Isolated ectopia lentis

Summary

Isolated ectopia lentis (MONDO:0015998) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 3
• Phenotypes (HPO): 11

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		90	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0001083	Ectopia lentis	Very frequent (80-99%)
HP:0001387	Joint stiffness	Very frequent (80-99%)
HP:0000272	Malar flattening	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000518	Cataract	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000646	Amblyopia	Occasional (5-29%)
HP:0000822	Hypertension	Occasional (5-29%)
HP:0009918	Ectopia pupillae	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated ectopia lentis
Mondo ID	MONDO:0015998
MeSH	C536184
Orphanet	1885
DOID	DOID:0111148
NCIT	C34566
SNOMED CT	74969002
UMLS	C1851286
MedGen	342716
GARD	0012251
MedDRA	10014145
Is cancer (heuristic)	no

Also known as: ectopia lentis syndrome · familial ectopia lentis · isolated lens position anomaly · nonsyndromic lens position anomaly

Data availability: 3 ClinVar variants · 2 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › lens disorder › isolated ectopia lentis

Related subtypes (9): lens subluxation, posterior dislocation of lens, cataract, blepharoptosis-myopia-ectopia lentis syndrome, classic homocystinuria, facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome, congenital primary aphakia, ectopia lentis-chorioretinal dystrophy-myopia syndrome, encephalopathy due to sulfite oxidase deficiency

Subtypes (3): ectopia lentis 1, isolated, autosomal dominant, ectopia lentis 2, isolated, autosomal recessive, ectopia lentis et pupillae

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

3 retrieved; paginated sample, class counts are floors:

1 pathogenic/likely pathogenic, 1 pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
3076001	NM_019032.6(ADAMTSL4):c.1786C>T (p.Gln596Ter)	ADAMTSL4	Pathogenic	criteria provided, single submitter
1120081	NM_019032.6(ADAMTSL4):c.1712C>A (p.Ser571Ter)	MIR4257	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
968811	NM_000138.5(FBN1):c.5018T>C (p.Ile1673Thr)	FBN1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 30 · Orphanet: 12 · 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
ADAMTSL4	Definitive	Autosomal recessive	ectopia lentis 2, isolated, autosomal recessive	6
FBN1	Supportive	Autosomal dominant	isolated ectopia lentis	24

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ADAMTSL4	Orphanet:1885	Isolated ectopia lentis
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

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ADAMTSL4	HGNC:19706	ENSG00000143382	Q6UY14	ADAMTS-like protein 4	gencc,clinvar
FBN1	HGNC:3603	ENSG00000166147	P35555	Fibrillin-1	gencc,clinvar
MIR4257	HGNC:38312	ENSG00000264553		microRNA 4257	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ADAMTSL4	ADAMTS-like protein 4	Positive regulation of apoptosis.
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ADAMTSL4	Other/Unknown	no		TSP1_rpt, ADAMTS_spacer1, PLAC
FBN1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
MIR4257	Other/Unknown	no

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
decidua	2
lower esophagus mucosa	1
mucosa of stomach	1
skin of hip	1
synovial joint	1
granulocyte	1
right uterine tube	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ADAMTSL4	216	ubiquitous	marker	decidua, mucosa of stomach, lower esophagus mucosa
FBN1	275	ubiquitous	marker	synovial joint, skin of hip, decidua
MIR4257	117		yes	sural nerve, granulocyte, right uterine tube

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBN1	3,640
ADAMTSL4	1,231
MIR4257	0

Intra-cohort edges

A	B	Sources
ADAMTSL4	FBN1	string_interaction

Structural data

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

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
ADAMTSL4	Q6UY14	65.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Elastic fibre formation	1	167.9×	0.021	FBN1
TGF-beta receptor signaling activates SMADs	1	163.1×	0.021	FBN1
Molecules associated with elastic fibres	1	154.3×	0.021	FBN1
Defective B3GALTL causes PpS	1	154.3×	0.021	ADAMTSL4
O-glycosylation of TSR domain-containing proteins	1	150.3×	0.021	ADAMTSL4
Diseases associated with O-glycosylation of proteins	1	107.7×	0.025	ADAMTSL4
O-linked glycosylation	1	72.3×	0.027	ADAMTSL4
Integrin cell surface interactions	1	67.2×	0.027	FBN1
Diseases of glycosylation	1	65.6×	0.027	ADAMTSL4
Degradation of the extracellular matrix	1	58.9×	0.027	FBN1
Post-translational protein phosphorylation	1	50.1×	0.029	FBN1
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.030	FBN1
Diseases of metabolism	1	40.2×	0.030	ADAMTSL4
Post-translational protein modification	1	9.6×	0.116	ADAMTSL4
Disease	1	6.5×	0.155	ADAMTSL4
Metabolism of proteins	1	6.2×	0.155	ADAMTSL4

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
pigment cell development	1	8426.0×	0.003	ADAMTSL4
post-embryonic eye morphogenesis	1	2808.7×	0.003	FBN1
obsolete sequestering of BMP in extracellular matrix	1	2106.5×	0.003	FBN1
obsolete sequestering of TGFbeta in extracellular matrix	1	2106.5×	0.003	FBN1
negative regulation of osteoclast development	1	1685.2×	0.003	FBN1
epithelial cell development	1	766.0×	0.004	ADAMTSL4
embryonic eye morphogenesis	1	766.0×	0.004	FBN1
cellular response to insulin-like growth factor stimulus	1	648.1×	0.004	FBN1
cell adhesion mediated by integrin	1	337.0×	0.007	FBN1
negative regulation of osteoclast differentiation	1	271.8×	0.008	FBN1
metanephros development	1	255.3×	0.008	FBN1
camera-type eye development	1	179.3×	0.010	FBN1
lung alveolus development	1	175.5×	0.010	FBN1
cellular response to transforming growth factor beta stimulus	1	138.1×	0.011	FBN1
glucose metabolic process	1	127.7×	0.011	FBN1
glucose homeostasis	1	65.3×	0.020	FBN1
skeletal system development	1	62.9×	0.020	FBN1
extracellular matrix organization	1	61.1×	0.020	ADAMTSL4
gene expression	1	39.9×	0.028	FBN1
heart development	1	39.4×	0.028	FBN1
positive regulation of apoptotic process	1	28.4×	0.037	ADAMTSL4
apoptotic process	1	14.3×	0.068	ADAMTSL4

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
ADAMTSL4	0	0
FBN1	0	0
MIR4257	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	0
E	Difficult family or no structure, no drug	3	ADAMTSL4, FBN1, MIR4257

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)
ADAMTSL4	0	—
FBN1	0	—
MIR4257	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.