Marshall syndrome

Summary

Marshall syndrome (MONDO:0007949) is a disease caused by COL11A1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: COL11A1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 98
• Phenotypes (HPO): 42

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		17	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

42 HPO clinical features (Orphanet curated; top 42 by frequency):

HPO ID	Term	Frequency
HP:0000164	Abnormality of the dentition	Very frequent (80-99%)
HP:0000179	Thick lower lip vermilion	Very frequent (80-99%)
HP:0000215	Thick upper lip vermilion	Very frequent (80-99%)
HP:0000248	Brachycephaly	Very frequent (80-99%)
HP:0000272	Malar flattening	Very frequent (80-99%)
HP:0000316	Hypertelorism	Very frequent (80-99%)
HP:0000343	Long philtrum	Very frequent (80-99%)
HP:0000347	Micrognathia	Very frequent (80-99%)
HP:0000407	Sensorineural hearing impairment	Very frequent (80-99%)
HP:0000431	Wide nasal bridge	Very frequent (80-99%)
HP:0000463	Anteverted nares	Very frequent (80-99%)
HP:0000518	Cataract	Very frequent (80-99%)
HP:0000545	Myopia	Very frequent (80-99%)
HP:0002829	Arthralgia	Very frequent (80-99%)
HP:0003196	Short nose	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0005280	Depressed nasal bridge	Very frequent (80-99%)
HP:0010669	Hypoplasia of the zygomatic bone	Very frequent (80-99%)
HP:0012368	Flat face	Very frequent (80-99%)
HP:0000175	Cleft palate	Frequent (30-79%)
HP:0000327	Hypoplasia of the maxilla	Frequent (30-79%)
HP:0000501	Glaucoma	Frequent (30-79%)
HP:0000505	Visual impairment	Frequent (30-79%)
HP:0000520	Proptosis	Frequent (30-79%)
HP:0000541	Retinal detachment	Frequent (30-79%)
HP:0000646	Amblyopia	Frequent (30-79%)
HP:0000966	Hypohidrosis	Frequent (30-79%)
HP:0001083	Ectopia lentis	Frequent (30-79%)
HP:0002514	Cerebral calcification	Frequent (30-79%)
HP:0002684	Thickened calvaria	Frequent (30-79%)
HP:0002738	Hypoplastic frontal sinuses	Frequent (30-79%)
HP:0002758	Osteoarthritis	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0004327	Abnormal vitreous humor morphology	Frequent (30-79%)
HP:0007773	Vitreoretinopathy	Frequent (30-79%)
HP:0008070	Sparse hair	Frequent (30-79%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000486	Strabismus	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000653	Sparse eyelashes	Occasional (5-29%)
HP:0002007	Frontal bossing	Occasional (5-29%)
HP:0045075	Sparse eyebrow	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Marshall syndrome
Mondo ID	MONDO:0007949
MeSH	C536025
OMIM	154780
Orphanet	560
DOID	DOID:0111510
ICD-11	1401051186
NCIT	C128115
SNOMED CT	33410002
UMLS	C0265235
MedGen	82694
GARD	0006984
NORD	1407
Is cancer (heuristic)	no

Also known as: deafness, myopia, cataract, saddle nose-Marshall type · Marshall syndrome · MRSHS

Data availability: 98 ClinVar variants · 5 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › Marshall syndrome

Related subtypes (119): ptosis, eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

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

98 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 25 conflicting classifications of pathogenicity, 17 benign, 12 likely pathogenic, 7 pathogenic, 6 pathogenic/likely pathogenic, 3 benign/likely benign, 1 likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1032776	NM_001854.4(COL11A1):c.3816+2dup	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1175708	NM_001854.4(COL11A1):c.4519-2del	COL11A1	Pathogenic	criteria provided, single submitter
1216773	NM_001854.4(COL11A1):c.2513G>A (p.Gly838Glu)	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1304338	NM_001854.4(COL11A1):c.2241+5G>T	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324096	NM_001854.4(COL11A1):c.1245+1G>A	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17134	NM_001854.4(COL11A1):c.3814_3816+1del	COL11A1	Pathogenic	no assertion criteria provided
3236626	NM_001854.4(COL11A1):c.1951C>T (p.Arg651Ter)	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3366895	NM_001854.4(COL11A1):c.2143G>A (p.Gly715Arg)	COL11A1	Pathogenic	no assertion criteria provided
39776	NM_001854.4(COL11A1):c.3816+1G>A	COL11A1	Pathogenic	criteria provided, multiple submitters, no conflicts
498797	NM_001854.4(COL11A1):c.4547G>T (p.Gly1516Val)	COL11A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620141	NM_001854.4(COL11A1):c.4084C>T (p.Arg1362Ter)	COL11A1	Pathogenic	criteria provided, multiple submitters, no conflicts
930420	NM_080629.2(COL11A1):c.2796_2813delTCAAGGACCTCAGGGTCC	COL11A1	Pathogenic	criteria provided, multiple submitters, no conflicts
976188	NM_001854.4(COL11A1):c.3816+1G>C	COL11A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1174529	NC_000001.10:g.(103388956_103400026)(104094395?)del	COL11A1	Likely pathogenic	criteria provided, single submitter
1179083	NM_001854.4(COL11A1):c.4186G>T (p.Gly1396Cys)	COL11A1	Likely pathogenic	criteria provided, single submitter
3064166	NM_001854.4(COL11A1):c.2702G>A (p.Gly901Glu)	COL11A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3236191	NM_001854.4(COL11A1):c.298del (p.Ser100fs)	COL11A1	Likely pathogenic	criteria provided, single submitter
4292685	NM_001854.4(COL11A1):c.4268del (p.Gly1423fs)	COL11A1	Likely pathogenic	criteria provided, single submitter
4293736	NM_001854.4(COL11A1):c.2557-1G>A	COL11A1	Likely pathogenic	criteria provided, single submitter
4294347	NM_001854.4(COL11A1):c.3168+1G>C	COL11A1	Likely pathogenic	criteria provided, single submitter
4294470	NM_001854.4(COL11A1):c.1939G>T (p.Glu647Ter)	COL11A1	Likely pathogenic	criteria provided, single submitter
4755420	NM_001854.4(COL11A1):c.2808+6T>G	COL11A1	Likely pathogenic	criteria provided, single submitter
4819664	NM_001854.4(COL11A1):c.2142+5G>C	COL11A1	Likely pathogenic	criteria provided, single submitter
973212	NM_001854.4(COL11A1):c.1168G>T (p.Glu390Ter)	COL11A1	Likely pathogenic	criteria provided, single submitter
998040	NM_001854.4(COL11A1):c.2508dup (p.Leu837fs)	COL11A1	Likely pathogenic	no assertion criteria provided
1021355	NM_001854.4(COL11A1):c.907G>A (p.Val303Ile)	COL11A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038628	NM_001854.4(COL11A1):c.3692G>T (p.Gly1231Val)	COL11A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1206960	NM_001854.4(COL11A1):c.3068C>A (p.Ala1023Glu)	COL11A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1300948	NM_001854.4(COL11A1):c.2644C>T (p.Arg882Cys)	COL11A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1314615	NM_001854.4(COL11A1):c.565C>T (p.Pro189Ser)	COL11A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 6 · 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
COL11A1	Definitive	Autosomal recessive	Marshall syndrome	17

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL11A1	Orphanet:2021	Fibrochondrogenesis
COL11A1	Orphanet:440354	Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome
COL11A1	Orphanet:560	Marshall syndrome
COL11A1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A1	Orphanet:90654	Stickler syndrome type 2
PCDH12	Orphanet:319192	Diencephalic-mesencephalic junction 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
COL11A1	HGNC:2186	ENSG00000060718	P12107	Collagen alpha-1(XI) chain	gencc,clinvar
AMY2A	HGNC:477	ENSG00000243480	P04746	Pancreatic alpha-amylase	clinvar
PCDH12	HGNC:8657	ENSG00000113555	Q9NPG4	Protocadherin-12	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL11A1	Collagen alpha-1(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
PCDH12	Protocadherin-12	Cellular adhesion molecule that may play an important role in cell-cell interactions at interendothelial junctions.

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
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL11A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
AMY2A	Enzyme (other)	yes	3.2.1.1	Alpha_amylase, GH13_cat_dom, A-amylase/branching_C
PCDH12	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Cadherin-like_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
cartilage tissue	1
periodontal ligament	1
tibia	1
body of pancreas	1
islet of Langerhans	1
pancreas	1
olfactory bulb	1
tendon of biceps brachii	1
type B pancreatic cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL11A1	209	broad	marker	tibia, cartilage tissue, periodontal ligament
AMY2A	125	tissue_specific	marker	body of pancreas, pancreas, islet of Langerhans
PCDH12	217	broad	marker	tendon of biceps brachii, type B pancreatic cell, olfactory bulb

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL11A1	2,433
AMY2A	1,844
PCDH12	657

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AMY2A	P04746	51

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PCDH12	Q9NPG4	66.22
COL11A1	P12107	53.06

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 13. Enrichment computed across 3 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
Digestion of dietary carbohydrate	1	475.8×	0.014	AMY2A
Digestion and absorption	1	380.7×	0.014	AMY2A
Digestion	1	285.5×	0.014	AMY2A
MET activates PTK2 signaling	1	190.3×	0.014	COL11A1
Developmental Lineage of Pancreatic Acinar Cells	1	150.3×	0.014	AMY2A
Collagen chain trimerization	1	129.8×	0.014	COL11A1
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.014	COL11A1
Developmental Cell Lineages	1	112.0×	0.014	AMY2A
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.014	COL11A1
Collagen degradation	1	87.8×	0.014	COL11A1
Collagen biosynthesis and modifying enzymes	1	85.2×	0.014	COL11A1
Non-integrin membrane-ECM interactions	1	77.2×	0.014	COL11A1
Developmental Biology	1	7.2×	0.134	AMY2A

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
tendon development	1	1404.3×	0.004	COL11A1
polysaccharide digestion	1	1404.3×	0.004	AMY2A
neuron recognition	1	1123.5×	0.004	PCDH12
carbohydrate catabolic process	1	1123.5×	0.004	AMY2A
labyrinthine layer development	1	702.2×	0.005	PCDH12
proteoglycan metabolic process	1	624.1×	0.005	COL11A1
chondrocyte development	1	312.1×	0.008	COL11A1
detection of mechanical stimulus involved in sensory perception of sound	1	312.1×	0.008	COL11A1
cartilage condensation	1	255.3×	0.009	COL11A1
ventricular cardiac muscle tissue morphogenesis	1	234.1×	0.009	COL11A1
glycogen metabolic process	1	175.5×	0.010	PCDH12
endodermal cell differentiation	1	165.2×	0.010	COL11A1
calcium-dependent cell-cell adhesion	1	160.5×	0.010	PCDH12
embryonic skeletal system morphogenesis	1	130.6×	0.011	COL11A1
inner ear morphogenesis	1	100.3×	0.013	COL11A1
collagen fibril organization	1	74.9×	0.017	COL11A1
homophilic cell-cell adhesion	1	46.8×	0.024	PCDH12
carbohydrate metabolic process	1	45.3×	0.024	AMY2A
sensory perception of sound	1	33.6×	0.031	COL11A1
visual perception	1	26.5×	0.037	COL11A1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
AMY2A	ACARBOSE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AMY2A	1	4
COL11A1	0	0
PCDH12	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ACARBOSE	4	AMY2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
AMY2A	20	Binding:15, Functional:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AMY2A	3.2.1.1	alpha-amylase

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

1 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)
ACARBOSE	4	AMY2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	AMY2A
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	2	COL11A1, PCDH12

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
COL11A1	0	—
PCDH12	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.