions	1	58.6×	0.040	CAV1
Extra-nuclear estrogen signaling	1	56.8×	0.040	CAV1
PKMTs methylate histone lysines	1	53.6×	0.041	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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of the force of heart contraction by chemical signal	1	2808.7×	0.008	CAV1
intracellular nitric oxide homeostasis	1	1872.4×	0.008	CAV1
insulin receptor internalization	1	1872.4×	0.008	CAV1
regulation of membrane repolarization during action potential	1	1872.4×	0.008	CAV1
protein localization to basolateral plasma membrane	1	1872.4×	0.008	CAV1
protein localization to plasma membrane raft	1	1404.3×	0.008	CAV1
negative regulation of pinocytosis	1	1404.3×	0.008	CAV1
tRNA threonylcarbamoyladenosine modification	1	1123.5×	0.008	OSGEP
maintenance of protein location in cell	1	1123.5×	0.008	CAV1
cellular response to hyperoxia	1	1123.5×	0.008	CAV1
caveolin-mediated endocytosis	1	1123.5×	0.008	CAV1
regulation of entry of bacterium into host cell	1	1123.5×	0.008	CAV1
mammary gland involution	1	936.2×	0.008	CAV1
positive regulation of gap junction assembly	1	802.5×	0.008	CAV1
glandular epithelial cell differentiation	1	702.2×	0.008	CAV1
caveola assembly	1	702.2×	0.008	CAV1
regulation of ruffle assembly	1	702.2×	0.008	CAV1
negative regulation of cytokine-mediated signaling pathway	1	624.1×	0.008	CAV1
regulation of fatty acid metabolic process	1	624.1×	0.008	CAV1
regulation of blood coagulation	1	624.1×	0.008	CAV1
regulation of cardiac muscle cell action potential involved in regulation of contraction	1	624.1×	0.008	CAV1
regulation of cell communication by electrical coupling involved in cardiac conduction	1	624.1×	0.008	CAV1
receptor-mediated endocytosis of virus by host cell	1	510.7×	0.008	CAV1
angiotensin-activated signaling pathway	1	510.7×	0.008	CAV1
nitric oxide metabolic process	1	468.1×	0.008	CAV1
cellular response to misfolded protein	1	468.1×	0.008	CAV1
regulation of ventricular cardiac muscle cell action potential	1	468.1×	0.008	CAV1
negative regulation of potassium ion transmembrane transport	1	468.1×	0.008	CAV1
heterochromatin organization	1	432.1×	0.008	MECOM
regulation of smooth muscle contraction	1	401.2×	0.008	CAV1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MECOM	0	0
CAV1	0	0
OSGEP	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
CAV1	5	Binding:5
MECOM	1	Binding:1
OSGEP	1	Binding:1

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	1	OSGEP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	MECOM, CAV1

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)
MECOM	1	—
CAV1	5	—
OSGEP	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.