Exfoliation syndrome

Summary

Exfoliation syndrome (MONDO:0008327) is a disease with 5 cohort genes (8 GWAS associations across 7 studies) and 29 clinical trials. The dominant Reactome pathway is Elastic fibre formation (3 cohort genes). Top therapeutic interventions include timolol, dorzolamide, and travoprost.

At a glance

• Cohort genes: 5
• GWAS associations: 8
• ClinVar variants: 4
• Clinical trials: 29

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	exfoliation syndrome
Mondo ID	MONDO:0008327
EFO	EFO:0004235
MeSH	D017889
Orphanet	529819
DOID	DOID:13641
NCIT	C129025
SNOMED CT	111514006
UMLS	C0206368
MedGen	60133
GARD	0027786
Is cancer (heuristic)	no

Also known as: pseudoexfoliation glaucoma · XFG · XFS

Data availability: 4 ClinVar variants · 8 GWAS associations (7 studies) · 1 cell line.

Disease family

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

Related subtypes (1): phacolytic glaucoma

Genetics & variants

GWAS landscape

8 GWAS associations across 7 studies. Top hits map to 4 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs4886776	2e-217	LOXL1	A	9.87
rs893818	3e-84	LOXL1	T	20.94
rs3825942	3e-21	LOXL1-AS1, LOXL1	G	20.1
rs16958445	2e-16	TBC1D21	G	5.18
rs4926244	3e-11	CACNA1A	G	1.16
rs2165241	3e-10	LOXL1	?	4.17

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST002787	Aung T	2015	1,484	1,188	A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome.
GCST90481914	Verma A	2024	1,099	449,812	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST002486	Nakano M	2014	201	0	Novel common variants and susceptible haplotype for exfoliation glaucoma specific to Asian population.
GCST000784	Krumbiegel M	2010	160	0	Genome-wide association study with DNA pooling identifies variants at CNTNAP2 associated with pseudoexfoliation syndrome.
GCST011297	Kobakhidze N	2019	132	0	NEW GENETIC MARKERS ASSOCIATED WITH SUSCEPTIBILITY TO EXFOLIATION SYNDROME AMONG GEORGIAN POPULATION.
GCST005347	Zagajewska K	2017	103	0	GWAS links variants in neuronal development and actin remodeling related loci with pseudoexfoliation syndrome without glaucoma.
GCST000067	Thorleifsson G	2007	75	14,474	Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	4

MAF distribution

Bucket	Variants
common (>=0.05)	6
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	4
missense_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs4886776	15	73932655	G>A,C	0.05	intron_variant	LOXL1	2e-217	Tier 4: intronic/intergenic
rs893818	15	73936854	G>A	0.465	intron_variant	LOXL1	3e-84	Tier 4: intronic/intergenic
rs3825942	15	73927241	G>A,C,T	0.15	missense_variant	LOXL1-AS1, LOXL1	3e-21	Tier 1: coding
rs16958445	15	73884216	G>A	0.166	missense_variant	TBC1D21	2e-16	Tier 1: coding
rs4926244	19	13264099	T>C	0.16	intron_variant	CACNA1A	3e-11	Tier 4: intronic/intergenic
rs2165241	15	73929861	T>A,C,G	0.05	intron_variant	LOXL1	3e-10	Tier 4: intronic/intergenic

ClinVar germline variants

4 retrieved; paginated sample, class counts are floors:

2 conflicting classifications of pathogenicity, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
126949	NM_000428.3(LTBP2):c.1295C>T (p.Pro432Leu)	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
132836	NM_000428.3(LTBP2):c.3527-14T>C	LTBP2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126953	NM_000428.3(LTBP2):c.1999A>C (p.Ile667Leu)	LTBP2	Uncertain significance	criteria provided, single submitter
132837	NM_000428.3(LTBP2):c.4699A>G (p.Met1567Val)	LTBP2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
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
gwas_only	3
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	gwas
TBC1D21	HGNC:28536	ENSG00000167139	Q8IYX1	TBC1 domain family member 21	gwas
LOXL1	HGNC:6665	ENSG00000129038	Q08397	Lysyl oxidase homolog 1	gwas
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)
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
TBC1D21	TBC1 domain family member 21	Acts as a GTPase-activating protein for Rab family protein(s).
LOXL1	Lysyl oxidase homolog 1	Catalyzes the oxidative deamination of lysine and hydroxylysine residues in collagen and elastin, resulting in the formation of covalent cross-linkages, and the stabilization of collagen and elastin fibers.
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: 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
Ion channel	1	22.3×	0.088
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
TBC1D21	Other/Unknown	no		Rab-GAP-TBC_dom, Rab-GAP_TBC_sf
LOXL1	Other/Unknown	no		Lysyl_oxidase, Lysyl_oxidase_CS,
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.

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
ascending aorta	3
descending thoracic aorta	3
thoracic aorta	3
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
TBC1D21	29	tissue_specific	yes	right testis, left testis, testis
LOXL1	232	ubiquitous	marker	thoracic aorta, ascending aorta, descending thoracic aorta
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
LOXL1	1,651
TBC1D21	567
CACNA1A	346

Intra-cohort edges

A	B	Sources
LOXL1	LTBP2	string_interaction
LOXL1	LTBP3	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1A	O00555	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBC1D21	Q8IYX1	93.19
LTBP3	Q9NS15	64.21
LOXL1	Q08397	59.91
LTBP2	Q14767	58.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. Enrichment computed across 5 evidence-associated genes (4 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 4 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	3	251.9×	2e-06	LOXL1, LTBP2, LTBP3
Extracellular matrix organization	3	47.3×	1e-04	LOXL1, LTBP2, LTBP3
TGF-beta receptor signaling activates SMADs	2	163.1×	2e-04	LTBP2, LTBP3
Molecules associated with elastic fibres	2	154.3×	2e-04	LTBP2, LTBP3
Signaling by TGF-beta Receptor Complex	2	100.2×	5e-04	LTBP2, LTBP3
Signaling by TGFB family members	2	57.7×	0.001	LTBP2, LTBP3
Presynaptic depolarization and calcium channel opening	1	237.9×	0.010	CACNA1A
Crosslinking of collagen fibrils	1	142.8×	0.014	LOXL1
Collagen formation	1	114.2×	0.016	LOXL1
Regulation of insulin secretion	1	54.9×	0.029	CACNA1A
Assembly of collagen fibrils and other multimeric structures	1	50.1×	0.029	LOXL1
Integration of energy metabolism	1	43.9×	0.030	CACNA1A
Transmission across Chemical Synapses	1	19.0×	0.059	CACNA1A
Signal Transduction	2	5.1×	0.059	LTBP2, LTBP3
Neuronal System	1	11.1×	0.093	CACNA1A
Metabolism	1	2.9×	0.302	CACNA1A

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
protein deamination	1	1685.2×	0.009	LOXL1
transforming growth factor beta receptor signaling pathway	2	63.6×	0.009	LTBP2, LTBP3
positive regulation of mesenchymal stem cell differentiation	1	481.5×	0.012	LTBP3
lung saccule development	1	421.3×	0.012	LTBP3
sperm mitochondrial sheath assembly	1	421.3×	0.012	TBC1D21
positive regulation of mesenchymal stem cell proliferation	1	421.3×	0.012	LTBP3
plasma membrane to endosome transport	1	306.4×	0.013	TBC1D21
supramolecular fiber organization	1	210.7×	0.013	LTBP2
positive regulation of bone resorption	1	198.3×	0.013	LTBP3
response to amyloid-beta	1	198.3×	0.013	CACNA1A
negative regulation of bone mineralization	1	187.2×	0.013	LTBP3
bone remodeling	1	187.2×	0.013	LTBP3
negative regulation of chondrocyte differentiation	1	134.8×	0.017	LTBP3
bone morphogenesis	1	120.4×	0.017	LTBP3
aorta development	1	112.3×	0.017	LOXL1
calcium ion import across plasma membrane	1	108.7×	0.017	CACNA1A
sperm axoneme assembly	1	93.6×	0.019	TBC1D21
cellular response to amyloid-beta	1	78.4×	0.021	CACNA1A
protein targeting	1	73.3×	0.021	LTBP2
chondrocyte differentiation	1	60.2×	0.025	LTBP3
bone mineralization	1	54.4×	0.026	LTBP3
protein secretion	1	52.7×	0.026	LTBP2
collagen fibril organization	1	44.9×	0.029	LOXL1
calcium ion transmembrane transport	1	42.1×	0.029	CACNA1A
modulation of chemical synaptic transmission	1	36.6×	0.032	CACNA1A
response to lipopolysaccharide	1	25.0×	0.045	LOXL1
positive regulation of cytosolic calcium ion concentration	1	23.4×	0.045	CACNA1A
flagellated sperm motility	1	23.4×	0.045	TBC1D21
chemical synaptic transmission	1	15.5×	0.065	CACNA1A
spermatogenesis	1	7.0×	0.134	TBC1D21

Therapeutics

Drugs indicated for this disease

0 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Timolol	Phase 3 (in late-stage trials)
Travoprost	Phase 3 (in late-stage trials)

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
CACNA1A	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1A	2	4
TBC1D21	0	0
LOXL1	0	0
LTBP2	0	0
LTBP3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA1A	19	Binding:18, Functional:1
LOXL1	1	Binding:1

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

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)
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1A
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	4	TBC1D21, LOXL1, LTBP2, LTBP3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TBC1D21	0	—
LOXL1	1	—
LTBP2	0	—
LTBP3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 29.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	24
PHASE4	2
PHASE3	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07228221	PHASE4	RECRUITING	Standalone iStent Infinite and iDose TR for Management of Moderate to Severe Open Angle Glaucoma
NCT00273442	PHASE4	COMPLETED	Assessing Cosopt Switch Patients
NCT00331240	PHASE3	COMPLETED	24-Hour Intraocular Pressure (IOP) Control With Travoprost/Timolol Fixed Combination
NCT01126203	PHASE3	COMPLETED	Randomized Prospective Study of Selective Laser Trabeculoplasty (SLT) Versus Argon Trabeculoplasty (ALT) in Patients With Pseudoexfoliation Glaucoma and Ocular Hypertension
NCT01936389	PHASE2	COMPLETED	A Prospective Study to Assess the Hypotensive Efficacy of Rho-Kinase Inhibitor AR-12286 Ophthalmic Solution 0.5% and 0.7% in Patients With Exfoliation Syndrome and Ocular Hypertension or Glaucoma
NCT03798223	Not specified	ACTIVE_NOT_RECRUITING	Optimal Treatment Protocol for Selective Laser Trabeculoplasty
NCT04416724	Not specified	RECRUITING	Phacoemulsification vs SLT as Initial Treatment for Pseudoexfoliation Glaucoma
NCT05159960	Not specified	ENROLLING_BY_INVITATION	Optimal Treatment Protocol for Selective Laser Trabeculoplasty - Repeat Trial
NCT05439161	Not specified	RECRUITING	XEN Glaucoma Gel Stent Versus Trabeculectomy
NCT05557721	Not specified	ENROLLING_BY_INVITATION	Uddevalla Skövde Transscleral Micropulse Study
NCT06523751	Not specified	RECRUITING	Trabeculopuncture as Predictive Test for the Success of Ab Interno Trabeculectomy
NCT06682962	Not specified	RECRUITING	Transcorneal Electrical Stimulation for the Treatment of Visual Field Defects in Patients With Open-Angle Glaucoma
NCT06691555	Not specified	RECRUITING	Long-term Safety and Efficacy of a Modified Suprachoroidal Silicone Tube (SST) Shunt
NCT06885827	Not specified	RECRUITING	Vitamin Mix (B6, B9, B12, And Choline) For Glaucoma Patients
NCT07401290	Not specified	NOT_YET_RECRUITING	The Safety and Efficacy of Direct SLT in Pseudoexfoliation Glaucoma
NCT00485108	Not specified	COMPLETED	Anti-inflammatory Therapy Following Selective Laser Trabeculoplasty
NCT00804115	Not specified	UNKNOWN	The International Collaborative Exfoliation Syndrome Treatment Study
NCT01022281	Not specified	COMPLETED	Early Diagnosis in Glaucoma With GDxVcc
NCT01023997	Not specified	COMPLETED	Central Corneal Thickness in Glaucoma
NCT01301378	Not specified	TERMINATED	Patch Graft Material Safety and Effectiveness in Covering Glaucoma Drainage Device Tube
NCT02042703	Not specified	TERMINATED	Imaging Lens Deposits in Exfoliation Syndrome
NCT02165631	Not specified	COMPLETED	The Diurnal and Nocturnal Effect of Simbrinza and Timolol on Intraocular Pressure and Ocular Perfusion Pressure
NCT02544646	Not specified	COMPLETED	Changes in Ocular Rigidity After Trabeculectomy in Patients With POAG
NCT03483402	Not specified	COMPLETED	Micropulse Laser Trabeculoplasty as Adjunctive Treatment in Patients With Pseudoexfoliation Glaucoma
NCT03494465	Not specified	COMPLETED	Efficacy and Safety of Lens Extraction in Patients With Pseudoexfoliation Glaucoma
NCT04440527	Not specified	UNKNOWN	Intraocular Pressure After Preserflo / Innfocus Microshunt Implantation vs Trabeculectomy
NCT04590651	Not specified	UNKNOWN	Cataract Surgery in Patients With Pseudoexfoliation and Pseudoexfoliation Glaucoma
NCT04609345	Not specified	UNKNOWN	Prevalence of Ocular Surface Disease in Malaysian Glaucoma Patients
NCT05198297	Not specified	TERMINATED	Safety and Effectiveness of the Hydrus Microstent

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TIMOLOL	4	3
DORZOLAMIDE	4	1
TRAVOPROST	4	1
VEROSUDIL	2	2