Weill-Marchesani syndrome 1

Summary

Weill-Marchesani syndrome 1 (MONDO:0010194) is a disease caused by ADAMTS10 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: ADAMTS10 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 53

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Weill-Marchesani syndrome 1
Mondo ID	MONDO:0010194
OMIM	277600
DOID	DOID:0061273
UMLS	C4552002
MedGen	1637058
GARD	0015246
Is cancer (heuristic)	no

Also known as: ADAMTS10 Weill-Marchesani syndrome · Weill-Marchesani syndrome 1 · Weill-Marchesani syndrome 1, recessive · Weill-Marchesani syndrome caused by mutation in ADAMTS10 · Weill-Marchesani syndrome type 1 · WMS1

Data availability: 53 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › Weill-Marchesani syndrome › Weill-Marchesani syndrome 1

Related subtypes (3): Weill-Marchesani syndrome 2, dominant, Weill-Marchesani 4 syndrome, recessive, Weill-Marchesani syndrome 3

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

53 retrieved; paginated sample, class counts are floors:

20 uncertain significance, 9 likely pathogenic, 8 conflicting classifications of pathogenicity, 8 pathogenic, 4 benign, 2 likely benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
427834	NM_030957.3(ADAMTS10):c.[2350C>T];[2521T>C]		Pathogenic	criteria provided, single submitter
1944	NM_030957.4(ADAMTS10):c.709C>T (p.Arg237Ter)	ADAMTS10	Pathogenic	criteria provided, multiple submitters, no conflicts
1945	NM_030957.4(ADAMTS10):c.1190+1G>A	ADAMTS10	Pathogenic	no assertion criteria provided
1948	NM_030957.4(ADAMTS10):c.952C>T (p.Gln318Ter)	ADAMTS10	Pathogenic	no assertion criteria provided
1949	NM_030957.4(ADAMTS10):c.1553G>A (p.Gly518Asp)	ADAMTS10	Pathogenic	no assertion criteria provided
1950	NM_030957.4(ADAMTS10):c.2098G>T (p.Gly700Cys)	ADAMTS10	Pathogenic	no assertion criteria provided
3776263	NM_030957.4(ADAMTS10):c.174_213del (p.Pro60fs)	ADAMTS10	Pathogenic	criteria provided, single submitter
37093	NM_000428.3(LTBP2):c.3529G>A (p.Val1177Met)	LTBP2	Pathogenic	no assertion criteria provided
1946	NM_030957.4(ADAMTS10):c.810+1G>A	ADAMTS10	Likely pathogenic	criteria provided, single submitter
2570574	NM_030957.4(ADAMTS10):c.1179G>C (p.Glu393Asp)	ADAMTS10	Likely pathogenic	criteria provided, single submitter
2570575	NM_030957.4(ADAMTS10):c.1219A>G (p.Asn407Asp)	ADAMTS10	Likely pathogenic	criteria provided, single submitter
2570582	NM_030957.4(ADAMTS10):c.2720G>A (p.Arg907His)	ADAMTS10	Likely pathogenic	criteria provided, single submitter
2570585	NM_030957.4(ADAMTS10):c.1462C>A (p.Arg488Ser)	ADAMTS10	Likely pathogenic	criteria provided, single submitter
2570586	NM_030957.4(ADAMTS10):c.2986C>T (p.Arg996Cys)	ADAMTS10	Likely pathogenic	criteria provided, single submitter
2570587	NM_030957.4(ADAMTS10):c.1893C>A (p.Tyr631Ter)	ADAMTS10	Likely pathogenic	criteria provided, single submitter
2570588	NM_030957.4(ADAMTS10):c.726_727del (p.Glu242fs)	ADAMTS10	Likely pathogenic	criteria provided, single submitter
2570589	NM_030957.4(ADAMTS10):c.3083T>G (p.Val1028Gly)	ADAMTS10	Likely pathogenic	criteria provided, single submitter
1046680	NM_030957.4(ADAMTS10):c.2421G>T (p.Glu807Asp)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1462884	NM_030957.4(ADAMTS10):c.373G>A (p.Ala125Thr)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1934151	NM_030957.4(ADAMTS10):c.1183G>A (p.Gly395Arg)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2570584	NM_030957.4(ADAMTS10):c.698G>A (p.Arg233Gln)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330593	NM_030957.4(ADAMTS10):c.1994G>A (p.Arg665His)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625879	NM_030957.4(ADAMTS10):c.350C>T (p.Ala117Val)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625880	NM_030957.4(ADAMTS10):c.1920G>A (p.Ser640=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
730428	NM_030957.4(ADAMTS10):c.2845G>A (p.Ala949Thr)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029985	NM_030957.4(ADAMTS10):c.2632G>A (p.Ala878Thr)	ADAMTS10	Uncertain significance	criteria provided, single submitter
1032917	NM_030957.4(ADAMTS10):c.3002G>A (p.Arg1001His)	ADAMTS10	Uncertain significance	criteria provided, single submitter
1424935	NM_030957.4(ADAMTS10):c.10G>A (p.Ala4Thr)	ADAMTS10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1947	NM_030957.4(ADAMTS10):c.73G>A (p.Ala25Thr)	ADAMTS10	Uncertain significance	criteria provided, single submitter
2169297	NM_030957.4(ADAMTS10):c.629G>A (p.Arg210Gln)	ADAMTS10	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
ADAMTS10	Definitive	Autosomal recessive	Weill-Marchesani syndrome 1	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAMTS10	Orphanet:3449	Weill-Marchesani syndrome
LTBP2	Orphanet:238763	Glaucoma secondary to spherophakia/ectopia lentis and megalocornea
LTBP2	Orphanet:3449	Weill-Marchesani syndrome
LTBP2	Orphanet:98976	Congenital glaucoma
LTBP3	Orphanet:2623	Geleophysic dysplasia
LTBP3	Orphanet:2899	Brachyolmia-amelogenesis imperfecta syndrome
LTBP3	Orphanet:969	Acromicric dysplasia

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
ADAMTS10	HGNC:13201	ENSG00000142303	Q9H324	A disintegrin and metalloproteinase with thrombospondin motifs 10	gencc,clinvar
LTBP2	HGNC:6715	ENSG00000119681	Q14767	Latent-transforming growth factor beta-binding protein 2	clinvar
LTBP3	HGNC:6716	ENSG00000168056	Q9NS15	Latent-transforming growth factor beta-binding protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADAMTS10	A disintegrin and metalloproteinase with thrombospondin motifs 10	Metalloprotease that participate in microfibrils assembly.
LTBP2	Latent-transforming growth factor beta-binding protein 2	May play an integral structural role in elastic-fiber architectural organization and/or assembly.
LTBP3	Latent-transforming growth factor beta-binding protein 3	Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · 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×	0.159
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADAMTS10	Protease	yes		TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
LTBP2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
LTBP3	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
descending thoracic aorta	3
ascending aorta	2
thoracic aorta	2
kidney epithelium	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADAMTS10	254	ubiquitous	yes	descending thoracic aorta, right coronary artery, kidney epithelium
LTBP2	276	ubiquitous	marker	descending thoracic aorta, thoracic aorta, ascending aorta
LTBP3	279	broad	marker	descending thoracic aorta, thoracic aorta, ascending aorta

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LTBP2	2,658
LTBP3	2,339
ADAMTS10	710

Intra-cohort edges

A	B	Sources
ADAMTS10	LTBP2	string_interaction
ADAMTS10	LTBP3	string_interaction

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADAMTS10	Q9H324	73.88
LTBP3	Q9NS15	64.21
LTBP2	Q14767	58.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Elastic fibre formation	2	223.9×	2e-04	LTBP2, LTBP3
TGF-beta receptor signaling activates SMADs	2	217.5×	2e-04	LTBP2, LTBP3
Molecules associated with elastic fibres	2	205.8×	2e-04	LTBP2, LTBP3
Signaling by TGF-beta Receptor Complex	2	133.6×	3e-04	LTBP2, LTBP3
Signaling by TGFB family members	2	76.9×	7e-04	LTBP2, LTBP3
Extracellular matrix organization	2	42.1×	0.002	LTBP2, LTBP3
Defective B3GALTL causes PpS	1	102.9×	0.020	ADAMTS10
O-glycosylation of TSR domain-containing proteins	1	100.2×	0.020	ADAMTS10
Diseases associated with O-glycosylation of proteins	1	71.8×	0.025	ADAMTS10
O-linked glycosylation	1	48.2×	0.033	ADAMTS10
Diseases of glycosylation	1	43.8×	0.033	ADAMTS10
Signal Transduction	2	6.8×	0.036	LTBP2, LTBP3
Diseases of metabolism	1	26.8×	0.045	ADAMTS10
Post-translational protein modification	1	6.4×	0.170	ADAMTS10
Disease	1	4.4×	0.223	ADAMTS10
Metabolism of proteins	1	4.1×	0.223	ADAMTS10

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
transforming growth factor beta receptor signaling pathway	2	106.0×	0.002	LTBP2, LTBP3
positive regulation of mesenchymal stem cell differentiation	1	802.5×	0.006	LTBP3
lung saccule development	1	702.2×	0.006	LTBP3
positive regulation of mesenchymal stem cell proliferation	1	702.2×	0.006	LTBP3
supramolecular fiber organization	1	351.1×	0.006	LTBP2
positive regulation of bone resorption	1	330.4×	0.006	LTBP3
negative regulation of bone mineralization	1	312.1×	0.006	LTBP3
bone remodeling	1	312.1×	0.006	LTBP3
negative regulation of chondrocyte differentiation	1	224.7×	0.008	LTBP3
bone morphogenesis	1	200.6×	0.008	LTBP3
protein targeting	1	122.1×	0.012	LTBP2
chondrocyte differentiation	1	100.3×	0.013	LTBP3
bone mineralization	1	90.6×	0.013	LTBP3
protein secretion	1	87.8×	0.013	LTBP2
extracellular matrix organization	1	40.7×	0.026	ADAMTS10
proteolysis	1	11.4×	0.085	ADAMTS10

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ADAMTS10	0	0
LTBP2	0	0
LTBP3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	1	ADAMTS10
E	Difficult family or no structure, no drug	2	LTBP2, LTBP3

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)
ADAMTS10	0	—
LTBP2	0	—
LTBP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.