Birdshot chorioretinopathy

Summary

Birdshot chorioretinopathy (MONDO:0011599) is a disease with 4 cohort genes (3 GWAS associations across 1 studies) and 4 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 4
• GWAS associations: 3
• Phenotypes (HPO): 23
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.35	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.14	United States	Validated

Signs & symptoms

Clinical features (HPO)

23 HPO clinical features (Orphanet curated; top 23 by frequency):

HPO ID	Term	Frequency
HP:0000532	Chorioretinal abnormality	Very frequent (80-99%)
HP:0000572	Visual loss	Very frequent (80-99%)
HP:0000610	Abnormal choroid morphology	Very frequent (80-99%)
HP:0007906	Ocular hypertension	Very frequent (80-99%)
HP:0008046	Abnormal retinal vascular morphology	Very frequent (80-99%)
HP:0011505	Cystoid macular edema	Very frequent (80-99%)
HP:0011531	Vitritis	Very frequent (80-99%)
HP:0030609	Photoreceptor layer loss on macular OCT	Very frequent (80-99%)
HP:0007843	Attenuation of retinal blood vessels	Frequent (30-79%)
HP:0011508	Macular hole	Frequent (30-79%)
HP:0030329	Retinal thinning	Frequent (30-79%)
HP:0030644	Blind-spot enlargment	Frequent (30-79%)
HP:0100014	Epiretinal membrane	Frequent (30-79%)
HP:0100533	Inflammatory abnormality of the eye	Frequent (30-79%)
HP:0100832	Vitreous floaters	Frequent (30-79%)
HP:0200056	Macular scar	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000543	Optic disc pallor	Frequent (30-79%)
HP:0000613	Photophobia	Frequent (30-79%)
HP:0000622	Blurred vision	Frequent (30-79%)
HP:0000541	Retinal detachment	Occasional (5-29%)
HP:0011506	Choroidal neovascularization	Occasional (5-29%)
HP:0030530	Arcuate scotoma	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	birdshot chorioretinopathy
Mondo ID	MONDO:0011599
MeSH	C537630
OMIM	605808
Orphanet	179
DOID	DOID:0111079
ICD-11	1954035043
SNOMED CT	231981005
UMLS	C1853959
MedGen	340098
GARD	0005926
Is cancer (heuristic)	no

Also known as: birdshot chorioretinitis · birdshot chorioretinopathy · birdshot retinochoroiditis · birdshot retinochoroidopathy · BSCR · multiple small, cream-colored lesions, symmetrically scattered mainly around the optic disc · multiple small, cream-colored lesions, symmetrically scattered mainly around the optic disk · vitiliginous choroiditis

Data availability: 3 GWAS associations (1 study).

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › uveal disorder › uveitis › posterior uveitis › birdshot chorioretinopathy

Related subtypes (2): choroiditis, retinitis

Genetics & variants

GWAS landscape

3 GWAS associations across 1 studies. Top hits map to 2 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
HLA-A*29:02	7e-74		?	157.5
rs7705093	2e-09	LNPEP	T	2.2
rs150571175	2e-07	TECPR2	A	4.6

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST002501	Kuiper JJ	2014	117	0	A genome-wide association study identifies a functional ERAP2 haplotype associated with birdshot chorioretinopathy.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

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

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	2
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	2
unknown	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
HLA-A*29:02				0.026			7e-74	Tier 4: intronic/intergenic
rs7705093	5	96954943	C>G,T	0.442	intron_variant	LNPEP	2e-09	Tier 4: intronic/intergenic
rs150571175	14	102379530	G>A,C,T	0.017	intron_variant	TECPR2	2e-07	Tier 4: intronic/intergenic

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ERAP1	Orphanet:117	Behçet disease
TECPR2	Orphanet:320385	Hereditary sensory and autonomic neuropathy due to TECPR2 mutation

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ERAP1	HGNC:18173	ENSG00000164307	Q9NZ08	Endoplasmic reticulum aminopeptidase 1	gwas
TECPR2	HGNC:19957	ENSG00000196663	O15040	Tectonin beta-propeller repeat-containing protein 2	gwas
ERAP2	HGNC:29499	ENSG00000164308	Q6P179	Endoplasmic reticulum aminopeptidase 2	gwas
LNPEP	HGNC:6656	ENSG00000113441	Q9UIQ6	Leucyl-cystinyl aminopeptidase	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ERAP1	Endoplasmic reticulum aminopeptidase 1	Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides.
TECPR2	Tectonin beta-propeller repeat-containing protein 2	Probably plays a role as positive regulator of autophagy.
ERAP2	Endoplasmic reticulum aminopeptidase 2	Aminopeptidase that plays a central role in peptide trimming, a step required for the generation of most HLA class I-binding peptides.
LNPEP	Leucyl-cystinyl aminopeptidase	Release of an N-terminal amino acid, cleaves before cysteine, leucine as well as other amino acids.

Protein-family classification

Druggable: 3 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.75

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	3	27.5×	2e-04
Scaffold/PPI	1	4.3×	0.212

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ERAP1	Protease	yes	3.4.11.1	Peptidase_M1, Peptidase_M1_dom, ERAP1-like_C_dom
TECPR2	Scaffold/PPI	no		WD40_rpt, Beta-propeller_rpt_TECPR, RCC1/BLIP-II
ERAP2	Protease	yes	3.4.11.1	Peptidase_M1, Peptidase_M1_dom, ERAP1-like_C_dom
LNPEP	Protease	yes	3.4.11.3	Peptidase_M1, Peptidase_M1_dom, ERAP1-like_C_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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
jejunal mucosa	1
monocyte	1
rectum	1
inferior vagus X ganglion	1
lateral globus pallidus	1
secondary oocyte	1
buccal mucosa cell	1
granulocyte	1
lymph node	1
Brodmann (1909) area 23	1
tibia	1
visceral pleura	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ERAP1	286	ubiquitous	marker	jejunal mucosa, rectum, monocyte
TECPR2	254	ubiquitous	marker	secondary oocyte, lateral globus pallidus, inferior vagus X ganglion
ERAP2	244	ubiquitous	marker	buccal mucosa cell, granulocyte, lymph node
LNPEP	275	ubiquitous	marker	visceral pleura, Brodmann (1909) area 23, tibia

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LNPEP	2,238
ERAP1	2,107
ERAP2	1,547
TECPR2	1,128

Intra-cohort edges

A	B	Sources
ERAP1	ERAP2	intact, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ERAP1	Q9NZ08	23
ERAP2	Q6P179	14
LNPEP	Q9UIQ6	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TECPR2	O15040	68.27

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 4 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
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	2	262.5×	2e-04	ERAP1, ERAP2
Endosomal/Vacuolar pathway	1	346.1×	0.014	LNPEP
Antigen processing-Cross presentation	1	105.7×	0.031	LNPEP
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	51.4×	0.048	LNPEP
Class I MHC mediated antigen processing & presentation	1	23.4×	0.084	LNPEP
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.105	LNPEP
Membrane Trafficking	1	12.4×	0.105	LNPEP
Vesicle-mediated transport	1	11.6×	0.105	LNPEP
Adaptive Immune System	1	9.9×	0.108	LNPEP
Immune System	1	4.3×	0.214	LNPEP

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
antigen processing and presentation of peptide antigen via MHC class I	2	1685.2×	4e-06	ERAP1, ERAP2
regulation of blood pressure	3	166.3×	4e-06	ERAP1, ERAP2, LNPEP
antigen processing and presentation of endogenous peptide antigen via MHC class I	2	1053.2×	8e-06	ERAP1, ERAP2
peptide catabolic process	2	526.6×	3e-05	ERAP1, ERAP2
proteolysis	3	25.7×	4e-04	ERAP1, ERAP2, LNPEP
antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-independent	1	4213.0×	8e-04	LNPEP
neuropeptide catabolic process	1	2106.5×	0.001	LNPEP
adaptive immune response	2	42.1×	0.002	ERAP1, ERAP2
protein exit from endoplasmic reticulum	1	526.6×	0.004	TECPR2
membrane protein ectodomain proteolysis	1	162.0×	0.012	ERAP1
regulation of innate immune response	1	162.0×	0.012	ERAP1
negative regulation of cold-induced thermogenesis	1	86.0×	0.020	LNPEP
protein catabolic process	1	59.3×	0.027	LNPEP
female pregnancy	1	52.7×	0.028	LNPEP
response to bacterium	1	48.4×	0.029	ERAP1
fat cell differentiation	1	45.3×	0.029	ERAP1
protein polyubiquitination	1	28.9×	0.040	LNPEP
positive regulation of angiogenesis	1	28.9×	0.040	ERAP1
autophagy	1	27.5×	0.040	TECPR2
cell-cell signaling	1	17.4×	0.059	LNPEP
angiogenesis	1	15.6×	0.063	ERAP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ERAP1	2	2
ERAP2	1	2
TECPR2	0	0
LNPEP	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TOSEDOSTAT	2	ERAP1, ERAP2
UBENIMEX	2	ERAP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
ERAP1	88	Binding:85, Functional:2, ADMET:1
ERAP2	46	Binding:40, ADMET:4, Functional:2
LNPEP	34	Binding:33, ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ERAP1	3.4.11.1, 3.4.11.22	leucyl aminopeptidase, aminopeptidase I
ERAP2	3.4.11.1, 3.4.11.6	leucyl aminopeptidase, aminopeptidase B
LNPEP	3.4.11.3	cystinyl aminopeptidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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)
TOSEDOSTAT	2	ERAP1, ERAP2
UBENIMEX	2	ERAP1

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	2	ERAP1, ERAP2
C	Druggable family + PDB, no drug	1	LNPEP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TECPR2

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)
TECPR2	0	—
LNPEP	34	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00508040	PHASE2	COMPLETED	Evaluation of Birdshot Retine Choroidopathy Treatment by Either Steroid or Interferon alpha2a
NCT05153057	Not specified	RECRUITING	Birdshot Chorioretinopathy : Prospective Follow-up and Immunogenetic Studies(CO-BIRD)
NCT06587828	Not specified	RECRUITING	A Biospecimen Collection Study to Identify the Targets of Disease-Reactive T Cells in Patients With Autoimmune Disease
NCT07065747	Not specified	RECRUITING	Quantification & Classification of Inflammatory Cells in Uveitis Using OCT

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CHEMBL15720	0	1