Weill-Marchesani syndrome

Summary

Weill-Marchesani syndrome (MONDO:0018096) is a disease with 5 cohort genes. The dominant Reactome pathway is Elastic fibre formation (4 cohort genes).

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide)
• Cohort genes: 5
• ClinVar variants: 505
• Phenotypes (HPO): 21

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0000501	Glaucoma	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0009778	Short thumb	Very frequent (80-99%)
HP:0011003	High myopia	Very frequent (80-99%)
HP:0030961	Microspherophakia	Very frequent (80-99%)
HP:0001072	Thickened skin	Frequent (30-79%)
HP:0001083	Ectopia lentis	Frequent (30-79%)
HP:0001376	Limitation of joint mobility	Frequent (30-79%)
HP:0030680	Abnormal cardiovascular system morphology	Frequent (30-79%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000572	Visual loss	Occasional (5-29%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001387	Joint stiffness	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001642	Pulmonic stenosis	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0001650	Aortic valve stenosis	Occasional (5-29%)
HP:0001653	Mitral regurgitation	Occasional (5-29%)
HP:0002750	Delayed skeletal maturation	Occasional (5-29%)
HP:0005184	Prolonged QTc interval	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Weill-Marchesani syndrome
Mondo ID	MONDO:0018096
MeSH	D056846
OMIM	277600
Orphanet	3449
DOID	DOID:0050475
NCIT	C85226
SNOMED CT	2884008
UMLS	C0265313
MedGen	82705
GARD	0004936
MedDRA	10064963
NORD	1842
Is cancer (heuristic)	no

Also known as: mesodermal dysmorphodystrophy congenital · spherophakia-brachymorphia syndrome · Weill Marchesani Syndrome · WM syndrome · WMS

Data availability: 505 ClinVar variants · 3 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

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

Related subtypes (7): autosomal dominant disease, autosomal recessive disease, septooptic dysplasia, congenital factor XII deficiency, camptodactyly-tall stature-scoliosis-hearing loss syndrome, brachydactyly-syndactyly syndrome, congenital factor XI deficiency

Subtypes (4): Weill-Marchesani syndrome 1, 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

505 retrieved; paginated sample, class counts are floors:

202 uncertain significance, 187 conflicting classifications of pathogenicity, 65 benign/likely benign, 44 benign, 5 likely benign, 1 likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
547334	NM_000138.5(FBN1):c.5826C>A (p.Cys1942Ter)	FBN1	Pathogenic	reviewed by expert panel
163474	NM_000138.5(FBN1):c.4675_4718del (p.Lys1559fs)	FBN1	Likely pathogenic	criteria provided, single submitter
330577	NM_030957.4(ADAMTS10):c.3202+13C>T	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330581	NM_030957.4(ADAMTS10):c.3043-8C>T	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330583	NM_030957.4(ADAMTS10):c.2530+9G>A	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330584	NM_030957.4(ADAMTS10):c.2433C>T (p.Leu811=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330586	NM_030957.4(ADAMTS10):c.2409G>C (p.Leu803=)	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
330595	NM_030957.4(ADAMTS10):c.1935G>A (p.Ala645=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330600	NM_030957.4(ADAMTS10):c.1794G>C (p.Thr598=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330602	NM_030957.4(ADAMTS10):c.1569G>A (p.Thr523=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330604	NM_030957.4(ADAMTS10):c.1530C>G (p.Thr510=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330606	NM_030957.4(ADAMTS10):c.1176C>T (p.His392=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330607	NM_030957.4(ADAMTS10):c.1085-5C>T	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330608	NM_030957.4(ADAMTS10):c.834G>A (p.Ser278=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
330612	NM_030957.4(ADAMTS10):c.303C>T (p.His101=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
715259	NM_030957.4(ADAMTS10):c.1743C>T (p.Ile581=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
724133	NM_030957.4(ADAMTS10):c.483G>A (p.Leu161=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
729473	NM_030957.4(ADAMTS10):c.1480-4G>T	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
741232	NM_030957.4(ADAMTS10):c.198C>T (p.Arg66=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
744188	NM_030957.4(ADAMTS10):c.1149C>T (p.Gly383=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
744760	NM_030957.4(ADAMTS10):c.1719C>T (p.His573=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
745984	NM_030957.4(ADAMTS10):c.2130C>T (p.Gly710=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892804	NM_030957.4(ADAMTS10):c.2415G>A (p.Arg805=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892836	NM_030957.4(ADAMTS10):c.1407G>A (p.Pro469=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892837	NM_030957.4(ADAMTS10):c.1395G>A (p.Pro465=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
892866	NM_030957.4(ADAMTS10):c.309C>T (p.Ser103=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
893610	NM_030957.4(ADAMTS10):c.2034+11C>T	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
893641	NM_030957.4(ADAMTS10):c.1212C>T (p.Gly404=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
893642	NM_030957.4(ADAMTS10):c.1194C>T (p.Phe398=)	ADAMTS10	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 69 · Orphanet: 18 · 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
FBN1	Strong	Autosomal dominant	Weill-Marchesani syndrome 2, dominant	24
LTBP2	Moderate	Autosomal recessive	Weill-Marchesani syndrome 3	20
LTBP3	Moderate	Autosomal recessive	Weill-Marchesani syndrome 3	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAMTS10	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:1885	Isolated ectopia lentis
FBN1	Orphanet:2084	Glaucoma-ectopia lentis-microspherophakia-stiff joints-short stature syndrome
FBN1	Orphanet:2462	Shprintzen-Goldberg syndrome
FBN1	Orphanet:2623	Geleophysic dysplasia
FBN1	Orphanet:2833	Stiff skin syndrome
FBN1	Orphanet:284963	Marfan syndrome type 1
FBN1	Orphanet:284979	Neonatal Marfan syndrome
FBN1	Orphanet:300382	Progeroid and marfanoid aspect-lipodystrophy syndrome
FBN1	Orphanet:3449	Weill-Marchesani syndrome
FBN1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
FBN1	Orphanet:969	Acromicric dysplasia
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

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADAMTS10	HGNC:13201	ENSG00000142303	Q9H324	A disintegrin and metalloproteinase with thrombospondin motifs 10	gencc,clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	gencc,clinvar
LTBP2	HGNC:6715	ENSG00000119681	Q14767	Latent-transforming growth factor beta-binding protein 2	gencc,clinvar
LTBP3	HGNC:6716	ENSG00000168056	Q9NS15	Latent-transforming growth factor beta-binding protein 3	gencc,clinvar
FBN3	HGNC:18794	ENSG00000142449	Q75N90	Fibrillin-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.
FBN1	Fibrillin-1	Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues.
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.
FBN3	Fibrillin-3	Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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	7.3×	0.259
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADAMTS10	Protease	yes		TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
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
FBN3	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom

Expression context

Cohort genes with no expression data: 0.

4 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)	5
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
decidua	1
skin of hip	1
synovial joint	1
cortical plate	1
embryo	1
ganglionic eminence	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
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua
LTBP2	276	ubiquitous	marker	descending thoracic aorta, thoracic aorta, ascending aorta
LTBP3	279	broad	marker	descending thoracic aorta, thoracic aorta, ascending aorta
FBN3	131	tissue_specific	marker	cortical plate, embryo, ganglionic eminence

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBN1	3,640
LTBP2	2,658
LTBP3	2,339
FBN3	1,607
ADAMTS10	710

Intra-cohort edges

A	B	Sources
ADAMTS10	FBN1	string_interaction
ADAMTS10	LTBP2	string_interaction
ADAMTS10	LTBP3	string_interaction
FBN1	LTBP2	string_interaction
FBN1	LTBP3	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBN1	P35555	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADAMTS10	Q9H324	73.88
LTBP3	Q9NS15	64.21
LTBP2	Q14767	58.33
FBN3	Q75N90

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 5 evidence-associated genes (5 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 5 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	4	268.7×	5e-09	FBN1, LTBP2, LTBP3, FBN3
Molecules associated with elastic fibres	4	246.9×	5e-09	FBN1, LTBP2, LTBP3, FBN3
TGF-beta receptor signaling activates SMADs	3	195.8×	2e-06	FBN1, LTBP2, LTBP3
Signaling by TGF-beta Receptor Complex	2	80.1×	0.001	LTBP2, LTBP3
Degradation of the extracellular matrix	2	47.1×	0.002	FBN1, FBN3
Signaling by TGFB family members	2	46.1×	0.002	LTBP2, LTBP3
Extracellular matrix organization	2	25.2×	0.007	LTBP2, LTBP3
Defective B3GALTL causes PpS	1	61.7×	0.037	ADAMTS10
O-glycosylation of TSR domain-containing proteins	1	60.1×	0.037	ADAMTS10
Diseases associated with O-glycosylation of proteins	1	43.1×	0.046	ADAMTS10
O-linked glycosylation	1	28.9×	0.058	ADAMTS10
Integrin cell surface interactions	1	26.9×	0.058	FBN1
Diseases of glycosylation	1	26.2×	0.058	ADAMTS10
Post-translational protein phosphorylation	1	20.0×	0.070	FBN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	17.3×	0.075	FBN1
Diseases of metabolism	1	16.1×	0.076	ADAMTS10
Signal Transduction	2	4.1×	0.093	LTBP2, LTBP3
Post-translational protein modification	1	3.8×	0.261	ADAMTS10
Disease	1	2.6×	0.344	ADAMTS10
Metabolism of proteins	1	2.5×	0.344	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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic eye morphogenesis	2	612.8×	1e-04	FBN1, FBN3
camera-type eye development	2	143.4×	0.001	FBN1, FBN3
glucose metabolic process	2	102.1×	0.002	FBN1, FBN3
transforming growth factor beta receptor signaling pathway	2	63.6×	0.003	LTBP2, LTBP3
glucose homeostasis	2	52.2×	0.004	FBN1, FBN3
post-embryonic eye morphogenesis	1	1123.5×	0.005	FBN1
obsolete sequestering of BMP in extracellular matrix	1	842.6×	0.005	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	842.6×	0.005	FBN1
negative regulation of osteoclast development	1	674.1×	0.005	FBN1
positive regulation of mesenchymal stem cell differentiation	1	481.5×	0.007	LTBP3
lung saccule development	1	421.3×	0.007	LTBP3
positive regulation of mesenchymal stem cell proliferation	1	421.3×	0.007	LTBP3
cellular response to insulin-like growth factor stimulus	1	259.3×	0.010	FBN1
supramolecular fiber organization	1	210.7×	0.010	LTBP2
positive regulation of bone resorption	1	198.3×	0.010	LTBP3
negative regulation of bone mineralization	1	187.2×	0.010	LTBP3
bone remodeling	1	187.2×	0.010	LTBP3
negative regulation of chondrocyte differentiation	1	134.8×	0.013	LTBP3
cell adhesion mediated by integrin	1	134.8×	0.013	FBN1
bone morphogenesis	1	120.4×	0.014	LTBP3
negative regulation of osteoclast differentiation	1	108.7×	0.014	FBN1
metanephros development	1	102.1×	0.015	FBN1
protein targeting	1	73.3×	0.019	LTBP2
lung alveolus development	1	70.2×	0.019	FBN1
chondrocyte differentiation	1	60.2×	0.022	LTBP3
cellular response to transforming growth factor beta stimulus	1	55.2×	0.022	FBN1
bone mineralization	1	54.4×	0.022	LTBP3
protein secretion	1	52.7×	0.022	LTBP2
skeletal system development	1	25.1×	0.044	FBN1
extracellular matrix organization	1	24.4×	0.044	ADAMTS10

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 5

Druggability breadth: 0 of 5 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
FBN1	0	0
LTBP2	0	0
LTBP3	0	0
FBN3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	4	FBN1, LTBP2, LTBP3, FBN3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ADAMTS10	0	—
FBN1	0	—
LTBP2	0	—
LTBP3	0	—
FBN3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.