Aneurysm-osteoarthritis syndrome

Summary

Aneurysm-osteoarthritis syndrome (MONDO:0013426) is a disease caused by SMAD3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SMAD3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 369
• Phenotypes (HPO): 51

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		45	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

51 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001763	Pes planus	Very frequent (80-99%)
HP:0002617	Dilatation	Very frequent (80-99%)
HP:0011645	Dilatation of the sinus of Valsalva	Very frequent (80-99%)
HP:0000023	Inguinal hernia	Frequent (30-79%)
HP:0000139	Uterine prolapse	Frequent (30-79%)
HP:0000193	Bifid uvula	Frequent (30-79%)
HP:0000218	High palate	Frequent (30-79%)
HP:0000272	Malar flattening	Frequent (30-79%)
HP:0000276	Long face	Frequent (30-79%)
HP:0000316	Hypertelorism	Frequent (30-79%)
HP:0000348	High forehead	Frequent (30-79%)
HP:0000689	Dental malocclusion	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0000987	Atypical scarring of skin	Frequent (30-79%)
HP:0001065	Striae distensae	Frequent (30-79%)
HP:0001166	Arachnodactyly	Frequent (30-79%)
HP:0001537	Umbilical hernia	Frequent (30-79%)
HP:0001653	Mitral regurgitation	Frequent (30-79%)
HP:0001659	Aortic regurgitation	Frequent (30-79%)
HP:0002076	Migraine	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002647	Aortic dissection	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002758	Osteoarthritis	Frequent (30-79%)
HP:0003179	Protrusio acetabuli	Frequent (30-79%)
HP:0004268	Osteoarthritis of the small joints of the hand	Frequent (30-79%)
HP:0004944	Dilatation of the cerebral artery	Frequent (30-79%)
HP:0005086	Knee osteoarthritis	Frequent (30-79%)
HP:0005116	Arterial tortuosity	Frequent (30-79%)
HP:0005294	Arterial dissection	Frequent (30-79%)
HP:0012432	Chronic fatigue	Frequent (30-79%)
HP:0025487	Abnormality of bladder morphology	Frequent (30-79%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0000768	Pectus carinatum	Occasional (5-29%)
HP:0001382	Joint hypermobility	Occasional (5-29%)
HP:0001519	Disproportionate tall stature	Occasional (5-29%)
HP:0001627	Abnormal heart morphology	Occasional (5-29%)
HP:0001642	Pulmonic stenosis	Occasional (5-29%)
HP:0001712	Left ventricular hypertrophy	Occasional (5-29%)
HP:0003302	Spondylolisthesis	Occasional (5-29%)
HP:0005110	Atrial fibrillation	Occasional (5-29%)
HP:0005112	Abdominal aortic aneurysm	Occasional (5-29%)
HP:0008419	Intervertebral disc degeneration	Occasional (5-29%)
HP:0010886	Osteochondritis Dissecans	Occasional (5-29%)
HP:0100490	Camptodactyly of finger	Occasional (5-29%)
HP:0100775	Dural ectasia	Occasional (5-29%)
HP:0001363	Craniosynostosis	Excluded (0%)
HP:0000175	Cleft palate	Very rare (<1-4%)
HP:0000939	Osteoporosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	aneurysm-osteoarthritis syndrome
Mondo ID	MONDO:0013426
OMIM	613795
Orphanet	284984
DOID	DOID:0070237
UMLS	C3151087
MedGen	462437
GARD	0010997
Is cancer (heuristic)	no

Also known as: aneurysm - osteoarthritis syndrome · aneurysm-osteoarthritis syndrome · LDS3 · Loeys-Dietz syndrome 3 · Loeys-Dietz syndrome type 3 · Loeys-Dietz syndrome, type 1C · Loeys-Dietz syndrome, type 1C (formerly) · Loeys-Dietz syndrome, type 1C, formerly · Loeys-Dietz syndrome, type 3

Data availability: 369 ClinVar variants · 5 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Loeys-Dietz syndrome › aneurysm-osteoarthritis syndrome

Related subtypes (5): Loeys-Dietz syndrome 1, Loeys-Dietz syndrome 2, Loeys-Dietz syndrome 4, Rienhoff syndrome, Loeys-Dietz syndrome 6

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

369 retrieved; paginated sample, class counts are floors:

161 uncertain significance, 87 likely benign, 48 conflicting classifications of pathogenicity, 23 likely pathogenic, 14 benign/likely benign, 13 pathogenic/likely pathogenic, 12 benign, 11 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1174530	NM_005902.4(SMAD3):c.3G>A (p.Met1Ile)	LOC130057352	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3075380	NM_005902.4(SMAD3):c.2T>C (p.Met1Thr)	LOC130057352	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
520186	NM_005902.4(SMAD3):c.1A>C (p.Met1Leu)	LOC130057352	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
930360	NM_005902.4(SMAD3):c.1A>T (p.Met1Leu)	LOC130057352	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1330798	NM_005902.4(SMAD3):c.445_455del (p.Glu149fs)	SMAD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453411	NM_005902.4(SMAD3):c.1141G>T (p.Gly381Ter)	SMAD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
155836	NM_005902.4(SMAD3):c.364G>A (p.Val122Met)	SMAD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
180524	NM_005902.4(SMAD3):c.860G>A (p.Arg287Gln)	SMAD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
213781	NM_005902.4(SMAD3):c.277C>T (p.Arg93Ter)	SMAD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
213782	NM_005902.4(SMAD3):c.401-6G>A	SMAD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2780301	NM_005902.4(SMAD3):c.770_771del (p.Val257fs)	SMAD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30306	NM_005902.4(SMAD3):c.859C>T (p.Arg287Trp)	SMAD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30307	NM_005902.4(SMAD3):c.741_742del (p.Phe248fs)	SMAD3	Pathogenic	no assertion criteria provided
30309	NM_005902.4(SMAD3):c.653del (p.Asn218fs)	SMAD3	Pathogenic	criteria provided, multiple submitters, no conflicts
30312	NM_005902.4(SMAD3):c.335C>T (p.Ala112Val)	SMAD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
30313	NM_005902.4(SMAD3):c.313del (p.Ala105fs)	SMAD3	Pathogenic	no assertion criteria provided
30315	NM_005902.4(SMAD3):c.1081G>T (p.Glu361Ter)	SMAD3	Pathogenic	no assertion criteria provided
420088	NM_005902.4(SMAD3):c.1102C>T (p.Arg368Ter)	SMAD3	Pathogenic	criteria provided, multiple submitters, no conflicts
4684974	NM_005902.4(SMAD3):c.75del (p.Gln26fs)	SMAD3	Pathogenic	criteria provided, single submitter
692110	NM_005902.4(SMAD3):c.871+1G>A	SMAD3	Pathogenic	criteria provided, multiple submitters, no conflicts
694380	NM_005902.4(SMAD3):c.736del (p.Glu246fs)	SMAD3	Pathogenic	criteria provided, single submitter
694381	NM_005902.4(SMAD3):c.266GCC[3] (p.Arg90dup)	SMAD3	Pathogenic	criteria provided, single submitter
694383	NM_005902.4(SMAD3):c.874del (p.Arg292fs)	SMAD3	Pathogenic	criteria provided, single submitter
694384	NM_005902.4(SMAD3):c.668del (p.Pro223fs)	SMAD3	Pathogenic	criteria provided, single submitter
1334527	NM_005902.4(SMAD3):c.808_812delinsAGA (p.Cys270fs)	SMAD3	Likely pathogenic	criteria provided, single submitter
1709587	NM_005902.4(SMAD3):c.916G>T (p.Glu306Ter)	SMAD3	Likely pathogenic	criteria provided, single submitter
2431521	NM_005902.4(SMAD3):c.435_436del (p.Glu145fs)	SMAD3	Likely pathogenic	criteria provided, single submitter
2574085	NM_005902.4(SMAD3):c.677A>C (p.Tyr226Ser)	SMAD3	Likely pathogenic	criteria provided, single submitter
2574086	NM_005902.4(SMAD3):c.67C>T (p.Gln23Ter)	SMAD3	Likely pathogenic	no assertion criteria provided
268091	NM_005902.4(SMAD3):c.228G>T (p.Gln76His)	SMAD3	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 4 · 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
SMAD3	Definitive	Unknown	aneurysm-osteoarthritis syndrome	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMAD3	Orphanet:284984	Aneurysm-osteoarthritis syndrome
SMAD3	Orphanet:60030	Loeys-Dietz syndrome
SMAD3	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
SMAD6	Orphanet:402075	Familial bicuspid aortic valve

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
SMAD3	HGNC:6769	ENSG00000166949	P84022	SMAD family member 3	gencc,clinvar
SMAD6	HGNC:6772	ENSG00000137834	O43541	SMAD family member 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMAD3	SMAD family member 3	Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases.
SMAD6	SMAD family member 6	Transforming growth factor-beta superfamily receptors signaling occurs through the Smad family of intracellular mediators.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMAD3	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
SMAD6	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_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
cartilage tissue	1
hindlimb stylopod muscle	1
tendon of biceps brachii	1
metanephric glomerulus	1
renal glomerulus	1
right lung	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMAD3	288	ubiquitous	marker	tendon of biceps brachii, cartilage tissue, hindlimb stylopod muscle
SMAD6	277	ubiquitous	marker	right lung, renal glomerulus, metanephric glomerulus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD3	6,440
SMAD6	2,006

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMAD3	P84022	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SMAD6	O43541	72.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 57. 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
Signaling by TGFB family members	2	115.3×	0.004	SMAD3, SMAD6
Loss of Function of SMAD4 in Cancer	1	1903.3×	0.006	SMAD3
SMAD4 MH2 Domain Mutants in Cancer	1	1903.3×	0.006	SMAD3
SMAD2/3 MH2 Domain Mutants in Cancer	1	1903.3×	0.006	SMAD3
Loss of Function of TGFBR1 in Cancer	1	1142.0×	0.006	SMAD3
RUNX3 regulates BCL2L11 (BIM) transcription	1	1142.0×	0.006	SMAD3
Loss of Function of SMAD2/3 in Cancer	1	951.7×	0.006	SMAD3
Signaling by TGF-beta Receptor Complex in Cancer	1	951.7×	0.006	SMAD3
SMAD2/3 Phosphorylation Motif Mutants in Cancer	1	951.7×	0.006	SMAD3
TGFBR1 KD Mutants in Cancer	1	951.7×	0.006	SMAD3
RUNX3 regulates CDKN1A transcription	1	815.7×	0.006	SMAD3
RUNX2 regulates bone development	1	407.9×	0.009	SMAD6
Formation of axial mesoderm	1	407.9×	0.009	SMAD3
Signaling by Activin	1	380.7×	0.009	SMAD3
Formation of definitive endoderm	1	356.9×	0.009	SMAD3
FOXO-mediated transcription of cell cycle genes	1	335.9×	0.009	SMAD3
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	1	335.9×	0.009	SMAD3
Germ layer formation at gastrulation	1	335.9×	0.009	SMAD3
RNA Polymerase II Transcription	2	22.5×	0.009	SMAD3, SMAD6
Gene expression (Transcription)	2	17.8×	0.009	SMAD3, SMAD6
NOTCH4 Intracellular Domain Regulates Transcription	1	285.5×	0.009	SMAD3
Interleukin-37 signaling	1	259.6×	0.010	SMAD3
Signaling by NODAL	1	248.3×	0.010	SMAD3
Signaling by NOTCH4	1	248.3×	0.010	SMAD3
TGFBR3 expression	1	228.4×	0.010	SMAD3
Generic Transcription Pathway	2	15.1×	0.010	SMAD3, SMAD6
Downregulation of TGF-beta receptor signaling	1	203.9×	0.010	SMAD3
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	190.3×	0.010	SMAD3
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	184.2×	0.010	SMAD3
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	184.2×	0.010	SMAD3

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
SMAD protein signal transduction	2	732.7×	1e-04	SMAD3, SMAD6
negative regulation of ossification	2	624.1×	1e-04	SMAD3, SMAD6
ureteric bud development	2	455.5×	2e-04	SMAD3, SMAD6
negative regulation of osteoblast differentiation	2	295.6×	3e-04	SMAD3, SMAD6
positive regulation of miRNA transcription	2	290.6×	3e-04	SMAD3, SMAD6
anatomical structure morphogenesis	2	139.3×	9e-04	SMAD3, SMAD6
negative regulation of lung blood pressure	1	8426.0×	0.002	SMAD3
regulation of miRNA transcription	1	8426.0×	0.002	SMAD3
positive regulation of transforming growth factor beta3 production	1	4213.0×	0.003	SMAD3
zygotic specification of dorsal/ventral axis	1	2808.7×	0.003	SMAD6
paraxial mesoderm morphogenesis	1	2808.7×	0.003	SMAD3
immune system development	1	2106.5×	0.003	SMAD3
regulation of transforming growth factor beta2 production	1	2106.5×	0.003	SMAD3
response to laminar fluid shear stress	1	2106.5×	0.003	SMAD6
immune response	2	47.1×	0.003	SMAD3, SMAD6
negative regulation of cell population proliferation	2	42.1×	0.004	SMAD3, SMAD6
regulation of striated muscle tissue development	1	1404.3×	0.005	SMAD3
trophoblast cell migration	1	1203.7×	0.005	SMAD3
negative regulation of apoptotic process	2	34.8×	0.005	SMAD3, SMAD6
transdifferentiation	1	1053.2×	0.005	SMAD3
pericardium development	1	936.2×	0.005	SMAD3
positive regulation of extracellular matrix assembly	1	936.2×	0.005	SMAD3
negative regulation of cardiac muscle hypertrophy in response to stress	1	936.2×	0.005	SMAD3
response to angiotensin	1	936.2×	0.005	SMAD3
mitral valve morphogenesis	1	842.6×	0.005	SMAD6
embryonic foregut morphogenesis	1	842.6×	0.005	SMAD3
cell differentiation	2	29.1×	0.005	SMAD3, SMAD6
negative regulation of osteoblast proliferation	1	766.0×	0.005	SMAD3
response to alcohol	1	766.0×	0.005	SMAD3
negative regulation of activin receptor signaling pathway	1	702.2×	0.005	SMAD6

Therapeutics

Drug target analysis

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

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

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SMAD3	FLUORESCEIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMAD3	2	4
SMAD6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FLUORESCEIN	4	SMAD3
ELLAGIC ACID	2	SMAD3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMAD3	24	Binding:18, Functional:6

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

2 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)
FLUORESCEIN	4	SMAD3
ELLAGIC ACID	2	SMAD3

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SMAD3
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	1	SMAD6

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMAD6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.