Congenital radioulnar synostosis

Summary

Congenital radioulnar synostosis (MONDO:0017985) is a disease with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 79
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		350	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0002818	Abnormal morphology of the radius	Very frequent (80-99%)
HP:0002974	Radioulnar synostosis	Very frequent (80-99%)
HP:0002996	Limited elbow movement	Very frequent (80-99%)
HP:0006394	Limited pronation/supination of forearm	Very frequent (80-99%)
HP:0040071	Abnormal morphology of ulna	Very frequent (80-99%)
HP:0001457	Abnormality of the musculature of the upper arm	Occasional (5-29%)
HP:0003083	Dislocated radial head	Occasional (5-29%)
HP:0030834	Shoulder pain	Occasional (5-29%)
HP:0030836	Wrist pain	Occasional (5-29%)
HP:0001159	Syndactyly	Very rare (<1-4%)
HP:0001374	Congenital hip dislocation	Very rare (<1-4%)
HP:0001762	Talipes equinovarus	Very rare (<1-4%)
HP:0010442	Polydactyly	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital radioulnar synostosis
Mondo ID	MONDO:0017985
MeSH	C562408
Orphanet	3269
DOID	DOID:9827
ICD-11	1098526181
SNOMED CT	33313004
UMLS	C0158761
MedGen	57861
GARD	0010876
Is cancer (heuristic)	no

Also known as: proximal, smooth fusion of 2-6 CM between the radius and ulna and absent head of the radius · radial-ulnar synostosis · radio-ulnar synostosis · radio-ulnar synostosis type 1 · radioulnar fusion · radioulnar synostosis · radioulnar synostosis (disease)

Data availability: 79 ClinVar variants · 3 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › dysostosis › synostosis › congenital radioulnar synostosis

Related subtypes (10): Banki syndrome, humeroradial synostosis, calcaneonavicular coalition, craniosynostosis, tibio-fibular synostosis, multiple synostoses syndrome, humero-radio-ulnar synostosis, humero-ulnar synostosis, coronal synostosis, syndactyly and jejunal atresia, non-syndromic pansynostosis

Subtypes (3): radioulnar synostosis-developmental delay-hypotonia syndrome, radio-ulnar synostosis, unilateral, radio-ulnar synostosis, bilateral

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

79 retrieved; paginated sample, class counts are floors:

28 pathogenic, 26 uncertain significance, 12 likely pathogenic, 9 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 2 uncertain significance; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1334182	NM_004991.4(MECOM):c.2905C>T (p.Arg969Cys)	MECOM	Pathogenic	no assertion criteria provided
1334186	NM_004991.4(MECOM):c.2906G>A (p.Arg969His)	MECOM	Pathogenic	no assertion criteria provided
1174545	NM_005585.5(SMAD6):c.957_958insGCAA (p.Ser320fs)	SMAD6	Pathogenic	no assertion criteria provided
1174547	NM_005585.5(SMAD6):c.3dup (p.Phe2fs)	SMAD6	Pathogenic	no assertion criteria provided
1174549	NM_005585.5(SMAD6):c.1012G>T (p.Glu338Ter)	SMAD6	Pathogenic	no assertion criteria provided
1174551	NM_005585.5(SMAD6):c.872del (p.Leu291fs)	SMAD6	Pathogenic	no assertion criteria provided
1174552	NM_005585.5(SMAD6):c.859G>T (p.Glu287Ter)	SMAD6	Pathogenic	no assertion criteria provided
1174553	NM_005585.5(SMAD6):c.439_457dup (p.Ala153fs)	SMAD6	Pathogenic	no assertion criteria provided
1174556	NM_005585.5(SMAD6):c.1416G>A (p.Trp472Ter)	SMAD6	Pathogenic	no assertion criteria provided
1174562	NM_005585.5(SMAD6):c.1309A>T (p.Lys437Ter)	SMAD6	Pathogenic	no assertion criteria provided
1174563	NM_005585.5(SMAD6):c.24del (p.Leu9fs)	SMAD6	Pathogenic	no assertion criteria provided
1174564	NM_005585.5(SMAD6):c.232_250del (p.Gln78fs)	SMAD6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1174568	NM_005585.5(SMAD6):c.283del (p.Glu95fs)	SMAD6	Pathogenic	no assertion criteria provided
1174569	NM_005585.5(SMAD6):c.294del (p.Gly99fs)	SMAD6	Pathogenic	no assertion criteria provided
1174570	NM_005585.5(SMAD6):c.325del (p.Glu109fs)	SMAD6	Pathogenic	no assertion criteria provided
1174571	NM_005585.5(SMAD6):c.67del (p.Glu23fs)	SMAD6	Pathogenic	no assertion criteria provided
1174574	NM_005585.5(SMAD6):c.511G>A (p.Glu171Lys)	SMAD6	Pathogenic	no assertion criteria provided
1174576	NM_005585.5(SMAD6):c.1227del (p.Ile410fs)	SMAD6	Pathogenic	no assertion criteria provided
1174578	NM_005585.5(SMAD6):c.1419del (p.Cys475fs)	SMAD6	Pathogenic	no assertion criteria provided
1174579	NM_005585.5(SMAD6):c.1285A>T (p.Lys429Ter)	SMAD6	Pathogenic	no assertion criteria provided
1174580	NM_005585.5(SMAD6):c.1010G>A (p.Trp337Ter)	SMAD6	Pathogenic	no assertion criteria provided
1174581	NM_005585.5(SMAD6):c.1132G>T (p.Glu378Ter)	SMAD6	Pathogenic	no assertion criteria provided
1174584	NM_005585.5(SMAD6):c.217G>T (p.Gly73Ter)	SMAD6	Pathogenic	no assertion criteria provided
1174585	NM_005585.5(SMAD6):c.1099dup (p.Cys367fs)	SMAD6	Pathogenic	no assertion criteria provided
1174586	NM_005585.5(SMAD6):c.165C>A (p.Cys55Ter)	SMAD6	Pathogenic	no assertion criteria provided
1342165	NM_005585.5(SMAD6):c.652C>T (p.Gln218Ter)	SMAD6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
690419	NM_005585.5(SMAD6):c.345G>A (p.Trp115Ter)	SMAD6	Pathogenic	criteria provided, single submitter
690420	NM_005585.5(SMAD6):c.943G>T (p.Glu315Ter)	SMAD6	Pathogenic	no assertion criteria provided
690422	NM_005585.5(SMAD6):c.106dup (p.Asp36fs)	SMAD6	Pathogenic	no assertion criteria provided
690424	NM_005585.5(SMAD6):c.589del (p.Ser197fs)	SMAD6	Pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · 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
SMAD6	Strong	Autosomal dominant	radioulnar synostosis, nonsyndromic, susceptibility to	14
ZMAT2	Limited	Autosomal dominant	congenital radioulnar synostosis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMAD6	Orphanet:402075	Familial bicuspid aortic valve
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

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMAD6	HGNC:6772	ENSG00000137834	O43541	SMAD family member 6	gencc,clinvar
ZMAT2	HGNC:26433	ENSG00000146007	Q96NC0	Zinc finger matrin-type protein 2	gencc
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)
SMAD6	SMAD family member 6	Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators.
ZMAT2	Zinc finger matrin-type protein 2	Involved in pre-mRNA splicing as a component of the spliceosome.
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: 1 · 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	5.5×	0.081
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMAD6	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
ZMAT2	Transcription factor	no		Matrin/U1-like-C_Znf_C2H2, Znf_C2H2_jaz, Znf_C2H2_sf
MECOM	Transcription factor	no		SET_dom, Znf_C2H2_type, Znf_C2H2_sf

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
metanephric glomerulus	1
renal glomerulus	1
right lung	1
cortical plate	1
islet of Langerhans	1
monocyte	1
cardia of stomach	1
pylorus	1
renal medulla	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMAD6	277	ubiquitous	marker	right lung, renal glomerulus, metanephric glomerulus
ZMAT2	261	ubiquitous	marker	cortical plate, monocyte, islet of Langerhans
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
SMAD6	2,006
ZMAT2	1,645

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ZMAT2	Q96NC0	13
MECOM	Q03112	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SMAD6	O43541	72.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. 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
RUNX2 regulates bone development	1	271.9×	0.030	SMAD6
Kidney development	1	271.9×	0.030	MECOM
Formation of the nephric duct	1	211.5×	0.030	MECOM
Signaling by BMP	1	119.0×	0.040	SMAD6
Transcriptional regulation by RUNX2	1	84.6×	0.041	SMAD6
PTEN Regulation	1	76.1×	0.041	MECOM
Regulation of PTEN gene transcription	1	59.5×	0.044	MECOM
PKMTs methylate histone lysines	1	53.6×	0.044	MECOM
Signaling by TGFB family members	1	38.5×	0.051	SMAD6
Signal Transduction	2	6.8×	0.051	SMAD6, MECOM
Intracellular signaling by second messengers	1	30.4×	0.056	MECOM
Chromatin organization	1	27.2×	0.058	MECOM
Chromatin modifying enzymes	1	24.1×	0.060	MECOM
PIP3 activates AKT signaling	1	22.3×	0.060	MECOM
mRNA Splicing - Major Pathway	1	18.2×	0.068	ZMAT2
RNA Polymerase II Transcription	1	7.5×	0.151	SMAD6
Gene expression (Transcription)	1	6.0×	0.178	SMAD6
Generic Transcription Pathway	1	5.0×	0.194	SMAD6
Developmental Biology	1	4.8×	0.194	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
zygotic specification of dorsal/ventral axis	1	1872.4×	0.013	SMAD6
response to laminar fluid shear stress	1	1404.3×	0.013	SMAD6
mitral valve morphogenesis	1	561.7×	0.013	SMAD6
negative regulation of activin receptor signaling pathway	1	468.1×	0.013	SMAD6
heterochromatin organization	1	432.1×	0.013	MECOM
pulmonary valve morphogenesis	1	312.1×	0.013	SMAD6
cell-substrate adhesion	1	255.3×	0.013	SMAD6
negative regulation of programmed cell death	1	244.2×	0.013	MECOM
SMAD protein signal transduction	1	244.2×	0.013	SMAD6
outflow tract septum morphogenesis	1	216.1×	0.013	SMAD6
hematopoietic stem cell proliferation	1	216.1×	0.013	MECOM
negative regulation of ossification	1	208.1×	0.013	SMAD6
coronary vasculature development	1	208.1×	0.013	SMAD6
negative regulation of SMAD protein signal transduction	1	200.6×	0.013	SMAD6
aorta development	1	187.2×	0.013	SMAD6
negative regulation of JNK cascade	1	187.2×	0.013	MECOM
ventricular septum development	1	165.2×	0.014	SMAD6
ureteric bud development	1	151.8×	0.015	SMAD6
aortic valve morphogenesis	1	144.0×	0.015	SMAD6
response to estrogen	1	114.6×	0.017	SMAD6
negative regulation of osteoblast differentiation	1	98.5×	0.018	SMAD6
negative regulation of BMP signaling pathway	1	96.8×	0.018	SMAD6
positive regulation of miRNA transcription	1	96.8×	0.018	SMAD6
BMP signaling pathway	1	66.9×	0.025	SMAD6
fat cell differentiation	1	60.4×	0.026	SMAD6
negative regulation of transforming growth factor beta receptor signaling pathway	1	57.9×	0.026	SMAD6
methylation	1	56.7×	0.026	MECOM
protein maturation	1	54.5×	0.026	MECOM
anatomical structure morphogenesis	1	46.4×	0.029	SMAD6
regulation of transcription by RNA polymerase II	2	7.8×	0.029	SMAD6, MECOM

Therapeutics

Drug target analysis

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

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
SMAD6	0	0
ZMAT2	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: 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SMAD6, ZMAT2, MECOM

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)
SMAD6	0	—
ZMAT2	0	—
MECOM	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.