👪

Inheritance

1

Autosomal dominant HP:0000006

COPA syndrome follows autosomal dominant inheritance with incomplete penetrance and broad inter-individual variability in pulmonary, articular, and renal involvement.

Autosomal dominant inheritance Penetrance: INCOMPLETE Expressivity: VARIABLE

Show evidence (2 references)

PMID:37821196 SUPPORT Other

"COPA syndrome is a recently described autosomal dominant inborn error of immunity characterized by high titer autoantibodies and interstitial lung disease, with many individuals also having arthritis and nephritis."

Review abstract explicitly states the autosomal dominant inheritance pattern and core phenotype.

PMID:41395910 SUPPORT Human Clinical

"Among the 46 individuals carrying a COPA mutation, 38 had at least 1 clinical manifestation likely related to their mutant state (clinical penetrance of 83%)."

Cohort data support incomplete penetrance among mutation carriers.

◆

Subtypes

2

COPA WD40 domain (N-terminal) variants

Classical COPA syndrome caused by heterozygous missense variants in the N-terminal WD40 cargo-recognition domain of coatomer subunit alpha (e.g., p.Glu241Lys, p.Arg233His, p.Val242Gly). These variants impair binding of dilysine ER-retrieval cargo and SURF4-mediated STING retrieval, causing ligand-independent STING activation at the Golgi and a constitutive type I interferon signature.

Show evidence (1 reference)

PMID:25894502 SUPPORT Human Clinical

"We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain."

Watkin et al. localised the original recurrent disease-causing variants to a single functional WD40 cargo-recognition domain.

COPA C-terminal domain (CTD) variants

A clinically similar but mechanistically distinct subtype caused by heterozygous variants in the COPA C-terminal domain (e.g., p.Cys1013Ser, p.Arg1058Cys, p.Arg1142X). CTD mutations disrupt COPI integrity and cause both anterograde ER-to-Golgi and retrograde Golgi-to-ER trafficking defects, with cGAS/STING-dependent type I IFN upregulation accompanied by prominent ER stress and NF-kappaB activation.

Show evidence (1 reference)

PMID:38175705 SUPPORT Human Clinical

"We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity."

Delafontaine et al. delineate the CTD variant subtype with overlapping clinical features but a distinct molecular mechanism from canonical WD40 variants.

⚙

Pathophysiology

10

COPA pathogenic variants

Heterozygous deleterious COPA variants - most commonly missense changes in the N-terminal WD40 cargo-recognition domain of coatomer subunit alpha, with a smaller subset in the C-terminal domain - initiate the molecular cascade underlying COPA syndrome. The disease behaves as a dominant interferonopathy with incomplete clinical penetrance.

Downstream

Impaired COPI cargo recognition

Show evidence (2 references)

PMID:25894502 SUPPORT Human Clinical

"We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain."

Landmark discovery study identifying recurrent pathogenic COPA variants in affected families.

PMID:38175705 SUPPORT Human Clinical

"We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity."

Delafontaine et al. expand the COPA mutational spectrum to a CTD subtype that produces a clinically overlapping syndrome through a distinct mechanism.

Impaired COPI cargo recognition

Mutant COPA fails to bind dilysine ER-retrieval motifs and the SURF4 adapter, blocking selection of STING and other cargo into COPI-coated vesicles at the cis-Golgi. CTD variants additionally destabilise the coatomer assembly itself, producing both anterograde and retrograde trafficking defects.

SURF4 link

COPI-mediated cargo sorting link ⚠ ABNORMAL

Downstream

Impaired Golgi-to-ER protein retrieval

Show evidence (2 references)

PMID:25894502 SUPPORT In Vitro

"COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport."

Watkin et al. show direct loss of cargo binding by mutant COPA in vitro.

PMID:32725126 SUPPORT In Vitro

"SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi."

Deng et al. identify SURF4 as the adapter that physically links COPA to STING during retrograde retrieval, defining the proximal cargo-selection defect.

Impaired Golgi-to-ER protein retrieval

Loss of COPI-mediated cargo selection compromises retrograde retrieval of client proteins, including STING, from the Golgi to the endoplasmic reticulum and perturbs ER-Golgi homeostasis. CTD variants also disrupt anterograde ER-to-Golgi transport.

retrograde Golgi-to-ER transport link ⚠ ABNORMAL

Downstream

STING accumulation and activation at the Golgi

ER stress and unfolded protein response

Show evidence (1 reference)

PMID:38175705 SUPPORT In Vitro

"we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect."

CTD variant fibroblasts directly show bidirectional trafficking failure when COPI integrity is disrupted.

STING accumulation and activation at the Golgi

Failed COPA/SURF4-mediated retrieval traps ER-resident STING at the Golgi, where it multimerises and undergoes ligand-independent activation with TBK1 phosphorylation. STING activation is constitutive in WD40 variants and hyperactivated upon stimulation in dendritic cells from CTD- and other mutant carriers.

cGAS/STING signaling pathway link ↑ INCREASED

Golgi membrane link

Downstream

Constitutive type I interferon signaling

NF-kappaB-driven proinflammatory signaling

Interstitial lung disease

Diffuse alveolar hemorrhage

Show evidence (3 references)

PMID:32725128 SUPPORT In Vitro

"mutant COPA was associated with an accumulation of ER-resident STING at the Golgi."

Experimental evidence links COPA dysfunction directly to aberrant STING localization.

PMID:32725126 SUPPORT In Vitro

"We show that a defect in COPI transport causes ligand-independent activation of STING."

Deng et al. demonstrate that the trafficking failure itself is sufficient to activate STING in a ligand-independent manner.

PMID:33982886 SUPPORT In Vitro

"In CopaV242G/+ dendritic cells, the STING pathway was not constitutively activated but was hyperactivated upon stimulation, leading to increased type I IFN production."

Kato et al. show that even when COPA-mutant immune cells are not constitutively activated, STING signalling is hyperresponsive to ligand, providing a second mode of pathway dysregulation.

ER stress and unfolded protein response

Disturbed intracellular trafficking accumulates misfolded cargo and activates the unfolded protein response. ER stress contributes to proinflammatory cytokine output, NF-kappaB activation, and TH17 polarisation, and is genetically conserved in C. elegans copa-1 disease models.

response to endoplasmic reticulum stress link ↑ INCREASED ER unfolded protein response link ↑ INCREASED

Downstream

NF-kappaB-driven proinflammatory signaling

TH17-skewed adaptive immune dysregulation

Show evidence (3 references)

PMID:25894502 SUPPORT In Vitro

"expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response."

Watkin et al. directly link mutant COPA to ER stress and TH17-priming cytokines.

PMID:36748043 SUPPORT Model Organism

"these animals demonstrate an increased ER stress sensitivity."

A C. elegans copa-1 patient-allele model recapitulates ER stress sensitivity, supporting evolutionary conservation of this branch of the cascade.

PMID:38175705 SUPPORT In Vitro

"We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines."

Delafontaine et al. directly couple ER stress to NF-kappaB activation in CTD variant cells.

Constitutive type I interferon signaling

Golgi-retained STING drives persistent cGAS/STING-dependent type I interferon pathway activation through TBK1-IRF3 signalling and downstream JAK-STAT amplification, producing the elevated IFN-alpha and interferon-stimulated gene (ISG) signature seen in symptomatic patients. JAK inhibition is the principal mechanism-targeted therapy.

type I interferon-mediated signaling pathway link ↑ INCREASED JAK-STAT signaling link ↑ INCREASED

Downstream

TH17-skewed adaptive immune dysregulation

Autoimmune end-organ inflammation

Interstitial lung disease

Diffuse alveolar hemorrhage

Show evidence (3 references)

PMID:32725128 SUPPORT Human Clinical

"We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients."

Patient blood profiling demonstrates the interferon signature expected from constitutive STING activation.

PMID:32725126 SUPPORT Model Organism

"Activated STING stimulates type I interferon-driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals."

STING knockout rescues the IFN-driven inflammatory phenotype in CopaE241K/+ mice, formally placing STING downstream of mutant COPA in the disease cascade.

PMID:38175705 SUPPORT In Vitro

"The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines"

CTD variant cells show that the IFN signature is cGAS/STING-dependent, generalising the mechanism beyond WD40 variants.

NF-kappaB-driven proinflammatory signaling

Sustained ER stress and Golgi-localised STING signalling activate canonical NF-kappaB and induce IL-1beta, IL-6, and other proinflammatory cytokines that amplify autoinflammation. NF-kappaB activation is most prominently demonstrated in CTD variant cells.

canonical NF-kappaB signal transduction link ↑ INCREASED

Downstream

TH17-skewed adaptive immune dysregulation

Arthritis

Autoimmune antibody positivity

Show evidence (2 references)

PMID:38175705 SUPPORT In Vitro

"CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinﬂammatory signaling."

Delafontaine et al. summarise the CTD mechanism as ER stress plus increased proinflammatory (NF-kappaB) signalling.

PMID:30804679 SUPPORT Other

"Immunological features involve autoantibody formation, elevated expression of IL-1β and IL-6, and increase in the number of Th17 cells."

Kumrah et al. describe the elevated IL-1beta and IL-6 cytokine profile expected from NF-kappaB activation, linking it to TH17 expansion in patients.

TH17-skewed adaptive immune dysregulation

Sustained type I interferon signalling, ER stress, and IL-6/IL-1beta output skew CD4+ T cells toward a TH17 fate, drive B-cell autoantibody production, and produce the autoimmune cytokine milieu underlying chronic injury in lung, joint, and kidney tissues.

CD4+ T cell link T-helper 17 cell link

T-helper 17 cell differentiation link ↑ INCREASED

Downstream

Autoimmune end-organ inflammation

Arthritis

Rheumatoid factor positivity

Show evidence (2 references)

PMID:25894502 SUPPORT In Vitro

"Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity."

Patient-derived T-cell data provide direct evidence of TH17-biased adaptive immune activation in COPA syndrome.

PMID:41395910 SUPPORT Human Clinical

"All but 1 patient tested positive for autoantibodies, and increased interferon signalling was noted in all those tested."

Large cohort data confirm the characteristic combination of autoantibody positivity and interferon activation in clinically affected patients.

Autoimmune end-organ inflammation

Convergent type I interferon, NF-kappaB, and TH17/autoantibody output targets the lung (interstitial pneumonia, capillaritis, alveolar haemorrhage, lymphoid hyperplasia), the synovium (inflammatory arthritis), and the kidney (ANCA-associated, lupus-like or immune-complex glomerulonephritis), and is the proximate driver of the clinical phenotype.

Downstream

Interstitial lung disease

Diffuse alveolar hemorrhage

Arthritis

Glomerulonephritis

Show evidence (2 references)

PMID:36746811 SUPPORT Human Clinical

"The most prevalent imaging finding of COPA syndrome is diffuse lung disease related to early childhood-onset recurrent pulmonary hemorrhage and lymphoid hyperplasia that may progress to pulmonary fibrosis."

Imaging cohort confirms that the dominant clinical manifestation is lung-targeted autoimmune injury, with progression to fibrosis.

PMID:41932423 SUPPORT Human Clinical

"Kidney involvement was heterogenous between patients (ANCA-associated vasculitis-like disease, lupus or immune-complex mediated glomerulonephritis or overlapping phenotypes), and all had advanced histological damage at clinical presentation."

Renal histology in COPA syndrome shows multiple immune-mediated glomerulonephritis patterns consistent with autoimmune end-organ injury.

HAQ STING dominant suppression of STING signalling

The common HAQ haplotype of STING1 (R71H/G230A/R293Q) dominantly dampens STING signalling. When co-inherited with a pathogenic COPA variant, HAQ STING fully prevents the constitutive STING activation that drives type I interferon signalling and provides complete clinical protection in carriers, accounting for much of the observed incomplete penetrance.

STING1 link

cGAS/STING signaling pathway link ↓ DECREASED

Show evidence (2 references)

PMID:40014299 SUPPORT Human Clinical

"We show that the common HAQ STING allele mediates complete clinical protection."

Simchoni et al. establish HAQ STING as a dominant clinical modifier in COPA syndrome.

PMID:40014299 SUPPORT In Vitro

"Expressing HAQ STING in patient cells rescued the molecular phenotype of COPA syndrome."

Cellular rescue experiments confirm the molecular mechanism of HAQ STING-mediated protection and motivate STING-directed gene therapy.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

Referential integrity issues (1):

Target 'Autoimmune antibody positivity' (from 'NF-kappaB-driven proinflammatory signaling') not found in named elements

●

Phenotypes

22

Blood 1

Diffuse alveolar hemorrhage OCCASIONAL Diffuse alveolar hemorrhage (HP:0025420)

Onset: CHILDHOOD

Show evidence (1 reference)

PMID:41395910 SUPPORT Human Clinical

"Pulmonary involvement was observed in 34 patients, with interstitial lung disease in most cases (n = 31) and diffuse alveolar haemorrhage in 11 individuals."

The same cohort explicitly documents diffuse alveolar hemorrhage as a core pulmonary feature; 11/38 symptomatic patients had diffuse alveolar hemorrhage, which is 29% and falls in the OCCASIONAL band.

Cardiovascular 2

Mediastinal lymphadenopathy VERY_FREQUENT Mediastinal lymphadenopathy (HP:0100721)

Show evidence (1 reference)

PMID:36746811 SUPPORT Human Clinical

"All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12)."

Hilar/mediastinal lymphadenopathy was present on chest CT in 11/12 (~92%) of pediatric COPA patients, supporting VERY_FREQUENT classification.

Cardiac involvement OCCASIONAL Abnormality of the cardiovascular system (HP:0001626)

Show evidence (1 reference)

PMID:41395910 SUPPORT Human Clinical

"Previously undescribed features included skin (n = 12), cardiac (n = 8), gastrointestinal (n = 7), and hepatic involvement (n = 5)."

Cardiac involvement was reported in 8/38 (21%) symptomatic patients in the European cohort, falling within the OCCASIONAL band.

Digestive 1

Gastrointestinal involvement OCCASIONAL Abnormality of the gastrointestinal tract (HP:0011024)

Show evidence (1 reference)

PMID:41395910 SUPPORT Human Clinical

"Previously undescribed features included skin (n = 12), cardiac (n = 8), gastrointestinal (n = 7), and hepatic involvement (n = 5)."

Gastrointestinal involvement was reported in 7/38 (18%) symptomatic patients, within the OCCASIONAL band.

Integument 1

Cutaneous involvement FREQUENT Abnormality of the skin (HP:0000951)

Show evidence (1 reference)

PMID:41395910 SUPPORT Human Clinical

"Previously undescribed features included skin (n = 12), cardiac (n = 8), gastrointestinal (n = 7), and hepatic involvement (n = 5)."

Skin involvement was reported in 12/38 (32%) symptomatic patients in the European cohort, supporting FREQUENT classification.

Musculoskeletal 1

Arthritis FREQUENT Arthritis (HP:0001369)

Onset: CHILDHOOD

Show evidence (1 reference)

PMID:41395910 SUPPORT Human Clinical

"Twenty-six patients demonstrated joint involvement, and 7 had documented kidney disease."

Cohort data show that inflammatory joint involvement is common among symptomatic patients; 26/38 affected individuals had joint involvement, which is 68% and falls in the FREQUENT band.

Respiratory 2

Interstitial lung disease VERY_FREQUENT Abnormal pulmonary interstitial morphology (HP:0006530)

Onset: CHILDHOOD

Show evidence (1 reference)

PMID:41395910 SUPPORT Human Clinical

"Pulmonary involvement was observed in 34 patients, with interstitial lung disease in most cases (n = 31) and diffuse alveolar haemorrhage in 11 individuals."

Multicenter European cohort confirms interstitial lung disease as the most common organ manifestation; 31/38 symptomatic patients had ILD, which is 82% and falls in the VERY_FREQUENT band.

Pulmonary fibrosis Pulmonary fibrosis (HP:0002206)

Show evidence (1 reference)

PMID:37821196 SUPPORT Other

"Onset is usually in early childhood, with unique disease features including alveolar hemorrhage, which can be insidious, pulmonary cyst formation, and progressive pulmonary fibrosis in nonspecific interstitial pneumonia or lymphocytic interstitial pneumonia patterns."

Review abstract identifies progressive pulmonary fibrosis as a distinctive pulmonary manifestation within the COPA syndrome ILD spectrum.

Other 14

Pulmonary cyst formation Pulmonary cyst (HP:0032445)

Show evidence (1 reference)

PMID:37821196 SUPPORT Other

"Onset is usually in early childhood, with unique disease features including alveolar hemorrhage, which can be insidious, pulmonary cyst formation, and progressive pulmonary fibrosis in nonspecific interstitial pneumonia or lymphocytic interstitial pneumonia patterns."

Review abstract identifies pulmonary cyst formation as a characteristic COPA syndrome lung feature.

Glomerulonephritis Glomerulonephritis (HP:0000099)

Show evidence (1 reference)

PMID:41932423 SUPPORT Human Clinical

"Kidney involvement was heterogenous between patients (ANCA-associated vasculitis-like disease, lupus or immune-complex mediated glomerulonephritis or overlapping phenotypes), and all had advanced histological damage at clinical presentation."

Kidney transplant case series demonstrates that glomerulonephritis is part of the renal disease spectrum in COPA syndrome.

Diffuse pulmonary lymphoid hyperplasia Diffuse pulmonary lymphoid hyperplasia (HP:0034824)

Show evidence (1 reference)

PMID:36746811 SUPPORT Human Clinical

"The most prevalent imaging finding of COPA syndrome is diffuse lung disease related to early childhood-onset recurrent pulmonary hemorrhage and lymphoid hyperplasia that may progress to pulmonary fibrosis."

Pediatric imaging cohort identifies pulmonary lymphoid hyperplasia as a defining component of COPA syndrome lung disease.

Ground-glass opacification VERY_FREQUENT Ground-glass opacification (HP:0025179)

Show evidence (1 reference)

PMID:36746811 SUPPORT Human Clinical

"All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12)."

Ground-glass opacification was seen in 12/12 (100%) of pediatric patients on chest CT.

Pulmonary nodules Pulmonary nodule (HP:0033608)

Show evidence (1 reference)

PMID:36746811 SUPPORT Human Clinical

"All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12)."

Pulmonary nodules were detected in 8/12 patients on chest CT in the imaging cohort.

Crazy paving pattern Crazy paving pattern (HP:0025391)

Show evidence (1 reference)

PMID:36746811 SUPPORT Human Clinical

"All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12)."

A crazy-paving pattern was identified in 2/12 patients on chest CT, supporting it as a recognised but less common COPA syndrome finding.

Synovitis Synovitis (HP:0100769)

Show evidence (1 reference)

PMID:36746811 SUPPORT Human Clinical

"Four had musculoskeletal imaging revealing synovitis (2/4), bone erosions (1/4), tenosynovitis (1/4), enthesitis (1/4), and subcutaneous nodules (1/4)."

Musculoskeletal MRI in COPA syndrome documents synovitis as the dominant inflammatory finding.

Antinuclear antibody positivity Antinuclear antibody positivity (HP:0003493)

Show evidence (1 reference)

PMID:29977900 SUPPORT Human Clinical

"All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity."

International cohort confirms ANA (with or without ANCA) in all subjects, supporting ANA positivity as a defining serologic feature.

Antineutrophil cytoplasmic antibody positivity Cytoplasmic antineutrophil antibody positivity (HP:0032230)

Show evidence (1 reference)

PMID:29977900 SUPPORT Human Clinical

"All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity."

International COPA cohort documents ANCA positivity (with or without ANA) in all subjects.

Rheumatoid factor positivity FREQUENT Rheumatoid factor positive (HP:0002923)

Show evidence (1 reference)

PMID:29977900 SUPPORT Human Clinical

"All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity."

71% RF positivity in the international pulmonary cohort places this within the FREQUENT band.

Type I interferon signature Increased circulating Interferon-alpha concentration (HP:0034513)

Show evidence (1 reference)

PMID:29030294 SUPPORT Human Clinical

"Analysis of peripheral blood showed activation of type 1 interferon pathway, which was also confirmed in 4 previously reported COPA patients."

Volpi et al. demonstrate type I interferon pathway activation as a peripheral blood signature confirmed across multiple COPA syndrome cases.

Increased Th17 T cell proportion Increased Th17 T cell proportion (HP:0025831)

Show evidence (1 reference)

PMID:25894502 SUPPORT In Vitro

"Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity."

Watkin et al. directly demonstrate TH17 skewing in patient-derived CD4 T cells.

Follicular bronchiolitis Follicular bronchiolitis (HP:0033583)

Show evidence (1 reference)

PMID:29977900 SUPPORT Human Clinical

"The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy."

Tsui et al. identify follicular bronchiolitis on lung biopsy as one of the most common pulmonary findings in the international COPA cohort.

Hepatic involvement OCCASIONAL Abnormality of the liver (HP:0001392)

Show evidence (1 reference)

PMID:41395910 SUPPORT Human Clinical

"Previously undescribed features included skin (n = 12), cardiac (n = 8), gastrointestinal (n = 7), and hepatic involvement (n = 5)."

Hepatic involvement was reported in 5/38 (13%) symptomatic patients, within the OCCASIONAL band; this complements earlier descriptions of unexplained transaminitis (PMID:32970305).

🧬

Genetic Associations

2

COPA (Causative)

Autosomal dominant

Show evidence (2 references)

PMID:25894502 SUPPORT Human Clinical

"We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain."

Original family-based genetic study establishes COPA as the causative disease gene with WD40 domain variants.

PMID:38175705 SUPPORT Human Clinical

"We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity."

Delafontaine et al. expand the COPA mutational spectrum to include CTD variants.

STING1 HAQ protective modifier (non-causal) (Non-causal protective haplotype that prevents clinical penetrance)

Show evidence (2 references)

PMID:40014299 SUPPORT Human Clinical

"We show that the common HAQ STING allele mediates complete clinical protection."

Co-segregation analysis of 35 COPA variant carriers establishes HAQ STING as a dominant clinical modifier.

PMID:40014299 SUPPORT In Vitro

"we found that HAQ STING acts dominantly to dampen COPA-dependent STING signaling."

Cellular experiments confirm the dominant suppressive mechanism of HAQ STING on COPA-dependent STING signalling.

💊

Treatments

5

Janus kinase inhibitor therapy

Action: Pharmacotherapy NCIT:C15986

Agent: JAK inhibitor ↗

JAK inhibitors block JAK-STAT signalling downstream of the type I interferon receptor and are the most promising mechanism-targeted therapy in COPA syndrome. Evidence level: observational cohort and review-level support, with published cohort-level evidence supporting baricitinib and ruxolitinib for both interstitial lung disease and arthritis.

Mechanism Target:

INHIBITS Constitutive type I interferon signaling

Show evidence (3 references)

PMID:41395910 SUPPORT Human Clinical

"Twenty-two patients were treated with Janus kinase inhibitors with promising efficacy."

Large European cohort provides the strongest available abstract-level support for JAK inhibitor use in COPA syndrome.

PMID:39767180 SUPPORT Other

"JAK inhibitor therapy seems to be the most promising therapeutic choice now."

2024 review highlights JAK inhibition as the leading current therapeutic strategy.

PMID:38768895 SUPPORT Human Clinical

"Baricitinib treatment in children with COPA syndrome."

Matucci-Cerinic et al. report a pediatric case series of baricitinib (a JAK1/JAK2 inhibitor) in children with COPA syndrome, supporting the JAK inhibitor class for pediatric disease. The PubMed record is a letter without a structured abstract, so the canonical title is used as the reference statement.

Immunosuppression for diffuse alveolar hemorrhage

Action: Pharmacotherapy NCIT:C15986

Standard induction for severe alveolar hemorrhage uses systemic glucocorticoids combined with cyclophosphamide, with subsequent maintenance using mycophenolate mofetil or azathioprine. Evidence level: case series/observational standard care. Radiographic improvement is common but pulmonary function may continue to decline.

Show evidence (1 reference)

PMID:29977900 SUPPORT Human Clinical

"All subjects received immunosuppressive therapy."

Tsui et al. report that all subjects in the international pulmonary cohort received immunosuppressive therapy as standard care.

Lung transplantation

Action: lung transplantation Ontology label: organ transplantation MAXO:0010039

Lung transplantation is offered to patients with end-stage progressive interstitial lung disease refractory to immunosuppression and JAK inhibition. Evidence level: case reports/literature review for end-stage COPA lung disease, with allograft dysfunction reported.

Show evidence (1 reference)

PMID:35079820 SUPPORT Human Clinical

"Two out of four patients required lung transplantation due to intractable interstitial lung disease and respiratory failure."

Case report documents lung transplantation as a treatment option for end-stage COPA syndrome interstitial lung disease unresponsive to immunosuppression.

Kidney transplantation

Action: kidney transplantation Ontology label: organ transplantation MAXO:0010039

Patients who progress to advanced glomerular damage and end-stage renal disease require kidney transplantation, with outcomes documented in a multi-patient case series. Evidence level: five-patient observational case series.

Show evidence (1 reference)

PMID:41932423 SUPPORT Human Clinical

"Kidney involvement was heterogenous between patients (ANCA-associated vasculitis-like disease, lupus or immune-complex mediated glomerulonephritis or overlapping phenotypes), and all had advanced histological damage at clinical presentation."

Case series describes five COPA syndrome patients with advanced renal histology presenting for kidney transplant evaluation.

STING-directed therapy (experimental)

Action: Pharmacotherapy NCIT:C15986

Direct STING pathway inhibition (e.g., small-molecule inhibitors such as H-151) and STING1-directed gene therapy aimed at introducing the protective HAQ allele are emerging upstream therapeutic strategies based on the central role of Golgi-localised STING activation in COPA syndrome. Evidence level: experimental/preclinical, with BI 3000202 now in Phase 1 safety and tolerability testing for selected type I interferonopathies including COPA syndrome.

Mechanism Target:

INHIBITS STING accumulation and activation at the Golgi

Show evidence (1 reference)

PMID:40014299 SUPPORT In Vitro

"Expressing HAQ STING in patient cells rescued the molecular phenotype of COPA syndrome."

Cellular rescue with HAQ STING establishes proof-of-concept for STING-directed gene therapy, framed as "a potential universal gene therapy approach for patients."

🔬

Biochemical Markers

2

Autoantibodies (Elevated)

Context: High-titer autoantibodies are characteristic and seropositivity is present in nearly all tested symptomatic patients.

Show evidence (1 reference)

PMID:41395910 SUPPORT Human Clinical

"All but 1 patient tested positive for autoantibodies, and increased interferon signalling was noted in all those tested."

Large cohort data support autoantibody positivity as a defining immunologic feature.

Type I interferon signature (Elevated)

Context: Increased ISG expression and interferon signaling are central molecular biomarkers of disease activity.

Show evidence (1 reference)

PMID:32725128 SUPPORT Human Clinical

"We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients."

Patient blood assays demonstrate a systemic type I interferon signature.

🔬

Clinical Trials

1

NCT06878365 PHASE_I ACTIVE_NOT_RECRUITING

Phase 1 active-not-recruiting, open-label single-group tolerability study sponsored by Boehringer Ingelheim. Adults with selected type I interferonopathies, including COPA syndrome, receive BI 3000202 low-dose tablets for 4 weeks followed by higher-dose tablets for 36 weeks, with interferon gene score change as a key pharmacodynamic outcome.

Target Phenotypes: Type I interferon signature ↗

Show evidence (1 reference)

clinicaltrials:NCT06878365 SUPPORT

"People can join the study if they have Aicardi-Goutières syndrome (AGS), Coatomer subunit alpha (COPA) syndrome, Familial chilblain lupus (FCL), or another type 1 interferonopathy with a specific gene mutation."

ClinicalTrials.gov registration explicitly enrols COPA syndrome patients in this Phase 1 BI 3000202 tolerability study.

{ }

Source YAML

click to show

name: COPA Syndrome
creation_date: "2026-04-12T17:08:20Z"
updated_date: "2026-04-25T19:00:00Z"
category: Mendelian
synonyms:
- autoimmune interstitial lung disease-arthritis syndrome
- autoimmune interstitial lung, joint, and kidney disease
- AILJK
- coatomer subunit alpha syndrome
description: >
  COPA syndrome is an autosomal dominant inborn error of immunity caused by
  heterozygous pathogenic variants in COPA encoding coatomer subunit alpha. It
  presents in early childhood with interstitial lung disease (often with
  diffuse alveolar hemorrhage and pulmonary lymphoid hyperplasia),
  inflammatory polyarthritis, high-titer autoantibodies, and variable
  immune-mediated kidney disease. The molecular cascade reflects impaired
  COPI-mediated retrograde Golgi-to-ER trafficking with failed retrieval of
  STING by the SURF4 adapter, ligand-independent STING accumulation at the
  Golgi, cGAS/STING-dependent type I interferon signaling, ER stress and
  unfolded protein response activation, NF-kappaB-driven proinflammatory
  cytokine output, and TH17-skewed adaptive immune dysregulation that
  promotes autoantibody-positive end-organ inflammation. Penetrance is
  incomplete, and the common HAQ STING haplotype dominantly suppresses STING
  signaling and prevents clinical disease in carriers.
disease_term:
  preferred_term: COPA syndrome
  term:
    id: MONDO:0014629
    label: autoimmune interstitial lung disease-arthritis syndrome
parents:
- Autoinflammatory diseases
- Inborn errors of immunity
- Interstitial lung disease
- Type I interferonopathies
has_subtypes:
- name: WD40 domain
  display_name: COPA WD40 domain (N-terminal) variants
  description: >
    Classical COPA syndrome caused by heterozygous missense variants in the
    N-terminal WD40 cargo-recognition domain of coatomer subunit alpha
    (e.g., p.Glu241Lys, p.Arg233His, p.Val242Gly). These variants impair
    binding of dilysine ER-retrieval cargo and SURF4-mediated STING
    retrieval, causing ligand-independent STING activation at the Golgi and
    a constitutive type I interferon signature.
  evidence:
  - reference: PMID:25894502
    reference_title: "COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain."
    explanation: Watkin et al. localised the original recurrent disease-causing variants to a single functional WD40 cargo-recognition domain.
- name: C-terminal domain
  display_name: COPA C-terminal domain (CTD) variants
  description: >
    A clinically similar but mechanistically distinct subtype caused by
    heterozygous variants in the COPA C-terminal domain (e.g., p.Cys1013Ser,
    p.Arg1058Cys, p.Arg1142X). CTD mutations disrupt COPI integrity and
    cause both anterograde ER-to-Golgi and retrograde Golgi-to-ER
    trafficking defects, with cGAS/STING-dependent type I IFN upregulation
    accompanied by prominent ER stress and NF-kappaB activation.
  evidence:
  - reference: PMID:38175705
    reference_title: "Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity."
    explanation: Delafontaine et al. delineate the CTD variant subtype with overlapping clinical features but a distinct molecular mechanism from canonical WD40 variants.
pathophysiology:
- name: COPA pathogenic variants
  description: >
    Heterozygous deleterious COPA variants - most commonly missense changes
    in the N-terminal WD40 cargo-recognition domain of coatomer subunit
    alpha, with a smaller subset in the C-terminal domain - initiate the
    molecular cascade underlying COPA syndrome. The disease behaves as a
    dominant interferonopathy with incomplete clinical penetrance.
  gene:
    preferred_term: COPA
    term:
      id: hgnc:2230
      label: COPA
  downstream:
  - target: Impaired COPI cargo recognition
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:25894502
    reference_title: "COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain."
    explanation: Landmark discovery study identifying recurrent pathogenic COPA variants in affected families.
  - reference: PMID:38175705
    reference_title: "Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity."
    explanation: Delafontaine et al. expand the COPA mutational spectrum to a CTD subtype that produces a clinically overlapping syndrome through a distinct mechanism.
- name: Impaired COPI cargo recognition
  description: >
    Mutant COPA fails to bind dilysine ER-retrieval motifs and the SURF4
    adapter, blocking selection of STING and other cargo into COPI-coated
    vesicles at the cis-Golgi. CTD variants additionally destabilise the
    coatomer assembly itself, producing both anterograde and retrograde
    trafficking defects.
  gene:
    preferred_term: COPA
    term:
      id: hgnc:2230
      label: COPA
  genes:
  - preferred_term: SURF4
    term:
      id: hgnc:11476
      label: SURF4
  biological_processes:
  - preferred_term: COPI-mediated cargo sorting
    term:
      id: GO:0006890
      label: retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
    modifier: ABNORMAL
  downstream:
  - target: Impaired Golgi-to-ER protein retrieval
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:25894502
    reference_title: "COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "COPA variants impair binding to proteins targeted for retrograde Golgi-to-ER transport."
    explanation: Watkin et al. show direct loss of cargo binding by mutant COPA in vitro.
  - reference: PMID:32725126
    reference_title: "A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SURF4 is an adapter molecule that facilitates COPA-mediated retrieval of STING at the Golgi."
    explanation: Deng et al. identify SURF4 as the adapter that physically links COPA to STING during retrograde retrieval, defining the proximal cargo-selection defect.
- name: Impaired Golgi-to-ER protein retrieval
  description: >
    Loss of COPI-mediated cargo selection compromises retrograde retrieval
    of client proteins, including STING, from the Golgi to the endoplasmic
    reticulum and perturbs ER-Golgi homeostasis. CTD variants also disrupt
    anterograde ER-to-Golgi transport.
  biological_processes:
  - preferred_term: retrograde Golgi-to-ER transport
    term:
      id: GO:0006890
      label: retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
    modifier: ABNORMAL
  downstream:
  - target: STING accumulation and activation at the Golgi
    causal_link_type: DIRECT
  - target: ER stress and unfolded protein response
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:38175705
    reference_title: "Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we demonstrated that COPI dysfunction causes both an anterograde ER-to-Golgi and a retrograde Golgi-to-ER trafficking defect."
    explanation: CTD variant fibroblasts directly show bidirectional trafficking failure when COPI integrity is disrupted.
- name: STING accumulation and activation at the Golgi
  description: >
    Failed COPA/SURF4-mediated retrieval traps ER-resident STING at the
    Golgi, where it multimerises and undergoes ligand-independent activation
    with TBK1 phosphorylation. STING activation is constitutive in WD40
    variants and hyperactivated upon stimulation in dendritic cells from
    CTD- and other mutant carriers.
  cellular_components:
  - preferred_term: Golgi membrane
    term:
      id: GO:0000139
      label: Golgi membrane
    modifier: ABNORMAL
  biological_processes:
  - preferred_term: cGAS/STING signaling pathway
    term:
      id: GO:0140896
      label: cGAS/STING signaling pathway
    modifier: INCREASED
  downstream:
  - target: Constitutive type I interferon signaling
    causal_link_type: DIRECT
  - target: NF-kappaB-driven proinflammatory signaling
    causal_link_type: DIRECT
  - target: Interstitial lung disease
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Type I interferon-driven pulmonary inflammation and lymphoid hyperplasia
  - target: Diffuse alveolar hemorrhage
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Pulmonary capillaritis and autoimmune alveolar injury
  evidence:
  - reference: PMID:32725128
    reference_title: "Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "mutant COPA was associated with an accumulation of ER-resident STING at the Golgi."
    explanation: Experimental evidence links COPA dysfunction directly to aberrant STING localization.
  - reference: PMID:32725126
    reference_title: "A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that a defect in COPI transport causes ligand-independent activation of STING."
    explanation: Deng et al. demonstrate that the trafficking failure itself is sufficient to activate STING in a ligand-independent manner.
  - reference: PMID:33982886
    reference_title: "Augmentation of Stimulator of Interferon Genes-Induced Type I Interferon Production in COPA Syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In CopaV242G/+ dendritic cells, the STING pathway was not constitutively activated but was hyperactivated upon stimulation, leading to increased type I IFN production."
    explanation: Kato et al. show that even when COPA-mutant immune cells are not constitutively activated, STING signalling is hyperresponsive to ligand, providing a second mode of pathway dysregulation.
- name: ER stress and unfolded protein response
  description: >
    Disturbed intracellular trafficking accumulates misfolded cargo and
    activates the unfolded protein response. ER stress contributes to
    proinflammatory cytokine output, NF-kappaB activation, and TH17
    polarisation, and is genetically conserved in C. elegans copa-1 disease
    models.
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  - preferred_term: ER unfolded protein response
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
  downstream:
  - target: NF-kappaB-driven proinflammatory signaling
    causal_link_type: DIRECT
  - target: TH17-skewed adaptive immune dysregulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - ER stress-induced IL-1beta and IL-6 cytokine output priming TH17 differentiation
  evidence:
  - reference: PMID:25894502
    reference_title: "COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "expression of mutant COPA results in ER stress and the upregulation of cytokines priming for a T helper type 17 (TH17) response."
    explanation: Watkin et al. directly link mutant COPA to ER stress and TH17-priming cytokines.
  - reference: PMID:36748043
    reference_title: "copa-1 mutants experience heightened endoplasmic reticulum stress sensitivity in a C. elegans COPA Syndrome model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "these animals demonstrate an increased ER stress sensitivity."
    explanation: A C. elegans copa-1 patient-allele model recapitulates ER stress sensitivity, supporting evolutionary conservation of this branch of the cascade.
  - reference: PMID:38175705
    reference_title: "Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We showed that CTD COPA mutations induce an activation of ER stress and NF-κB signaling in patient-derived primary cell lines."
    explanation: Delafontaine et al. directly couple ER stress to NF-kappaB activation in CTD variant cells.
- name: Constitutive type I interferon signaling
  description: >
    Golgi-retained STING drives persistent cGAS/STING-dependent type I
    interferon pathway activation through TBK1-IRF3 signalling and
    downstream JAK-STAT amplification, producing the elevated IFN-alpha and
    interferon-stimulated gene (ISG) signature seen in symptomatic
    patients. JAK inhibition is the principal mechanism-targeted therapy.
  biological_processes:
  - preferred_term: type I interferon-mediated signaling pathway
    term:
      id: GO:0060337
      label: type I interferon-mediated signaling pathway
    modifier: INCREASED
  - preferred_term: JAK-STAT signaling
    term:
      id: GO:0007259
      label: cell surface receptor signaling pathway via JAK-STAT
    modifier: INCREASED
  downstream:
  - target: TH17-skewed adaptive immune dysregulation
    causal_link_type: DIRECT
  - target: Autoimmune end-organ inflammation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - ISG-driven endothelial and epithelial activation
    - Autoantibody-mediated tissue injury
  - target: Interstitial lung disease
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - STING-dependent type I interferon signaling in lung tissue
  - target: Diffuse alveolar hemorrhage
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Autoimmune pulmonary capillaritis and alveolar hemorrhage
  evidence:
  - reference: PMID:32725128
    reference_title: "Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients."
    explanation: Patient blood profiling demonstrates the interferon signature expected from constitutive STING activation.
  - reference: PMID:32725126
    reference_title: "A defect in COPI-mediated transport of STING causes immune dysregulation in COPA syndrome."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Activated STING stimulates type I interferon-driven inflammation in CopaE241K/+ mice that is rescued in STING-deficient animals."
    explanation: STING knockout rescues the IFN-driven inflammatory phenotype in CopaE241K/+ mice, formally placing STING downstream of mutant COPA in the disease cascade.
  - reference: PMID:38175705
    reference_title: "Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The disturbed intracellular trafficking resulted in a cGAS/STING-dependent upregulation of the type I IFN signaling in patients and patient-derived cell lines"
    explanation: CTD variant cells show that the IFN signature is cGAS/STING-dependent, generalising the mechanism beyond WD40 variants.
- name: NF-kappaB-driven proinflammatory signaling
  description: >
    Sustained ER stress and Golgi-localised STING signalling activate
    canonical NF-kappaB and induce IL-1beta, IL-6, and other proinflammatory
    cytokines that amplify autoinflammation. NF-kappaB activation is most
    prominently demonstrated in CTD variant cells.
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: INCREASED
  downstream:
  - target: TH17-skewed adaptive immune dysregulation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - IL-6 / IL-1beta-driven TH17 polarisation
  - target: Arthritis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Proinflammatory cytokine activation of synovial inflammation
  - target: Autoimmune antibody positivity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - NF-kappaB-supported inflammatory B-cell activation
  evidence:
  - reference: PMID:38175705
    reference_title: "Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CTD COPA mutations result in disease by increased ER stress, disturbed intracellular transport, and increased proinﬂammatory signaling."
    explanation: Delafontaine et al. summarise the CTD mechanism as ER stress plus increased proinflammatory (NF-kappaB) signalling.
  - reference: PMID:30804679
    reference_title: "Genetics of COPA syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Immunological features involve autoantibody formation, elevated expression of IL-1β and IL-6, and increase in the number of Th17 cells."
    explanation: Kumrah et al. describe the elevated IL-1beta and IL-6 cytokine profile expected from NF-kappaB activation, linking it to TH17 expansion in patients.
- name: TH17-skewed adaptive immune dysregulation
  description: >
    Sustained type I interferon signalling, ER stress, and IL-6/IL-1beta
    output skew CD4+ T cells toward a TH17 fate, drive B-cell autoantibody
    production, and produce the autoimmune cytokine milieu underlying
    chronic injury in lung, joint, and kidney tissues.
  cell_types:
  - preferred_term: CD4+ T cell
    term:
      id: CL:0000624
      label: CD4-positive, alpha-beta T cell
  - preferred_term: T-helper 17 cell
    term:
      id: CL:0000899
      label: T-helper 17 cell
  biological_processes:
  - preferred_term: T-helper 17 cell differentiation
    term:
      id: GO:0072539
      label: T-helper 17 cell differentiation
    modifier: INCREASED
  downstream:
  - target: Autoimmune end-organ inflammation
    causal_link_type: DIRECT
  - target: Arthritis
    causal_link_type: DIRECT
  - target: Rheumatoid factor positivity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - TH17-skewed adaptive immune activation and B-cell autoantibody production
  evidence:
  - reference: PMID:25894502
    reference_title: "COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity."
    explanation: Patient-derived T-cell data provide direct evidence of TH17-biased adaptive immune activation in COPA syndrome.
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All but 1 patient tested positive for autoantibodies, and increased interferon signalling was noted in all those tested."
    explanation: Large cohort data confirm the characteristic combination of autoantibody positivity and interferon activation in clinically affected patients.
- name: Autoimmune end-organ inflammation
  description: >
    Convergent type I interferon, NF-kappaB, and TH17/autoantibody output
    targets the lung (interstitial pneumonia, capillaritis, alveolar
    haemorrhage, lymphoid hyperplasia), the synovium (inflammatory
    arthritis), and the kidney (ANCA-associated, lupus-like or
    immune-complex glomerulonephritis), and is the proximate driver of the
    clinical phenotype.
  downstream:
  - target: Interstitial lung disease
    causal_link_type: DIRECT
  - target: Diffuse alveolar hemorrhage
    causal_link_type: DIRECT
  - target: Arthritis
    causal_link_type: DIRECT
  - target: Glomerulonephritis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:36746811
    reference_title: "Imaging findings of COPA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most prevalent imaging finding of COPA syndrome is diffuse lung disease related to early childhood-onset recurrent pulmonary hemorrhage and lymphoid hyperplasia that may progress to pulmonary fibrosis."
    explanation: Imaging cohort confirms that the dominant clinical manifestation is lung-targeted autoimmune injury, with progression to fibrosis.
  - reference: PMID:41932423
    reference_title: "Kidney Transplant Outcomes in Coatomer Protein Complex Subunit Alpha (COPA) Syndrome: Report of Five Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney involvement was heterogenous between patients (ANCA-associated vasculitis-like disease, lupus or immune-complex mediated glomerulonephritis or overlapping phenotypes), and all had advanced histological damage at clinical presentation."
    explanation: Renal histology in COPA syndrome shows multiple immune-mediated glomerulonephritis patterns consistent with autoimmune end-organ injury.
- name: HAQ STING dominant suppression of STING signalling
  description: >
    The common HAQ haplotype of STING1 (R71H/G230A/R293Q) dominantly
    dampens STING signalling. When co-inherited with a pathogenic COPA
    variant, HAQ STING fully prevents the constitutive STING activation
    that drives type I interferon signalling and provides complete clinical
    protection in carriers, accounting for much of the observed incomplete
    penetrance.
  genes:
  - preferred_term: STING1
    term:
      id: hgnc:27962
      label: STING1
  biological_processes:
  - preferred_term: cGAS/STING signaling pathway
    term:
      id: GO:0140896
      label: cGAS/STING signaling pathway
    modifier: DECREASED
  evidence:
  - reference: PMID:40014299
    reference_title: "The common HAQ STING allele prevents clinical penetrance of COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that the common HAQ STING allele mediates complete clinical protection."
    explanation: Simchoni et al. establish HAQ STING as a dominant clinical modifier in COPA syndrome.
  - reference: PMID:40014299
    reference_title: "The common HAQ STING allele prevents clinical penetrance of COPA syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expressing HAQ STING in patient cells rescued the molecular phenotype of COPA syndrome."
    explanation: Cellular rescue experiments confirm the molecular mechanism of HAQ STING-mediated protection and motivate STING-directed gene therapy.
phenotypes:
- name: Interstitial lung disease
  category: Respiratory
  frequency: VERY_FREQUENT
  description: >
    Pulmonary disease is the dominant organ manifestation and is most often an
    interstitial lung disease pattern.
  phenotype_term:
    preferred_term: Interstitial lung disease
    term:
      id: HP:0006530
      label: Abnormal pulmonary interstitial morphology
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary involvement was observed in 34 patients, with interstitial lung disease in most cases (n = 31) and diffuse alveolar haemorrhage in 11 individuals."
    explanation: Multicenter European cohort confirms interstitial lung disease as the most common organ manifestation; 31/38 symptomatic patients had ILD, which is 82% and falls in the VERY_FREQUENT band.
- name: Diffuse alveolar hemorrhage
  category: Respiratory
  frequency: OCCASIONAL
  description: >
    Alveolar hemorrhage may be clinically overt or insidious and is a distinctive
    pulmonary complication of COPA syndrome.
  phenotype_term:
    preferred_term: Diffuse alveolar hemorrhage
    term:
      id: HP:0025420
      label: Diffuse alveolar hemorrhage
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pulmonary involvement was observed in 34 patients, with interstitial lung disease in most cases (n = 31) and diffuse alveolar haemorrhage in 11 individuals."
    explanation: The same cohort explicitly documents diffuse alveolar hemorrhage as a core pulmonary feature; 11/38 symptomatic patients had diffuse alveolar hemorrhage, which is 29% and falls in the OCCASIONAL band.
- name: Pulmonary fibrosis
  category: Respiratory
  description: >
    Progressive pulmonary fibrosis can develop within the interstitial lung
    disease spectrum of COPA syndrome, including nonspecific interstitial
    pneumonia and lymphocytic interstitial pneumonia patterns.
  phenotype_term:
    preferred_term: Pulmonary fibrosis
    term:
      id: HP:0002206
      label: Pulmonary fibrosis
  evidence:
  - reference: PMID:37821196
    reference_title: "COPA Syndrome from Diagnosis to Treatment: A Clinician's Guide."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Onset is usually in early childhood, with unique disease features including alveolar hemorrhage, which can be insidious, pulmonary cyst formation, and progressive pulmonary fibrosis in nonspecific interstitial pneumonia or lymphocytic interstitial pneumonia patterns."
    explanation: Review abstract identifies progressive pulmonary fibrosis as a distinctive pulmonary manifestation within the COPA syndrome ILD spectrum.
- name: Pulmonary cyst formation
  category: Respiratory
  description: >
    Cystic lung changes are a recognized pulmonary feature of COPA syndrome and
    may accompany chronic interstitial lung disease.
  phenotype_term:
    preferred_term: Pulmonary cyst formation
    term:
      id: HP:0032445
      label: Pulmonary cyst
  evidence:
  - reference: PMID:37821196
    reference_title: "COPA Syndrome from Diagnosis to Treatment: A Clinician's Guide."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Onset is usually in early childhood, with unique disease features including alveolar hemorrhage, which can be insidious, pulmonary cyst formation, and progressive pulmonary fibrosis in nonspecific interstitial pneumonia or lymphocytic interstitial pneumonia patterns."
    explanation: Review abstract identifies pulmonary cyst formation as a characteristic COPA syndrome lung feature.
- name: Arthritis
  category: Musculoskeletal
  frequency: FREQUENT
  description: >
    Inflammatory joint disease is a common extrapulmonary manifestation and can
    precede or accompany lung disease.
  phenotype_term:
    preferred_term: Arthritis
    term:
      id: HP:0001369
      label: Arthritis
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-six patients demonstrated joint involvement, and 7 had documented kidney disease."
    explanation: Cohort data show that inflammatory joint involvement is common among symptomatic patients; 26/38 affected individuals had joint involvement, which is 68% and falls in the FREQUENT band.
- name: Glomerulonephritis
  category: Renal
  description: >
    Immune-mediated kidney disease occurs in a subset of patients and may present
    as ANCA-associated, lupus-like, or immune-complex glomerulonephritis.
  phenotype_term:
    preferred_term: Glomerulonephritis
    term:
      id: HP:0000099
      label: Glomerulonephritis
  evidence:
  - reference: PMID:41932423
    reference_title: "Kidney Transplant Outcomes in Coatomer Protein Complex Subunit Alpha (COPA) Syndrome: Report of Five Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney involvement was heterogenous between patients (ANCA-associated vasculitis-like disease, lupus or immune-complex mediated glomerulonephritis or overlapping phenotypes), and all had advanced histological damage at clinical presentation."
    explanation: Kidney transplant case series demonstrates that glomerulonephritis is part of the renal disease spectrum in COPA syndrome.
- name: Diffuse pulmonary lymphoid hyperplasia
  category: Respiratory
  description: >
    Florid pulmonary lymphoid hyperplasia, often manifesting on biopsy as
    follicular bronchiolitis or lymphocytic interstitial pneumonia, is a
    characteristic histopathological feature of COPA syndrome lung disease.
  phenotype_term:
    preferred_term: Diffuse pulmonary lymphoid hyperplasia
    term:
      id: HP:0034824
      label: Diffuse pulmonary lymphoid hyperplasia
  evidence:
  - reference: PMID:36746811
    reference_title: "Imaging findings of COPA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most prevalent imaging finding of COPA syndrome is diffuse lung disease related to early childhood-onset recurrent pulmonary hemorrhage and lymphoid hyperplasia that may progress to pulmonary fibrosis."
    explanation: Pediatric imaging cohort identifies pulmonary lymphoid hyperplasia as a defining component of COPA syndrome lung disease.
- name: Mediastinal lymphadenopathy
  category: Respiratory
  frequency: VERY_FREQUENT
  description: >
    Hilar and mediastinal lymphadenopathy is a near-universal radiologic
    finding in pediatric COPA syndrome and reflects the lymphoproliferative
    aspect of pulmonary disease.
  phenotype_term:
    preferred_term: Mediastinal lymphadenopathy
    term:
      id: HP:0100721
      label: Mediastinal lymphadenopathy
  evidence:
  - reference: PMID:36746811
    reference_title: "Imaging findings of COPA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12)."
    explanation: Hilar/mediastinal lymphadenopathy was present on chest CT in 11/12 (~92%) of pediatric COPA patients, supporting VERY_FREQUENT classification.
- name: Ground-glass opacification
  category: Respiratory
  frequency: VERY_FREQUENT
  description: >
    Ground-glass opacification is the most consistent chest CT finding in
    COPA syndrome and reflects diffuse alveolar inflammation, hemorrhage,
    and lymphoid infiltration.
  phenotype_term:
    preferred_term: Ground-glass opacification
    term:
      id: HP:0025179
      label: Ground-glass opacification
  evidence:
  - reference: PMID:36746811
    reference_title: "Imaging findings of COPA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12)."
    explanation: Ground-glass opacification was seen in 12/12 (100%) of pediatric patients on chest CT.
- name: Pulmonary nodules
  category: Respiratory
  description: >
    Pulmonary nodules are a recurrent CT finding in COPA syndrome and may
    correspond to lymphoid follicles or inflammatory foci that improve on
    immunosuppression.
  phenotype_term:
    preferred_term: Pulmonary nodule
    term:
      id: HP:0033608
      label: Pulmonary nodule
  evidence:
  - reference: PMID:36746811
    reference_title: "Imaging findings of COPA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12)."
    explanation: Pulmonary nodules were detected in 8/12 patients on chest CT in the imaging cohort.
- name: Crazy paving pattern
  category: Respiratory
  description: >
    A crazy-paving pattern (combined ground-glass opacification with
    superimposed septal thickening) can occur in COPA syndrome, often
    reflecting alveolar hemorrhage or organizing pneumonia.
  phenotype_term:
    preferred_term: Crazy paving pattern
    term:
      id: HP:0025391
      label: Crazy paving pattern
  evidence:
  - reference: PMID:36746811
    reference_title: "Imaging findings of COPA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12)."
    explanation: A crazy-paving pattern was identified in 2/12 patients on chest CT, supporting it as a recognised but less common COPA syndrome finding.
- name: Synovitis
  category: Musculoskeletal
  description: >
    Active inflammatory synovitis can be detected by MRI in COPA syndrome
    arthritis, supporting an inflammatory rather than mechanical
    pathophysiology.
  phenotype_term:
    preferred_term: Synovitis
    term:
      id: HP:0100769
      label: Synovitis
  evidence:
  - reference: PMID:36746811
    reference_title: "Imaging findings of COPA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four had musculoskeletal imaging revealing synovitis (2/4), bone erosions (1/4), tenosynovitis (1/4), enthesitis (1/4), and subcutaneous nodules (1/4)."
    explanation: Musculoskeletal MRI in COPA syndrome documents synovitis as the dominant inflammatory finding.
- name: Antinuclear antibody positivity
  category: Immunological
  description: >
    Antinuclear antibodies are common in COPA syndrome and contribute to
    diagnostic confusion with juvenile systemic lupus erythematosus or
    juvenile idiopathic arthritis.
  phenotype_term:
    preferred_term: Antinuclear antibody positivity
    term:
      id: HP:0003493
      label: Antinuclear antibody positivity
  evidence:
  - reference: PMID:29977900
    reference_title: "Analysis of pulmonary features and treatment approaches in the COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity."
    explanation: International cohort confirms ANA (with or without ANCA) in all subjects, supporting ANA positivity as a defining serologic feature.
- name: Antineutrophil cytoplasmic antibody positivity
  category: Immunological
  description: >
    Cytoplasmic and perinuclear ANCA positivity is common and contributes
    to ANCA-associated vasculitis-like renal and pulmonary phenotypes in
    COPA syndrome.
  phenotype_term:
    preferred_term: Cytoplasmic antineutrophil antibody positivity
    term:
      id: HP:0032230
      label: Cytoplasmic antineutrophil antibody positivity
  evidence:
  - reference: PMID:29977900
    reference_title: "Analysis of pulmonary features and treatment approaches in the COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity."
    explanation: International COPA cohort documents ANCA positivity (with or without ANA) in all subjects.
- name: Rheumatoid factor positivity
  category: Immunological
  frequency: FREQUENT
  description: >
    Rheumatoid factor is positive in a majority of patients and frequently
    leads to misdiagnosis as juvenile idiopathic arthritis or rheumatoid
    arthritis before genetic testing.
  phenotype_term:
    preferred_term: Rheumatoid factor positive
    term:
      id: HP:0002923
      label: Rheumatoid factor positive
  evidence:
  - reference: PMID:29977900
    reference_title: "Analysis of pulmonary features and treatment approaches in the COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity."
    explanation: 71% RF positivity in the international pulmonary cohort places this within the FREQUENT band.
- name: Type I interferon signature
  category: Immunological
  description: >
    A peripheral blood type I interferon signature is a defining
    immunological feature of COPA syndrome and is mechanistically driven by
    Golgi-localised STING activation.
  phenotype_term:
    preferred_term: Increased circulating Interferon-alpha concentration
    term:
      id: HP:0034513
      label: Increased circulating Interferon-alpha concentration
  evidence:
  - reference: PMID:29030294
    reference_title: "Type I interferon pathway activation in COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of peripheral blood showed activation of type 1 interferon pathway, which was also confirmed in 4 previously reported COPA patients."
    explanation: Volpi et al. demonstrate type I interferon pathway activation as a peripheral blood signature confirmed across multiple COPA syndrome cases.
- name: Increased Th17 T cell proportion
  category: Immunological
  description: >
    Patient-derived CD4+ T cells show skewing toward a TH17 phenotype with
    elevated IL-1beta, IL-6 and IL-17 cytokine output, contributing to
    autoimmune end-organ inflammation.
  phenotype_term:
    preferred_term: Increased Th17 T cell proportion
    term:
      id: HP:0025831
      label: Increased Th17 T cell proportion
  evidence:
  - reference: PMID:25894502
    reference_title: "COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient-derived CD4(+) T cells also demonstrate significant skewing toward a TH17 phenotype that is implicated in autoimmunity."
    explanation: Watkin et al. directly demonstrate TH17 skewing in patient-derived CD4 T cells.
- name: Follicular bronchiolitis
  category: Respiratory
  description: >
    Follicular bronchiolitis is a histopathologic hallmark of COPA syndrome
    pulmonary disease, identified on lung biopsy and reflecting the
    underlying lymphoproliferative response in airways.
  phenotype_term:
    preferred_term: Follicular bronchiolitis
    term:
      id: HP:0033583
      label: Follicular bronchiolitis
  evidence:
  - reference: PMID:29977900
    reference_title: "Analysis of pulmonary features and treatment approaches in the COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common pulmonary findings included cysts on chest computed tomography and evidence of follicular bronchiolitis on lung biopsy."
    explanation: Tsui et al. identify follicular bronchiolitis on lung biopsy as one of the most common pulmonary findings in the international COPA cohort.
- name: Cutaneous involvement
  category: Cutaneous
  frequency: FREQUENT
  description: >
    Skin manifestations are now recognised as a previously underappreciated
    feature of COPA syndrome, present in roughly one-third of symptomatic
    patients in the largest published cohort.
  phenotype_term:
    preferred_term: Abnormality of the skin
    term:
      id: HP:0000951
      label: Abnormality of the skin
  evidence:
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously undescribed features included skin (n = 12), cardiac (n = 8), gastrointestinal (n = 7), and hepatic involvement (n = 5)."
    explanation: Skin involvement was reported in 12/38 (32%) symptomatic patients in the European cohort, supporting FREQUENT classification.
- name: Cardiac involvement
  category: Cardiac
  frequency: OCCASIONAL
  description: >
    Cardiac involvement is an emerging extrapulmonary manifestation of COPA
    syndrome, reported in roughly one in five symptomatic patients in the
    largest cohort to date.
  phenotype_term:
    preferred_term: Abnormality of the cardiovascular system
    term:
      id: HP:0001626
      label: Abnormality of the cardiovascular system
  evidence:
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously undescribed features included skin (n = 12), cardiac (n = 8), gastrointestinal (n = 7), and hepatic involvement (n = 5)."
    explanation: Cardiac involvement was reported in 8/38 (21%) symptomatic patients in the European cohort, falling within the OCCASIONAL band.
- name: Gastrointestinal involvement
  category: Gastrointestinal
  frequency: OCCASIONAL
  description: >
    Gastrointestinal manifestations are now recognised in COPA syndrome and
    contribute to the multisystem phenotype, particularly in symptomatic
    children.
  phenotype_term:
    preferred_term: Abnormality of the gastrointestinal tract
    term:
      id: HP:0011024
      label: Abnormality of the gastrointestinal tract
  evidence:
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously undescribed features included skin (n = 12), cardiac (n = 8), gastrointestinal (n = 7), and hepatic involvement (n = 5)."
    explanation: Gastrointestinal involvement was reported in 7/38 (18%) symptomatic patients, within the OCCASIONAL band.
- name: Hepatic involvement
  category: Hepatic
  frequency: OCCASIONAL
  description: >
    Liver involvement (which can include unexplained transaminitis) is a
    recognised but uncommon manifestation of COPA syndrome, present in
    around one in eight symptomatic patients.
  phenotype_term:
    preferred_term: Abnormality of the liver
    term:
      id: HP:0001392
      label: Abnormality of the liver
  evidence:
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously undescribed features included skin (n = 12), cardiac (n = 8), gastrointestinal (n = 7), and hepatic involvement (n = 5)."
    explanation: Hepatic involvement was reported in 5/38 (13%) symptomatic patients, within the OCCASIONAL band; this complements earlier descriptions of unexplained transaminitis (PMID:32970305).
biochemical:
- name: Autoantibodies
  presence: Elevated
  context: >
    High-titer autoantibodies are characteristic and seropositivity is present in
    nearly all tested symptomatic patients.
  evidence:
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All but 1 patient tested positive for autoantibodies, and increased interferon signalling was noted in all those tested."
    explanation: Large cohort data support autoantibody positivity as a defining immunologic feature.
- name: Type I interferon signature
  presence: Elevated
  context: >
    Increased ISG expression and interferon signaling are central molecular
    biomarkers of disease activity.
  evidence:
  - reference: PMID:32725128
    reference_title: "Mutations in COPA lead to abnormal trafficking of STING to the Golgi and interferon signaling."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed elevated levels of ISGs and IFN-α in blood of symptomatic COPA patients."
    explanation: Patient blood assays demonstrate a systemic type I interferon signature.
genetic:
- name: COPA
  gene_term:
    preferred_term: COPA
    term:
      id: hgnc:2230
      label: COPA
  association: Causative
  relationship_type: CAUSATIVE
  presence: PRESENT
  inheritance:
  - name: Autosomal dominant
  notes: >
    Heterozygous pathogenic COPA variants are the cause of COPA syndrome.
    Classical disease variants are missense changes in the N-terminal WD40
    cargo-recognition domain (recurrent residues include Lys230, Arg233,
    Glu241, Asp243, and Val242), which impair binding of dilysine
    ER-retrieval cargo. A second variant class affects the C-terminal
    domain (e.g., p.Cys1013Ser, p.Arg1058Cys, p.Arg1142X) and disrupts COPI
    integrity, producing a clinically similar but mechanistically distinct
    phenotype.
  evidence:
  - reference: PMID:25894502
    reference_title: "COPA mutations impair ER-Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified four unique deleterious variants in the COPA gene (encoding coatomer subunit α) affecting the same functional domain."
    explanation: Original family-based genetic study establishes COPA as the causative disease gene with WD40 domain variants.
  - reference: PMID:38175705
    reference_title: "Heterozygous mutations in the C-terminal domain of COPA underlie a complex autoinflammatory syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We described 3 heterozygous mutations in the C-terminal domain (CTD) of COPA (p.C1013S, p.R1058C, and p.R1142X) in 6 children from 3 unrelated families with a similar syndrome of autoinflammation and autoimmunity."
    explanation: Delafontaine et al. expand the COPA mutational spectrum to include CTD variants.
- name: STING1 HAQ protective modifier (non-causal)
  gene_term:
    preferred_term: STING1
    term:
      id: hgnc:27962
      label: STING1
  association: Non-causal protective haplotype that prevents clinical penetrance
  relationship_type: PROTECTIVE
  presence: PRESENT
  notes: >
    STING1 is not a causal COPA syndrome gene. The common HAQ STING haplotype
    (R71H/G230A/R293Q in STING1) is represented here only as a dominant
    protective modifier: when co-inherited with a pathogenic COPA variant, HAQ
    STING dampens STING signalling and provides complete clinical protection.
    It accounts for much of the ~15-20% nonpenetrance observed in COPA syndrome
    families and motivates STING-directed gene therapy strategies.
  evidence:
  - reference: PMID:40014299
    reference_title: "The common HAQ STING allele prevents clinical penetrance of COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show that the common HAQ STING allele mediates complete clinical protection."
    explanation: Co-segregation analysis of 35 COPA variant carriers establishes HAQ STING as a dominant clinical modifier.
  - reference: PMID:40014299
    reference_title: "The common HAQ STING allele prevents clinical penetrance of COPA syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we found that HAQ STING acts dominantly to dampen COPA-dependent STING signaling."
    explanation: Cellular experiments confirm the dominant suppressive mechanism of HAQ STING on COPA-dependent STING signalling.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: INCOMPLETE
  expressivity: VARIABLE
  description: >
    COPA syndrome follows autosomal dominant inheritance with incomplete
    penetrance and broad inter-individual variability in pulmonary, articular,
    and renal involvement.
  evidence:
  - reference: PMID:37821196
    reference_title: "COPA Syndrome from Diagnosis to Treatment: A Clinician's Guide."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "COPA syndrome is a recently described autosomal dominant inborn error of immunity characterized by high titer autoantibodies and interstitial lung disease, with many individuals also having arthritis and nephritis."
    explanation: Review abstract explicitly states the autosomal dominant inheritance pattern and core phenotype.
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among the 46 individuals carrying a COPA mutation, 38 had at least 1 clinical manifestation likely related to their mutant state (clinical penetrance of 83%)."
    explanation: Cohort data support incomplete penetrance among mutation carriers.
diagnosis:
- name: COPA molecular genetic testing
  description: >-
    COPA syndrome should be confirmed by molecular genetic testing for a
    heterozygous pathogenic COPA variant, particularly in a child or adult with
    early-onset interstitial lung disease, diffuse alveolar hemorrhage,
    arthritis, nephritis, high-titer autoantibodies, or a family history
    consistent with autosomal dominant disease. Sequencing should cover both
    canonical WD40 cargo-recognition variants and the newer C-terminal domain
    variant class.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: MAXO:0000533
      label: molecular genetic testing
  evidence:
  - reference: PMID:37821196
    reference_title: "COPA Syndrome from Diagnosis to Treatment: A Clinician's Guide."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This review explores the clinical presentation, genetics, molecular mechanisms, organ manifestations, and treatment approaches for COPA syndrome, and presents a diagnostic framework of suggested indications for patient testing."
    explanation: Clinician's guide supports a testing framework for suspected COPA syndrome.
  - reference: PMID:29977900
    reference_title: "Analysis of pulmonary features and treatment approaches in the COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Targeted sequencing should be performed in all subjects suspected of having the disease to establish the diagnosis and distinguish the COPA syndrome from other disorders in which DPLD may occur such as lymphangioleiomyomatosis, Sjögren's syndrome and JIA (table 5)."
    explanation: Pulmonary cohort recommends COPA sequencing to establish diagnosis and distinguish phenocopies.
- name: Pulmonary workup for ILD and diffuse alveolar hemorrhage
  description: >-
    Pulmonary evaluation should include high-resolution chest CT or equivalent
    chest CT review, pulmonary function tests, and hemorrhage-focused evaluation
    when hemoptysis, anemia, ground-glass opacities, or suspected diffuse
    alveolar hemorrhage are present. Bronchoscopy/biopsy can document diffuse
    alveolar hemorrhage, capillaritis, hemosiderin-laden macrophages, follicular
    bronchiolitis, or lymphoid hyperplasia when clinically indicated.
  diagnosis_term:
    preferred_term: computed tomography procedure
    term:
      id: MAXO:0000571
      label: computed tomography procedure
  evidence:
  - reference: PMID:36746811
    reference_title: "Imaging findings of COPA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12)."
    explanation: Pediatric imaging series supports chest CT as a high-yield pulmonary diagnostic study.
  - reference: PMID:29977900
    reference_title: "Analysis of pulmonary features and treatment approaches in the COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Data were collected for a minimum of 5 years, up to 25 years. The majority of PFTs were performed at UCSF according to American Thoracic Society (ATS) standards."
    explanation: Pulmonary cohort used serial pulmonary function testing to characterize COPA lung disease.
  - reference: PMID:29977900
    reference_title: "Analysis of pulmonary features and treatment approaches in the COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three subjects were biopsied at the time they developed haemoptysis and diagnosed with DAH via bronchoscopy."
    explanation: Supports bronchoscopy/biopsy when diffuse alveolar hemorrhage is suspected.
- name: Renal evaluation for immune-mediated glomerulonephritis
  description: >-
    Renal evaluation should screen for nephritis with urinalysis, kidney
    function testing, renal imaging when indicated, and kidney biopsy when
    immune-mediated glomerulonephritis or advanced renal involvement is
    suspected.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:36746811
    reference_title: "Imaging findings of COPA Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Five had at least one renal US, revealing renal size abnormalities (4/5) and cortical hyperechogenicity (3/5)."
    explanation: Imaging cohort supports renal imaging as part of COPA renal phenotyping.
  - reference: PMID:29977900
    reference_title: "Analysis of pulmonary features and treatment approaches in the COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three (21%) out of 14 patients developed biopsy confirmed immune-mediated kidney disease and concurrent DAH."
    explanation: Supports renal biopsy when immune-mediated kidney involvement is suspected.
  - reference: PMID:41932423
    reference_title: "Kidney Transplant Outcomes in Coatomer Protein Complex Subunit Alpha (COPA) Syndrome: Report of Five Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney involvement was heterogenous between patients (ANCA-associated vasculitis-like disease, lupus or immune-complex mediated glomerulonephritis or overlapping phenotypes), and all had advanced histological damage at clinical presentation."
    explanation: Transplant case series supports broad renal differential and histologic assessment in severe kidney disease.
- name: Autoantibody and type I interferon signature testing
  description: >-
    Serologic workup should include autoantibodies that often misdirect the
    initial diagnosis, including ANA, ANCA, rheumatoid factor, and related
    lupus/vasculitis/arthritis markers. A peripheral blood type I interferon or
    interferon-stimulated gene signature can support mechanism-based diagnosis
    and monitoring, although it is not specific to COPA syndrome.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:29977900
    reference_title: "Analysis of pulmonary features and treatment approaches in the COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects were positive for anti-neutrophil cytoplasmic antibody, anti-nuclear antibody or both and 71% of subjects had rheumatoid factor positivity."
    explanation: Supports ANA/ANCA/RF testing as part of COPA serologic workup.
  - reference: PMID:29030294
    reference_title: "Type I interferon pathway activation in COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of peripheral blood showed activation of type 1 interferon pathway, which was also confirmed in 4 previously reported COPA patients."
    explanation: Supports peripheral interferon pathway testing as a mechanistic biomarker.
- name: Differential diagnosis with pulmonary-renal autoimmunity and interferonopathies
  description: >-
    Differential diagnosis should include SAVI and other type I
    interferonopathies, systemic lupus erythematosus, ANCA-associated
    vasculitis, juvenile idiopathic arthritis/rheumatoid arthritis, Sjögren
    syndrome, lymphangioleiomyomatosis, idiopathic pulmonary hemosiderosis, and
    other causes of childhood-onset diffuse parenchymal lung disease.
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: MAXO:0000487
      label: clinical assessment
  evidence:
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "further demonstrating the clinical overlap with SAVI and other type I interferonopathies."
    explanation: Large cohort supports SAVI and other interferonopathies in the differential diagnosis.
  - reference: PMID:29977900
    reference_title: "Analysis of pulmonary features and treatment approaches in the COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The presence of ANA and/or ANCA in the COPA syndrome suggests a connection to systemic lupus erythematous (SLE) or ANCA-associated vasculitides such as granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA)."
    explanation: Supports lupus and ANCA-associated vasculitis in the pulmonary-renal differential.
treatments:
- name: Janus kinase inhibitor therapy
  description: >
    JAK inhibitors block JAK-STAT signalling downstream of the type I
    interferon receptor and are the most promising mechanism-targeted
    therapy in COPA syndrome. Evidence level: observational cohort and
    review-level support, with published cohort-level evidence
    supporting baricitinib and ruxolitinib for both interstitial lung
    disease and arthritis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: JAK inhibitor
      term:
        id: NCIT:C172200
        label: JAK Inhibitor
  target_mechanisms:
  - target: Constitutive type I interferon signaling
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:41395910
    reference_title: "Insights from a novel monogenic autoinflammatory disease: overview of a multicentric European cohort of 38 patients with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-two patients were treated with Janus kinase inhibitors with promising efficacy."
    explanation: Large European cohort provides the strongest available abstract-level support for JAK inhibitor use in COPA syndrome.
  - reference: PMID:39767180
    reference_title: "COPA Syndrome-From Pathogenesis to Treatment."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "JAK inhibitor therapy seems to be the most promising therapeutic choice now."
    explanation: 2024 review highlights JAK inhibition as the leading current therapeutic strategy.
  - reference: PMID:38768895
    reference_title: "Baricitinib treatment in children with COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Baricitinib treatment in children with COPA syndrome."
    explanation: Matucci-Cerinic et al. report a pediatric case series of baricitinib (a JAK1/JAK2 inhibitor) in children with COPA syndrome, supporting the JAK inhibitor class for pediatric disease. The PubMed record is a letter without a structured abstract, so the canonical title is used as the reference statement.
- name: Immunosuppression for diffuse alveolar hemorrhage
  description: >
    Standard induction for severe alveolar hemorrhage uses systemic
    glucocorticoids combined with cyclophosphamide, with subsequent
    maintenance using mycophenolate mofetil or azathioprine. Evidence level:
    case series/observational standard care. Radiographic improvement is common
    but pulmonary function may continue to decline.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:29977900
    reference_title: "Analysis of pulmonary features and treatment approaches in the COPA syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All subjects received immunosuppressive therapy."
    explanation: Tsui et al. report that all subjects in the international pulmonary cohort received immunosuppressive therapy as standard care.
- name: Lung transplantation
  description: >
    Lung transplantation is offered to patients with end-stage progressive
    interstitial lung disease refractory to immunosuppression and JAK
    inhibition. Evidence level: case reports/literature review for end-stage
    COPA lung disease, with allograft dysfunction reported.
  treatment_term:
    preferred_term: lung transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:35079820
    reference_title: "Allograft dysfunction after lung transplantation for COPA syndrome: A case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two out of four patients required lung transplantation due to intractable interstitial lung disease and respiratory failure."
    explanation: Case report documents lung transplantation as a treatment option for end-stage COPA syndrome interstitial lung disease unresponsive to immunosuppression.
- name: Kidney transplantation
  description: >
    Patients who progress to advanced glomerular damage and end-stage renal
    disease require kidney transplantation, with outcomes documented in a
    multi-patient case series. Evidence level: five-patient observational case
    series.
  treatment_term:
    preferred_term: kidney transplantation
    term:
      id: MAXO:0010039
      label: organ transplantation
  evidence:
  - reference: PMID:41932423
    reference_title: "Kidney Transplant Outcomes in Coatomer Protein Complex Subunit Alpha (COPA) Syndrome: Report of Five Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Kidney involvement was heterogenous between patients (ANCA-associated vasculitis-like disease, lupus or immune-complex mediated glomerulonephritis or overlapping phenotypes), and all had advanced histological damage at clinical presentation."
    explanation: Case series describes five COPA syndrome patients with advanced renal histology presenting for kidney transplant evaluation.
- name: STING-directed therapy (experimental)
  description: >
    Direct STING pathway inhibition (e.g., small-molecule inhibitors such
    as H-151) and STING1-directed gene therapy aimed at introducing the
    protective HAQ allele are emerging upstream therapeutic strategies
    based on the central role of Golgi-localised STING activation in COPA
    syndrome. Evidence level: experimental/preclinical, with BI 3000202 now in
    Phase 1 safety and tolerability testing for selected type I
    interferonopathies including COPA syndrome.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: STING accumulation and activation at the Golgi
    treatment_effect: INHIBITS
  evidence:
  - reference: PMID:40014299
    reference_title: "The common HAQ STING allele prevents clinical penetrance of COPA syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Expressing HAQ STING in patient cells rescued the molecular phenotype of COPA syndrome."
    explanation: Cellular rescue with HAQ STING establishes proof-of-concept for STING-directed gene therapy, framed as "a potential universal gene therapy approach for patients."
clinical_trials:
- name: NCT06878365
  phase: PHASE_I
  status: ACTIVE_NOT_RECRUITING
  description: >
    Phase 1 active-not-recruiting, open-label single-group tolerability study
    sponsored by Boehringer Ingelheim. Adults with selected type I
    interferonopathies, including COPA syndrome, receive BI 3000202 low-dose
    tablets for 4 weeks followed by higher-dose tablets for 36 weeks, with
    interferon gene score change as a key pharmacodynamic outcome.
  target_phenotypes:
  - preferred_term: Type I interferon signature
    term:
      id: HP:0034513
      label: Increased circulating Interferon-alpha concentration
  evidence:
  - reference: clinicaltrials:NCT06878365
    supports: SUPPORT
    snippet: "People can join the study if they have Aicardi-Goutières syndrome (AGS), Coatomer subunit alpha (COPA) syndrome, Familial chilblain lupus (FCL), or another type 1 interferonopathy with a specific gene mutation."
    explanation: ClinicalTrials.gov registration explicitly enrols COPA syndrome patients in this Phase 1 BI 3000202 tolerability study.

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 39 citations 2026-04-25T17:49:20.180381

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: COPA Syndrome
MONDO ID: MONDO:0014629 (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on COPA Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

COPA Syndrome (MONDO:0014629) — Comprehensive Disease Characteristics Report

Executive summary

COPA syndrome (also termed autoimmune interstitial lung disease–arthritis syndrome) is a Mendelian, autosomal dominant immune-dysregulation disorder caused by heterozygous variants in COPA, encoding the α-subunit of the COPI coatomer complex required for Golgi↔ER trafficking. It classically presents in childhood with diffuse parenchymal lung disease (often with diffuse alveolar hemorrhage), inflammatory arthritis, and variably kidney disease, with frequent autoantibody positivity and a type I interferon (IFN-I)–driven immunophenotype. Key mechanistic work links COPA dysfunction to mis-trafficking and ligand-independent activation of STING, and more recent work (2024) expands pathogenic variation beyond the WD40 domain to the C-terminal domain (CTD), implicating cGAS/STING, ER stress, and NF-κB signaling in disease biology. (vece2016copasyndromea pages 2-4, tsui2018analysisofpulmonary pages 8-10, deng2020adefectin pages 1-5, delafontaine2024heterozygousmutationsin pages 1-2)

1. Disease information

1.1 What is COPA syndrome?

COPA syndrome is a novel autosomal dominant immune dysregulatory disease centered on lung, joint, and sometimes kidney autoimmunity/inflammation, attributed to pathogenic variants in COPA. (vece2016copasyndromea pages 1-2, vece2016copasyndromea pages 2-4)

Key concept (definition-level): COPA syndrome is best understood as an intracellular trafficking disorder with immune dysregulation, rather than a single-organ disease, because COPA is ubiquitous yet the phenotype localizes to lung/joint/kidney. (vece2016copasyndromea pages 1-2, padureanu2024copasyndrome—frompathogenesis pages 2-4)

1.2 Key identifiers and ontology mapping

MONDO: MONDO:0014629 (mapped in Open Targets as “autoimmune interstitial lung disease-arthritis syndrome”). (padureanu2024copasyndrome—frompathogenesis pages 1-2)
OMIM: 616414 (explicitly stated). (kato2021augmentationofstimulator pages 6-10)
Gene: COPA (coat protein complex I subunit alpha). (kumrah2019geneticsofcopa pages 1-2)

Synonyms / alternative names (used in literature/resources): - “autoimmune interstitial lung disease-arthritis syndrome” (ontology label). (padureanu2024copasyndrome—frompathogenesis pages 1-2) - “autoinflammatory interstitial lung, joint, and kidney disease” (terminology used in mechanistic/clinical literature). (kato2021augmentationofstimulator pages 6-10)

Evidence provenance: Most detailed disease knowledge is derived from aggregated disease-level resources (reviews) and small cohorts/case series, given rarity; some clinical data are from international cohorts (e.g., N=14 pulmonary cohort) and multi-family mechanistic studies. (tsui2018analysisofpulmonary pages 8-10, lepelley2020mutationsincopa pages 1-2, padureanu2024copasyndrome—frompathogenesis pages 4-5)

Concept	Value	Notes/Source
Disease name	COPA syndrome	Described as a Mendelian immune dysregulation / autoimmune-autoinflammatory syndrome caused by heterozygous COPA mutations; initial disease-defining report published in 2015. DOI: https://doi.org/10.1038/ng.3279 (watkin2015copamutationsimpair pages 1-11, padureanu2024copasyndrome—frompathogenesis pages 1-2)
MONDO ID	MONDO:0014629	Open Targets evidence maps MONDO_0014629 to “autoimmune interstitial lung disease-arthritis syndrome,” corresponding to COPA syndrome nomenclature in current disease ontologies. (padureanu2024copasyndrome—frompathogenesis pages 1-2)
Common synonym	autoimmune interstitial lung disease-arthritis syndrome	Used as a disease synonym/label in disease-target resources; consistent with lung and joint-predominant phenotype. (padureanu2024copasyndrome—frompathogenesis pages 1-2)
Causal gene	COPA	COPA encodes coat protein complex I subunit alpha (coatomer subunit α), a COPI component involved in Golgi-to-ER retrograde transport. DOI: https://doi.org/10.2147/TACG.S153600 ; https://doi.org/10.1007/s10875-016-0271-8 (kumrah2019geneticsofcopa pages 1-2, vece2016copasyndromea pages 1-2)
Inheritance	Autosomal dominant	Repeatedly described as autosomal dominant/heterozygous with variable expressivity or penetrance. DOI: https://doi.org/10.1007/s10875-016-0271-8 ; https://doi.org/10.2147/TACG.S153600 (vece2016copasyndromea pages 1-2, kumrah2019geneticsofcopa pages 1-2)
OMIM	616414	Explicitly stated in Kato et al. 2021 excerpt: “COPA syndrome (OMIM 616414).” DOI: https://doi.org/10.1002/art.41790 (kato2021augmentationofstimulator pages 6-10)
Discovery year	2015	First disease-gene report identified COPA mutations in affected families in 2015. DOI: https://doi.org/10.1038/ng.3279 (watkin2015copamutationsimpair pages 1-11)
Core clinical triad	Interstitial/diffuse parenchymal lung disease or diffuse alveolar hemorrhage; arthritis; renal disease/glomerulonephritis	Summarized in early clinical series and reviews as the defining phenotype. DOI: https://doi.org/10.1007/s10875-016-0271-8 ; https://doi.org/10.2147/TACG.S153600 (vece2016copasyndromea pages 2-4, kumrah2019geneticsofcopa pages 1-2)
Key protein domain (classical disease variants)	N-terminal WD40 domain	Previously recognized pathogenic variants cluster in the N-terminal WD40 domain and impair retrograde cargo retrieval. DOI: https://doi.org/10.1084/jem.20201045 ; https://doi.org/10.1172/JCI163604 (deng2020adefectin pages 1-5, delafontaine2024heterozygousmutationsin pages 2-3)
Additional pathogenic domain recognized in 2024	C-terminal domain (CTD)	Delafontaine et al. 2024 reported CTD variants causing a COPA-related autoinflammatory syndrome and disrupting COPI integrity/function. DOI: https://doi.org/10.1172/JCI163604 (delafontaine2024heterozygousmutationsin pages 1-2, delafontaine2024heterozygousmutationsin pages 2-3)
Recurrent/landmark variant	K230N (p.Lys230Asn)	Explicitly mentioned among COPA missense variants in early disease reports/summaries; associated with impaired dilysine cargo binding. DOI: https://doi.org/10.1038/ng.3279 (watkin2015copamutationsimpair pages 1-11, kumrah2019geneticsofcopa pages 2-3)
Recurrent/landmark variant	R233H (p.Arg233His)	Reported in multiple families and later cohorts; one of the classic WD40-domain disease variants. DOI: https://doi.org/10.1084/jem.20200600 ; https://doi.org/10.1038/ng.3279 (lepelley2020mutationsincopa pages 1-2, watkin2015copamutationsimpair pages 1-11)
Recurrent/landmark variant	E241K (p.Glu241Lys)	Classic WD40-domain variant; modeled in CopaE241K/+ mice and recurrent in human families. DOI: https://doi.org/10.1084/jem.20201045 ; https://doi.org/10.1002/art.41790 (deng2020adefectin pages 1-5, kato2021augmentationofstimulator pages 6-10)
Recurrent/landmark variant	D243G (p.Asp243Gly)	Early disease-associated WD40-domain variant from the discovery series. DOI: https://doi.org/10.1038/ng.3279 (watkin2015copamutationsimpair pages 1-11, kumrah2019geneticsofcopa pages 2-3)
Additional variant noted in later cohort	D243N (p.Asp243Asn)	Reported in Lepelley et al. cohort alongside p.R233H, expanding residue-243 pathogenic substitutions. DOI: https://doi.org/10.1084/jem.20200600 (lepelley2020mutationsincopa pages 1-2)
2024 CTD variant	p.C1013S	One of three heterozygous C-terminal domain variants reported in 6 children from 3 unrelated families. DOI: https://doi.org/10.1172/JCI163604 (delafontaine2024heterozygousmutationsin pages 1-2, delafontaine2024heterozygousmutationsin pages 2-3)
2024 CTD variant	p.R1058C	C-terminal domain missense variant associated with COPI dysfunction, trafficking defects, and cGAS/STING-dependent IFN signaling. DOI: https://doi.org/10.1172/JCI163604 (delafontaine2024heterozygousmutationsin pages 1-2, delafontaine2024heterozygousmutationsin pages 2-3)
2024 CTD variant	p.R1142X	C-terminal domain nonsense variant reported in the same 2024 JCI series. DOI: https://doi.org/10.1172/JCI163604 (delafontaine2024heterozygousmutationsin pages 1-2, delafontaine2024heterozygousmutationsin pages 2-3)

Table: This table summarizes the core identifiers, nomenclature, inheritance, and major pathogenic COPA variants/domains for COPA syndrome. It is useful as a quick reference for knowledge-base curation and genetic interpretation.

Recent reference (2024 review): Padureanu et al., Diagnostics (publication: Dec 2024), DOI: https://doi.org/10.3390/diagnostics14242819. (padureanu2024copasyndrome—frompathogenesis pages 1-2)

2. Etiology

2.1 Disease causal factors

Primary cause: germline heterozygous pathogenic variants in COPA (autosomal dominant). (kumrah2019geneticsofcopa pages 1-2, vece2016copasyndromea pages 1-2)

Core molecular function: COPA is part of the COPI complex mediating Golgi-to-ER retrograde transport (and more broadly ER–Golgi trafficking). Pathogenic COPA variants impair cargo retrieval/trafficking, setting up downstream immune activation. (kumrah2019geneticsofcopa pages 1-2, padureanu2024copasyndrome—frompathogenesis pages 2-4)

Key pathogenic variant classes/domains - Classic COPA syndrome variants cluster in the N-terminal WD40 domain, impairing COPA-mediated retrieval of cargo proteins. (deng2020adefectin pages 1-5, delafontaine2024heterozygousmutationsin pages 2-3) - New (2024) disease-associated variants in the C-terminal domain (CTD) (p.C1013S, p.R1058C, p.R1142X) can cause a COPA-related autoinflammatory syndrome through COPI integrity/trafficking disruption and distinct mechanistic features (see §6). (delafontaine2024heterozygousmutationsin pages 1-2, delafontaine2024heterozygousmutationsin pages 2-3)

2.2 Risk factors

Genetic risk factor: carrying a pathogenic heterozygous COPA variant (e.g., K230N, R233H, E241K, D243G, and CTD variants). (watkin2015copamutationsimpair pages 1-11, delafontaine2024heterozygousmutationsin pages 2-3)

Clinical non-penetrance / modifiers: In one multi-family study, ~30% clinical nonpenetrance was reported, supporting modifier effects and variable expressivity among carriers. (lepelley2020mutationsincopa pages 4-5)

2.3 Protective factors

Direct protective variants are not established in the provided corpus. A 2025 computational/structural hypothesis paper discusses a potentially protective STING haplotype, but this is outside the requested 2023–2024 prioritization and not primary clinical evidence in the present dataset. (padureanu2024copasyndrome—frompathogenesis pages 4-5)

2.4 Gene–environment interactions

Evidence for specific environmental triggers (e.g., infection, exposures) driving onset/severity is not explicitly supported by the retrieved text excerpts; this remains an evidence gap in this tool-retrieved set.

3. Phenotypes (clinical spectrum)

3.1 Major phenotype clusters

A. Pulmonary disease (core): - Interstitial/diffuse parenchymal lung disease; cysts on CT; follicular bronchiolitis on biopsy; may progress despite therapy. (tsui2018analysisofpulmonary pages 8-10, tsui2018analysisofpulmonary media 5488c39b) - Diffuse alveolar hemorrhage (DAH) is common and can occur in childhood; in an international cohort (N=14), DAH occurred in 50%. (tsui2018analysisofpulmonary pages 8-10, tsui2018analysisofpulmonary media 5488c39b)

B. Arthritis (core): inflammatory arthritis/polyarthritis is the most common extra-pulmonary feature. Reviews summarize arthritis in ~95% of patients; a clinical immunology cohort reported arthritis 95% (20/21). (padureanu2024copasyndrome—frompathogenesis pages 4-5, volpi2018typeiinterferon pages 9-12)

C. Renal involvement (variable): immune-complex glomerulonephritis/nephritis occurs in a subset; one summary of the original cohort reported renal involvement in 4/21. (kumrah2019geneticsofcopa pages 2-3)

D. Autoantibodies and immune dysregulation: ANA, ANCA, RF, anti-CCP can be present; one series reported ~80% ANA positivity; RF positivity was 71% in one pulmonary cohort. (vece2016copasyndromea pages 2-4, tsui2018analysisofpulmonary pages 8-10)

3.2 Onset, severity, and progression

Early onset is typical: 76% had symptom onset before age 5 in one clinical series; mean presentation ~3.5 years was summarized for the initial cohort. (vece2016copasyndromea pages 2-4, kumrah2019geneticsofcopa pages 2-3)
Nonetheless, later onset cases exist (including adult onset), indicating a spectrum of expressivity. (padureanu2024copasyndrome—frompathogenesis pages 4-5)
Longitudinal data show radiographic improvement can occur under immunosuppression, but pulmonary function may decline overall. (tsui2018analysisofpulmonary pages 8-10)

3.3 Suggested HPO terms (with frequencies where available)

Clinical feature	Suggested HPO term(s)	Typical onset/course	Frequency/statistics (with N if known)	Key evidence/source
Interstitial / diffuse parenchymal lung disease	HP:0006530 Interstitial lung disease; HP:0002205 Pulmonary fibrosis (if fibrosing progression); HP:0002093 Respiratory insufficiency (advanced disease)	Usually early childhood onset; often chronic/progressive; pulmonary disease may precede arthritis; median onset 2.5 years in one cohort	Pulmonary involvement 100% (21/21) in Volpi 2018; pulmonary involvement 98% of 59 cases with detailed clinical data in Padureanu 2024 review; all 14/14 in Tsui 2018 had clinically apparent lung disease (volpi2018typeiinterferon pages 9-12, padureanu2024copasyndrome—frompathogenesis pages 4-5, tsui2018analysisofpulmonary pages 8-10)	Volpi 2018 showed universal lung involvement in 21/21; Padureanu 2024 summarized near-universal pulmonary disease; Tsui 2018 international cohort required genetically confirmed lung disease (volpi2018typeiinterferon pages 9-12, padureanu2024copasyndrome—frompathogenesis pages 4-5, tsui2018analysisofpulmonary pages 8-10)
Diffuse alveolar hemorrhage	HP:0001892 Pulmonary hemorrhage; HP:0002105 Hemoptysis; HP:0030973 Diffuse alveolar hemorrhage	Often pediatric onset; can be episodic/relapsing; may present in infancy and recur despite treatment	50% (7/14) in Tsui 2018 cohort; described as frequent and often immune-mediated in Vece 2016; alveolar hemorrhage may occur as early as infancy in Padureanu 2024 (tsui2018analysisofpulmonary pages 8-10, vece2016copasyndromea pages 2-4, padureanu2024copasyndrome—frompathogenesis pages 4-5)	Tsui 2018: DAH in 50% of subjects; Vece 2016 and Padureanu 2024 describe pulmonary hemorrhage as a hallmark manifestation (tsui2018analysisofpulmonary pages 8-10, vece2016copasyndromea pages 2-4, padureanu2024copasyndrome—frompathogenesis pages 4-5)
Pulmonary cysts / cystic lung disease	HP:0100607 Pulmonary cyst; HP:0002110 Cystic lung disease	Childhood onset to early adulthood; may slowly progress over time	Common pulmonary CT finding in Tsui 2018; highlighted in imaging/clinical summaries and Padureanu 2024 review, but exact percentage not given in retrieved text (tsui2018analysisofpulmonary pages 8-10, tsui2018analysisofpulmonary media 5488c39b, padureanu2024copasyndrome—frompathogenesis pages 4-5)	Tsui 2018 identified cysts as among the most common pulmonary findings; imaging review in later literature supports cystic changes as characteristic (tsui2018analysisofpulmonary pages 8-10, tsui2018analysisofpulmonary media 5488c39b, padureanu2024copasyndrome—frompathogenesis pages 4-5)
Follicular bronchiolitis	HP:0012382 Bronchiolitis; HP:0033379 Follicular bronchiolitis	Chronic airway-centered inflammatory lung disease; often identified on biopsy after pulmonary symptoms	Common biopsy finding in Tsui 2018 and Icelandic family report; no pooled percentage in retrieved text (tsui2018analysisofpulmonary pages 8-10, tsui2018analysisofpulmonary pages 8-8, tsui2018analysisofpulmonary media 5488c39b)	Tsui 2018 reported follicular bronchiolitis as a common histopathologic feature and a diagnostic clue (tsui2018analysisofpulmonary pages 8-10, tsui2018analysisofpulmonary media 5488c39b)
Arthritis / inflammatory polyarthritis	HP:0001369 Arthritis; HP:0001371 Flexion contracture (if advanced); HP:0012399 Polyarthritis	Usually early childhood; chronic, inflammatory; may precede or follow lung disease; often non-erosive but variable	95% (20/21) in Volpi 2018 table; ~95% overall in Padureanu 2024 review; all 14/14 in Tsui 2018 had arthritis (volpi2018typeiinterferon pages 9-12, padureanu2024copasyndrome—frompathogenesis pages 4-5, tsui2018analysisofpulmonary pages 8-10)	Arthritis is the dominant extrapulmonary feature across cohorts and reviews (volpi2018typeiinterferon pages 9-12, padureanu2024copasyndrome—frompathogenesis pages 4-5, tsui2018analysisofpulmonary pages 8-10)
Glomerulonephritis / nephritis / renal involvement	HP:0000123 Nephritis; HP:0000099 Glomerulonephritis; HP:0000083 Renal insufficiency; HP:0002907 Hematuria	Variable; less common than lung/joint disease; may emerge later or be absent	Renal disease in 4/21 patients in Watkin cohort summary; Vece 2016 describes renal disease as part of classic triad; nephritis emphasized in mechanistic papers and 2024 CTD series (kumrah2019geneticsofcopa pages 2-3, vece2016copasyndromea pages 2-4, delafontaine2024heterozygousmutationsin pages 1-2)	Watkin cohort summary reported renal involvement in 4/21; renal disease is recognized but less penetrant than lung or arthritis (kumrah2019geneticsofcopa pages 2-3, vece2016copasyndromea pages 2-4, delafontaine2024heterozygousmutationsin pages 1-2)
ANA positivity	HP:0012012 Positive antinuclear antibody test	Early in disease course or during autoimmune manifestations; persistent seropositivity is common	~80% ANA positivity in Vece 2016; ANA/ANCA and/or RF positivity was common in Tsui 2018 cohort (vece2016copasyndromea pages 2-4, tsui2018analysisofpulmonary pages 8-10)	Vece 2016 reported approximately 80% of patients develop positive ANA; Tsui 2018 included ANA positivity among common clues (vece2016copasyndromea pages 2-4, tsui2018analysisofpulmonary pages 8-10)
ANCA positivity	HP:0032063 Positive antineutrophil cytoplasmic antibody test	Often accompanies pulmonary/renal autoimmune phenotype	In Tsui 2018, all subjects were positive for ANCA, ANA, or both; exact isolated ANCA frequency not specified in retrieved text; Vece 2016 reports variable cANCA/pANCA positivity (tsui2018analysisofpulmonary pages 8-10, vece2016copasyndromea pages 2-4)	ANCA seropositivity is common and diagnostically useful, especially with lung disease and arthritis (tsui2018analysisofpulmonary pages 8-10, vece2016copasyndromea pages 2-4)
Rheumatoid factor positivity	HP:0032060 Rheumatoid factor positive	Often present in inflammatory arthritis phenotype	71% RF positivity in Tsui 2018 cohort; 43% RF positivity across 32 cases summarized in Kumrah 2019 review (tsui2018analysisofpulmonary pages 8-10, kumrah2019geneticsofcopa pages 2-3)	RF positivity is frequent and may lead to misclassification as juvenile idiopathic arthritis or rheumatoid arthritis (tsui2018analysisofpulmonary pages 8-10, kumrah2019geneticsofcopa pages 2-3)
Early childhood onset	HP:0011462 Childhood onset	Usually before age 5 years in many patients; some adult-onset exceptions occur	76% had symptom onset before age 5 in Vece 2016; mean age at presentation 3.5 years in Watkin cohort summary; median onset 2.5 years in Lepelley 2020 cohort (vece2016copasyndromea pages 2-4, kumrah2019geneticsofcopa pages 2-3, lepelley2020mutationsincopa pages 1-2)	COPA syndrome is predominantly pediatric-onset, though later-onset milder disease is recognized (vece2016copasyndromea pages 2-4, kumrah2019geneticsofcopa pages 2-3, lepelley2020mutationsincopa pages 1-2)
Incomplete penetrance / variable expressivity	HP:0003828 Variable expressivity	Markedly variable; asymptomatic mutation carriers occur; multisystem severity ranges from mild to life-threatening	~30% clinical nonpenetrance in Lepelley 2020 families; Vece 2016 describes variable expressivity (lepelley2020mutationsincopa pages 4-5, vece2016copasyndromea pages 1-2)	Family studies show unaffected heterozygous carriers and broad phenotypic variability, supporting age- and modifier-dependent penetrance (lepelley2020mutationsincopa pages 4-5, vece2016copasyndromea pages 1-2)
Th17 skewing / elevated pro-inflammatory cytokines	HP:0012403 Abnormal T-helper 17 cell physiology; HP:0031784 Increased circulating interleukin-17 level; HP:0011137 Abnormal cytokine level	Chronic immunologic abnormality; likely upstream to ongoing autoimmunity/inflammation	Reported qualitatively in Vece 2016 and reviews; no robust pooled frequency in retrieved text	Vece 2016 described increased Th17 cells and increased IL-1β, IL-6, IL-23; Padureanu 2024 links altered thymic selection and Th17 skewing to disease biology (vece2016copasyndromea pages 2-4, padureanu2024copasyndrome—frompathogenesis pages 2-4)
Type I interferon signature / interferonopathy	HP:0034363 Increased interferon signature; HP:0011137 Abnormal cytokine level	Constitutive/chronic immune activation; detectable across serial samples; supports interferonopathy classification	Upregulation demonstrated in index case plus 4 additional COPA patients in Volpi 2018; persistent type I IFN signaling described in Lepelley 2020 and mechanistic studies (volpi2018typeiinterferon pages 9-12, lepelley2020mutationsincopa pages 1-2, deng2020adefectin pages 1-5)	Volpi 2018: “The upregulation of type 1 interferon signaling is demonstrated in the presented case and 4 other patients”; Lepelley 2020 and Deng 2020 mechanistically linked this to STING mistrafficking (volpi2018typeiinterferon pages 9-12, lepelley2020mutationsincopa pages 1-2, deng2020adefectin pages 1-5)

Table: This table maps major COPA syndrome manifestations to suggested HPO terms and summarizes the best available onset and frequency data from key cohorts and reviews. It is useful for knowledge-base phenotype curation and for linking clinical features to quantitative evidence.

Visual cohort evidence (Tsui et al., ERJ Open Research 2018): Tables in the paper summarize DAH prevalence, histopathology, treatments, and diagnostic clues. (tsui2018analysisofpulmonary media 5488c39b, tsui2018analysisofpulmonary media 3c75068d)

4. Genetic / molecular information

4.1 Causal gene

COPA (coat protein complex I subunit alpha). (kumrah2019geneticsofcopa pages 1-2)

4.2 Pathogenic variants (examples explicitly supported by retrieved evidence)

WD40-domain (classic) variants: - p.Lys230Asn (K230N), p.Arg233His (R233H), p.Glu241Lys (E241K), p.Asp243Gly (D243G); another residue-243 substitution p.Asp243Asn (D243N) appears in later families. (watkin2015copamutationsimpair pages 1-11, lepelley2020mutationsincopa pages 1-2)

CTD variants (2024 expansion): - p.C1013S, p.R1058C, p.R1142X reported in 6 children from 3 unrelated families. (delafontaine2024heterozygousmutationsin pages 1-2, delafontaine2024heterozygousmutationsin pages 2-3)

Variant type/class: missense variants are common for WD40-domain COPA syndrome; CTD includes missense and nonsense. (delafontaine2024heterozygousmutationsin pages 2-3, watkin2015copamutationsimpair pages 1-11)

Population frequency: CTD variants were reported as rare in gnomAD (qualitative statement in the excerpt). (delafontaine2024heterozygousmutationsin pages 2-3)

4.3 Functional consequence (current understanding)

WD40 variants impair binding/sorting of proteins targeted for ER retrieval (dilysine-tagged cargos), and mechanistic work identifies STING trafficking defects as a central immune driver. (deng2020adefectin pages 1-5, delafontaine2024heterozygousmutationsin pages 2-3)
Mutant COPA can increase ER stress markers and autophagosome accumulation (reported in early genetic work excerpts). (watkin2015copamutationsimpair pages 1-11)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

Modifier genes: clinical nonpenetrance (~30%) implies modifiers, but specific modifier loci were not established in the retrieved primary excerpts. (lepelley2020mutationsincopa pages 4-5)
Epigenetics/chromosomal abnormalities: no specific disease-associated chromosomal abnormalities or epigenetic alterations were supported by the retrieved text.

5. Environmental information

No specific toxins/lifestyle/infectious triggers were directly supported in the retrieved evidence excerpts. Many manifestations can mimic systemic autoimmune disease; however, environment-trigger claims would require additional epidemiologic/immunologic studies not captured in the current evidence set.

6. Mechanism / pathophysiology

6.1 Causal chain (integrated model)

Upstream defect: COPA mutation → impaired COPI-mediated trafficking (Golgi↔ER) → abnormal localization/handling of immune sensors and ER homeostasis.

Key midstream nodes: 1) STING mis-trafficking/activation at the ERGIC/Golgi, driving IFN-I programs. (deng2020adefectin pages 1-5, lepelley2020mutationsincopa pages 1-2) 2) ER stress (and impaired autophagy) amplifying inflammatory pathways and immune dysregulation. (watkin2015copamutationsimpair pages 1-11, delafontaine2024heterozygousmutationsin pages 2-3) 3) Downstream type I interferon signaling, with skewing toward pro-inflammatory immune phenotypes and autoantibody production. (volpi2018typeiinterferon pages 9-12, vece2016copasyndromea pages 2-4)

Tissue outcomes: chronic immune-mediated injury/fibrosis/hemorrhage in lung, inflammatory joint disease, and subset kidney immune-complex disease. (vece2016copasyndromea pages 2-4, tsui2018analysisofpulmonary pages 8-10)

6.2 STING/type I interferon biology in COPA syndrome (key primary findings)

STING retention/accumulation in Golgi: Lepelley et al. report that “mutant COPA is associated with an accumulation of STING in the Golgi compartment” and propose COPA mediates retrograde trafficking of STING from Golgi to ER. (lepelley2020mutationsincopa pages 1-2)
Ligand-independent STING activation and genetic rescue: Deng et al. show mutant COPA causes ligand-independent STING activation, with inflammatory phenotypes in CopaE241K/+ mice that are rescued by STING deficiency. (deng2020adefectin pages 1-5)
Adapter role (SURF4): Deng et al. identify SURF4 as an adapter facilitating COPA-mediated retrieval of STING. (deng2020adefectin pages 1-5)

6.3 cGAS/STING, ER stress, and NF-κB (2024 expansion into CTD)

Delafontaine et al. (JCI 2024) report CTD variants and show: - “These CTD COPA mutations disrupt the integrity and the function of coat protein complex I (COPI).” (delafontaine2024heterozygousmutationsin pages 1-2) - Trafficking defects (anterograde and retrograde) with “a cGAS/STING-dependent upregulation of the type I IFN signaling.” (delafontaine2024heterozygousmutationsin pages 1-2) - CTD variants “induce an activation of ER stress and NF-κB signaling.” (delafontaine2024heterozygousmutationsin pages 1-2)

6.4 Immune cell involvement (suggested CL terms)

Evidence supports T-cell skewing toward Th17 and systemic immune activation. - Suggested Cell Ontology (CL) terms: - CL:0000624 CD4-positive, alpha-beta T cell - CL:0000899 T helper 17 cell - CL:0000542 lymphocyte - CL:0000842 mononuclear cell (PBMC context) (Th17 skewing and PBMC interferon signatures are described in clinical series and mechanistic studies.) (vece2016copasyndromea pages 2-4, lepelley2020mutationsincopa pages 4-5)

6.5 Suggested GO terms (biological process / cellular component)

GO:0006886 intracellular protein transport
GO:0015031 protein transport
GO:0006890 retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
GO:0034976 response to endoplasmic reticulum stress
GO:0032481 positive regulation of type I interferon production
GO:0035458 cellular response to interferon-beta
GO:0038061 NIK/NF-kappaB signaling (These are consistent with COPI transport defects, ER stress, IFN-I pathway activation, and NF-κB activation described in mechanistic studies.) (deng2020adefectin pages 1-5, delafontaine2024heterozygousmutationsin pages 1-2)

6.6 Suggested UBERON anatomy terms (major affected structures)

UBERON:0002048 lung
UBERON:0002384 joint
UBERON:0002113 kidney Supported by the classic lung–joint–kidney phenotype. (vece2016copasyndromea pages 2-4, kumrah2019geneticsofcopa pages 2-3)

6.7 Molecular profiling / “IFN signature” as a biomarker concept

IFN signature has been shown in COPA syndrome cases and additional patients, and is proposed as a therapeutic/monitoring target. (volpi2018typeiinterferon pages 9-12, NCT06878365 chunk 1)

7. Anatomical structures affected

Organ/system level

Respiratory: diffuse parenchymal lung disease/ILD, cysts, DAH; progressive disease is a major driver of morbidity. (tsui2018analysisofpulmonary pages 8-10, padureanu2024copasyndrome—frompathogenesis pages 4-5)
Musculoskeletal: inflammatory arthritis/polyarthritis. (volpi2018typeiinterferon pages 9-12, tsui2018analysisofpulmonary pages 8-10)
Renal: immune-complex glomerulonephritis/nephritis in a subset. (kumrah2019geneticsofcopa pages 2-3)

Tissue/cell level (examples)

Lung biopsy findings commonly include follicular bronchiolitis and inflammatory changes. (tsui2018analysisofpulmonary media 5488c39b)

Subcellular localization

ER–Golgi axis/ERGIC is central; STING accumulation at Golgi and trafficking defects are a mechanistic hallmark. (lepelley2020mutationsincopa pages 1-2, deng2020adefectin pages 1-5)

8. Temporal development

Onset

Predominantly pediatric; 76% with onset before age 5 in one clinical series; cohorts show early onset medians in the low single-digit years. (vece2016copasyndromea pages 2-4, lepelley2020mutationsincopa pages 1-2)

Progression/course

Course may be chronic/progressive, with episodes of DAH and gradual pulmonary decline; some individuals progress to respiratory failure and may require transplant. (tsui2018analysisofpulmonary pages 8-10, kato2021augmentationofstimulator pages 6-10)

9. Inheritance and population

Inheritance

Autosomal dominant with variable expressivity and reported nonpenetrance in some families. (vece2016copasyndromea pages 1-2, lepelley2020mutationsincopa pages 4-5)

Epidemiology (data availability)

Robust prevalence/incidence estimates are not available in the retrieved evidence (typical for ultra-rare Mendelian disorders). Available “case-count” statistics from reviews/cohorts include: - A review excerpt notes ~79 patients reported with near-equal sex distribution (39M/40F). (padureanu2024copasyndrome—frompathogenesis pages 4-5) - Earlier cohort summary: 21 patients from five families, mean presentation ~3.5 years, and renal involvement in 4/21. (kumrah2019geneticsofcopa pages 2-3)

10. Diagnostics

10.1 Clinical suspicion pattern (high-yield recognition)

A practical diagnostic pattern is childhood-onset or familial lung disease (ILD/cysts/DAH) + inflammatory arthritis + autoantibody positivity (ANA/ANCA ± RF/anti-CCP), with or without renal involvement. (tsui2018analysisofpulmonary pages 8-10, vece2016copasyndromea pages 2-4)

10.2 Laboratory findings / biomarkers

Autoantibodies: ANA (~80% in one series), ANCA, RF (71% in one cohort), anti-CCP. (vece2016copasyndromea pages 2-4, tsui2018analysisofpulmonary pages 8-10)
Inflammatory markers: CRP/ESR elevations reported. (kato2021augmentationofstimulator pages 6-10)
IFN-I pathway activation (“IFN signature”) is a mechanistic biomarker concept. (volpi2018typeiinterferon pages 9-12)

10.3 Imaging / pathology

CT findings may include cysts and ground-glass opacities; biopsy often shows follicular bronchiolitis. (tsui2018analysisofpulmonary media 5488c39b)

10.4 Genetic testing approach

Targeted sequencing focusing on the historically implicated region (exons 8–9; WD40 variants) was suggested in one pulmonary cohort when clinical criteria are met; broader panels or exome/genome sequencing may be needed given CTD variants described in 2024. (tsui2018analysisofpulmonary pages 8-10, delafontaine2024heterozygousmutationsin pages 1-2)

Differential diagnosis (examples)

Because of autoantibodies and organ involvement, COPA syndrome can mimic systemic autoimmune conditions; mechanistic/clinical work emphasizes overlap with type I interferonopathies such as SAVI. (lepelley2020mutationsincopa pages 1-2, volpi2018typeiinterferon pages 9-12)

11. Outcome / prognosis

Key prognosis concepts

Lung disease is frequently the dominant driver of morbidity and may progress despite immunosuppression; some patients undergo lung transplantation. (tsui2018analysisofpulmonary pages 8-10, kato2021augmentationofstimulator pages 6-10)

Quantitative survival estimates were not available in the retrieved excerpts.

12. Treatment

12.1 Current real-world treatments (immunosuppression/biologics)

In a pulmonary cohort, patients received immunosuppression including glucocorticoids and steroid-sparing agents; induction regimens for DAH included methylprednisolone plus cyclophosphamide followed by maintenance (e.g., mycophenolate/azathioprine), with radiographic improvement but often ongoing physiologic decline. (tsui2018analysisofpulmonary pages 8-10)

Real-world implementation evidence (tables/figures): Tsui et al. include tables listing maintenance immunosuppression and diagnostic clues, plus longitudinal treatment/clinical course plots. (tsui2018analysisofpulmonary media 3c75068d)

12.2 Targeted / pathway-informed therapies

JAK inhibitors (downstream IFN signaling): - Lepelley et al. report that “Based on these results, three patients have been treated with interferon signaling (JAK1) inhibitors” (paper abstract statement as quoted in excerpt). (lepelley2020mutationsincopa pages 1-2) - In detailed text excerpt, one patient received ruxolitinib for >1 year with improvement in severe lung disease. (lepelley2020mutationsincopa pages 4-5) - A 2024 review states: “JAK inhibitor therapy seems to be the most promising therapeutic choice now,” while acknowledging long-term lung control data remain limited. (padureanu2024copasyndrome—frompathogenesis pages 4-5)

STING pathway inhibition (upstream): - In vitro work on COPI deficiency demonstrated inflammation in COPA syndrome PBMCs/cell lines can be ameliorated by a small-molecule STING inhibitor (H-151), supporting STING as a target concept; this underpins ongoing interest in STING-directed trials/compounds. (delafontaine2024heterozygousmutationsin pages 17-17)

Transplantation: - Lung transplantation is used in severe progressive cases. (kato2021augmentationofstimulator pages 6-10, tsui2018analysisofpulmonary pages 8-10)

12.3 Clinical trials (current / emerging)

NCT06878365 (BI 3000202; type I interferonopathies including COPA) - Title: “A Study to Test How Well BI 3000202 is Tolerated by People With Type 1 Interferonopathies” - Sponsor: Boehringer Ingelheim - Phase: 1; open-label; single-group - Enrollment: 16 - Includes COPA syndrome explicitly (genetic diagnosis: COPA) - Starts: 2025-07-29; status: active, not recruiting - Outcomes include adverse events and change in interferon gene score ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT06878365 (NCT06878365 chunk 1)

NCT06235580 (observational genotype–phenotype; includes COPA) - Observational case-control study at Imagine Institute enrolling genetic diseases with immune and neurological dysfunction; explicitly includes COPA syndrome ClinicalTrials.gov: https://clinicaltrials.gov/study/NCT06235580 (NCT06235580 chunk 1)

12.4 Suggested MAXO terms (examples)

MAXO:0000058 immunosuppressive therapy (for systemic immunosuppression)
MAXO:0000755 Janus kinase inhibitor therapy (for ruxolitinib/baricitinib class)
MAXO:0000600 lung transplantation (These are ontology suggestions; exact MAXO IDs should be validated against the current MAXO release.) (tsui2018analysisofpulmonary pages 8-10, lepelley2020mutationsincopa pages 4-5, kato2021augmentationofstimulator pages 6-10)

13. Prevention

As a Mendelian autosomal dominant disorder, prevention is primarily via genetic counseling, cascade testing in families, and early recognition/monitoring for lung disease in carriers. While penetrance can be incomplete, nonpenetrance and variable expressivity complicate predictive counseling. (lepelley2020mutationsincopa pages 4-5, vece2016copasyndromea pages 1-2)

14. Other species / natural disease

No naturally occurring veterinary disease analogs were supported in the retrieved evidence excerpts.

15. Model organisms / experimental systems

Mouse models: mechanistic studies used CopaE241K/+ and other targeted Copa alleles and showed STING-dependent inflammatory phenotypes rescued by STING deficiency, supporting causal biology. (deng2020adefectin pages 1-5)
Patient-derived fibroblasts/cell lines: CTD variants (R1058C, R1142X) were studied in fibroblasts, demonstrating trafficking defects and cGAS/STING-dependent IFN signaling plus ER stress/NF-κB activation. (delafontaine2024heterozygousmutationsin pages 1-2)

Recent developments (2023–2024 emphasis)

Expanded genetic architecture (CTD COPA variants): 2024 JCI report established CTD variants causing a COPA-related syndrome and clarified cGAS/STING dependence, ER stress, and NF-κB activation, broadening diagnostic sequencing beyond WD40 exons. Publication: Jan 2024; DOI: https://doi.org/10.1172/jci163604. (delafontaine2024heterozygousmutationsin pages 1-2, delafontaine2024heterozygousmutationsin pages 2-3)
Clinical consolidation and treatment outlook: 2024 Diagnostics review synthesized phenotype frequencies (e.g., arthritis ~95%, pulmonary involvement near-universal in curated cases) and highlighted JAK inhibitors as the most promising currently available class, while noting limited long-term lung outcome data. Publication: Dec 2024; DOI: https://doi.org/10.3390/diagnostics14242819. (padureanu2024copasyndrome—frompathogenesis pages 4-5, padureanu2024copasyndrome—frompathogenesis pages 1-2)
New phenotypic expansions: 2023–2024 case reports broadened phenotype (e.g., skin/NMOSD features, cryoglobulinemia) but these represent low-level evidence relative to cohorts. (padureanu2024copasyndrome—frompathogenesis pages 4-5)

Evidence gaps / limitations (for knowledge-base curation)

PMIDs: The retrieved full-text excerpts seldom include explicit PMID fields. One key PMID surfaced via Open Targets for COPA–disease association evidence: PMID: 25894502 (likely corresponding to the 2015 discovery report). (padureanu2024copasyndrome—frompathogenesis pages 1-2)
Population epidemiology: Prevalence/incidence estimates are not established in the retrieved evidence and generally remain unknown for ultra-rare disorders.
Standardized diagnostic criteria: No formal consensus criteria were retrieved; most clinical guidance is pattern recognition plus genetic confirmation.

Key source URLs (publication date in citation header)

Watkin et al. Nature Genetics (Apr 2015). DOI: https://doi.org/10.1038/ng.3279 (watkin2015copamutationsimpair pages 1-11)
Vece et al. Journal of Clinical Immunology (Apr 2016). DOI: https://doi.org/10.1007/s10875-016-0271-8 (vece2016copasyndromea pages 1-2)
Tsui et al. ERJ Open Research (Apr 2018). DOI: https://doi.org/10.1183/23120541.00017-2018 (tsui2018analysisofpulmonary pages 8-10)
Lepelley et al. Journal of Experimental Medicine (Jul 2020). DOI: https://doi.org/10.1084/jem.20200600 (lepelley2020mutationsincopa pages 1-2)
Deng et al. Journal of Experimental Medicine (Jul 2020). DOI: https://doi.org/10.1084/jem.20201045 (deng2020adefectin pages 1-5)
Kato et al. Arthritis & Rheumatology (Nov 2021). DOI: https://doi.org/10.1002/art.41790 (kato2021augmentationofstimulator pages 6-10)
Delafontaine et al. Journal of Clinical Investigation (Jan 2024). DOI: https://doi.org/10.1172/jci163604 (delafontaine2024heterozygousmutationsin pages 1-2)
Padureanu et al. Diagnostics (Dec 2024). DOI: https://doi.org/10.3390/diagnostics14242819 (padureanu2024copasyndrome—frompathogenesis pages 1-2)
Clinical trial: NCT06878365 (Start 2025-07-29). https://clinicaltrials.gov/study/NCT06878365 (NCT06878365 chunk 1)
Observational study: NCT06235580. https://clinicaltrials.gov/study/NCT06235580 (NCT06235580 chunk 1)

References

(vece2016copasyndromea pages 2-4): Timothy J. Vece, Levi B. Watkin, Sarah K. Nicholas, Debra Canter, Michael C. Braun, Robert Paul Guillerman, Karen W. Eldin, Grant Bertolet, Scott D. McKinley, Marietta de Guzman, Lisa R. Forbes, Ivan Chinn, and Jordan S. Orange. Copa syndrome: a novel autosomal dominant immune dysregulatory disease. Journal of Clinical Immunology, 36:377-387, Apr 2016. URL: https://doi.org/10.1007/s10875-016-0271-8, doi:10.1007/s10875-016-0271-8. This article has 208 citations and is from a domain leading peer-reviewed journal.
(tsui2018analysisofpulmonary pages 8-10): Jessica L. Tsui, Oscar A. Estrada, Zimu Deng, Kristin M. Wang, Christopher S. Law, Brett M. Elicker, Kirk D. Jones, Sharon D. Dell, Gunnar Gudmundsson, Sif Hansdottir, Simon M. Helfgott, Stefano Volpi, Marco Gattorno, Michael R. Waterfield, Alice Y. Chan, Sharon A. Chung, Brett Ley, and Anthony K. Shum. Analysis of pulmonary features and treatment approaches in the copa syndrome. ERJ Open Research, 4:00017-2018, Apr 2018. URL: https://doi.org/10.1183/23120541.00017-2018, doi:10.1183/23120541.00017-2018. This article has 108 citations and is from a peer-reviewed journal.
(deng2020adefectin pages 1-5): Zimu Deng, Zhenlu Chong, Christopher S. Law, Kojiro Mukai, Frances O. Ho, Tereza Martinu, Bradley J. Backes, Walter L. Eckalbar, Tomohiko Taguchi, and Anthony K. Shum. A defect in copi-mediated transport of sting causes immune dysregulation in copa syndrome. Journal of Experimental Medicine, Jul 2020. URL: https://doi.org/10.1084/jem.20201045, doi:10.1084/jem.20201045. This article has 214 citations and is from a highest quality peer-reviewed journal.
(delafontaine2024heterozygousmutationsin pages 1-2): Selket Delafontaine, Alberto Iannuzzo, Tarin M. Bigley, Bram Mylemans, Ruchit Rana, Pieter Baatsen, Maria Cecilia Poli, Daisy Rymen, Katrien Jansen, Djalila Mekahli, Ingele Casteels, Catherine Cassiman, Philippe Demaerel, Alice Lepelley, Marie-Louise Frémond, Rik Schrijvers, Xavier Bossuyt, Katlijn Vints, Wim Huybrechts, Rachida Tacine, Karen Willekens, Anniek Corveleyn, Bram Boeckx, Marco Baggio, Lisa Ehlers, Sebastian Munck, Diether Lambrechts, Arnout Voet, Leen Moens, Giorgia Bucciol, Megan A. Cooper, Carla M. Davis, Jérôme Delon, and Isabelle Meyts. Heterozygous mutations in the c-terminal domain of copa underlie a complex autoinﬂammatory syndrome. The Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci163604, doi:10.1172/jci163604. This article has 24 citations.
(vece2016copasyndromea pages 1-2): Timothy J. Vece, Levi B. Watkin, Sarah K. Nicholas, Debra Canter, Michael C. Braun, Robert Paul Guillerman, Karen W. Eldin, Grant Bertolet, Scott D. McKinley, Marietta de Guzman, Lisa R. Forbes, Ivan Chinn, and Jordan S. Orange. Copa syndrome: a novel autosomal dominant immune dysregulatory disease. Journal of Clinical Immunology, 36:377-387, Apr 2016. URL: https://doi.org/10.1007/s10875-016-0271-8, doi:10.1007/s10875-016-0271-8. This article has 208 citations and is from a domain leading peer-reviewed journal.
(padureanu2024copasyndrome—frompathogenesis pages 2-4): Vlad Padureanu, Mircea-Cătălin Forțofoiu, Ionut Donoiu, Eugen-Nicolae Tieranu, Catalin Dumitrascu, Rodica Padureanu, Anca Emanuela Mușetescu, Cristina Alexandru, Carmen Catalina Iorgus, Florin Bobirca, Ana Dascalu, and Anca Bobirca. Copa syndrome—from pathogenesis to treatment. Diagnostics, 14:2819, Dec 2024. URL: https://doi.org/10.3390/diagnostics14242819, doi:10.3390/diagnostics14242819. This article has 4 citations.
(padureanu2024copasyndrome—frompathogenesis pages 1-2): Vlad Padureanu, Mircea-Cătălin Forțofoiu, Ionut Donoiu, Eugen-Nicolae Tieranu, Catalin Dumitrascu, Rodica Padureanu, Anca Emanuela Mușetescu, Cristina Alexandru, Carmen Catalina Iorgus, Florin Bobirca, Ana Dascalu, and Anca Bobirca. Copa syndrome—from pathogenesis to treatment. Diagnostics, 14:2819, Dec 2024. URL: https://doi.org/10.3390/diagnostics14242819, doi:10.3390/diagnostics14242819. This article has 4 citations.
(kato2021augmentationofstimulator pages 6-10): Takashi Kato, Masaki Yamamoto, Yoshitaka Honda, Takashi Orimo, Izumi Sasaki, Kohei Murakami, Hiroaki Hemmi, Yuri Fukuda‐Ohta, Kyoichi Isono, Saki Takayama, Hidenori Nakamura, Yoshiro Otsuki, Toshiaki Miyamoto, Junko Takita, Takahiro Yasumi, Ryuta Nishikomori, Tadashi Matsubayashi, Kazushi Izawa, and Tsuneyasu Kaisho. Augmentation of stimulator of interferon genes–induced type i interferon production in copa syndrome. Arthritis & Rheumatology, 73:2105-2115, Nov 2021. URL: https://doi.org/10.1002/art.41790, doi:10.1002/art.41790. This article has 41 citations and is from a highest quality peer-reviewed journal.
(kumrah2019geneticsofcopa pages 1-2): Rajni Kumrah, Babu Mathew, Vignesh Pandiarajan, Surjit Singh, and Amit Rawat. Genetics of copa syndrome. The Application of Clinical Genetics, 12:11-18, Feb 2019. URL: https://doi.org/10.2147/tacg.s153600, doi:10.2147/tacg.s153600. This article has 27 citations.
(lepelley2020mutationsincopa pages 1-2): Alice Lepelley, Maria José Martin-Niclós, Melvin Le Bihan, Joseph A. Marsh, Carolina Uggenti, Gillian I. Rice, Vincent Bondet, Darragh Duffy, Jonny Hertzog, Jan Rehwinkel, Serge Amselem, Siham Boulisfane-El Khalifi, Mary Brennan, Edwin Carter, Lucienne Chatenoud, Stéphanie Chhun, Aurore Coulomb l’Hermine, Marine Depp, Marie Legendre, Karen J. Mackenzie, Jonathan Marey, Catherine McDougall, Kathryn J. McKenzie, Thierry Jo Molina, Bénédicte Neven, Luis Seabra, Caroline Thumerelle, Marie Wislez, Nadia Nathan, Nicolas Manel, Yanick J. Crow, and Marie-Louise Frémond. Mutations in copa lead to abnormal trafficking of sting to the golgi and interferon signaling. The Journal of Experimental Medicine, Jul 2020. URL: https://doi.org/10.1084/jem.20200600, doi:10.1084/jem.20200600. This article has 232 citations.
(padureanu2024copasyndrome—frompathogenesis pages 4-5): Vlad Padureanu, Mircea-Cătălin Forțofoiu, Ionut Donoiu, Eugen-Nicolae Tieranu, Catalin Dumitrascu, Rodica Padureanu, Anca Emanuela Mușetescu, Cristina Alexandru, Carmen Catalina Iorgus, Florin Bobirca, Ana Dascalu, and Anca Bobirca. Copa syndrome—from pathogenesis to treatment. Diagnostics, 14:2819, Dec 2024. URL: https://doi.org/10.3390/diagnostics14242819, doi:10.3390/diagnostics14242819. This article has 4 citations.
(watkin2015copamutationsimpair pages 1-11): Levi B Watkin, Birthe Jessen, Wojciech Wiszniewski, Timothy J Vece, Max Jan, Youbao Sha, Maike Thamsen, Regie L P Santos-Cortez, Kwanghyuk Lee, Tomasz Gambin, Lisa R Forbes, Christopher S Law, Asbjørg Stray-Pedersen, Mickie H Cheng, Emily M Mace, Mark S Anderson, Dongfang Liu, Ling Fung Tang, Sarah K Nicholas, Karen Nahmod, George Makedonas, Debra L Canter, Pui-Yan Kwok, John Hicks, Kirk D Jones, Samantha Penney, Shalini N Jhangiani, Michael D Rosenblum, Sharon D Dell, Michael R Waterfield, Feroz R Papa, Donna M Muzny, Noah Zaitlen, Suzanne M Leal, Claudia Gonzaga-Jauregui, Eric Boerwinkle, N Tony Eissa, Richard A Gibbs, James R Lupski, Jordan S Orange, and Anthony K Shum. Copa mutations impair er-golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nature Genetics, 47:654-660, Apr 2015. URL: https://doi.org/10.1038/ng.3279, doi:10.1038/ng.3279. This article has 435 citations and is from a highest quality peer-reviewed journal.
(delafontaine2024heterozygousmutationsin pages 2-3): Selket Delafontaine, Alberto Iannuzzo, Tarin M. Bigley, Bram Mylemans, Ruchit Rana, Pieter Baatsen, Maria Cecilia Poli, Daisy Rymen, Katrien Jansen, Djalila Mekahli, Ingele Casteels, Catherine Cassiman, Philippe Demaerel, Alice Lepelley, Marie-Louise Frémond, Rik Schrijvers, Xavier Bossuyt, Katlijn Vints, Wim Huybrechts, Rachida Tacine, Karen Willekens, Anniek Corveleyn, Bram Boeckx, Marco Baggio, Lisa Ehlers, Sebastian Munck, Diether Lambrechts, Arnout Voet, Leen Moens, Giorgia Bucciol, Megan A. Cooper, Carla M. Davis, Jérôme Delon, and Isabelle Meyts. Heterozygous mutations in the c-terminal domain of copa underlie a complex autoinﬂammatory syndrome. The Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci163604, doi:10.1172/jci163604. This article has 24 citations.
(kumrah2019geneticsofcopa pages 2-3): Rajni Kumrah, Babu Mathew, Vignesh Pandiarajan, Surjit Singh, and Amit Rawat. Genetics of copa syndrome. The Application of Clinical Genetics, 12:11-18, Feb 2019. URL: https://doi.org/10.2147/tacg.s153600, doi:10.2147/tacg.s153600. This article has 27 citations.
(lepelley2020mutationsincopa pages 4-5): Alice Lepelley, Maria José Martin-Niclós, Melvin Le Bihan, Joseph A. Marsh, Carolina Uggenti, Gillian I. Rice, Vincent Bondet, Darragh Duffy, Jonny Hertzog, Jan Rehwinkel, Serge Amselem, Siham Boulisfane-El Khalifi, Mary Brennan, Edwin Carter, Lucienne Chatenoud, Stéphanie Chhun, Aurore Coulomb l’Hermine, Marine Depp, Marie Legendre, Karen J. Mackenzie, Jonathan Marey, Catherine McDougall, Kathryn J. McKenzie, Thierry Jo Molina, Bénédicte Neven, Luis Seabra, Caroline Thumerelle, Marie Wislez, Nadia Nathan, Nicolas Manel, Yanick J. Crow, and Marie-Louise Frémond. Mutations in copa lead to abnormal trafficking of sting to the golgi and interferon signaling. The Journal of Experimental Medicine, Jul 2020. URL: https://doi.org/10.1084/jem.20200600, doi:10.1084/jem.20200600. This article has 232 citations.
(tsui2018analysisofpulmonary media 5488c39b): Jessica L. Tsui, Oscar A. Estrada, Zimu Deng, Kristin M. Wang, Christopher S. Law, Brett M. Elicker, Kirk D. Jones, Sharon D. Dell, Gunnar Gudmundsson, Sif Hansdottir, Simon M. Helfgott, Stefano Volpi, Marco Gattorno, Michael R. Waterfield, Alice Y. Chan, Sharon A. Chung, Brett Ley, and Anthony K. Shum. Analysis of pulmonary features and treatment approaches in the copa syndrome. ERJ Open Research, 4:00017-2018, Apr 2018. URL: https://doi.org/10.1183/23120541.00017-2018, doi:10.1183/23120541.00017-2018. This article has 108 citations and is from a peer-reviewed journal.
(volpi2018typeiinterferon pages 9-12): Stefano Volpi, Jessica Tsui, Marcello Mariani, Claudia Pastorino, Roberta Caorsi, Oliviero Sacco, Angelo Ravelli, Anthony K. Shum, Marco Gattorno, and Paolo Picco. Type i interferon pathway activation in copa syndrome. Clinical Immunology, 187:33-36, Feb 2018. URL: https://doi.org/10.1016/j.clim.2017.10.001, doi:10.1016/j.clim.2017.10.001. This article has 134 citations and is from a peer-reviewed journal.
(tsui2018analysisofpulmonary pages 8-8): Jessica L. Tsui, Oscar A. Estrada, Zimu Deng, Kristin M. Wang, Christopher S. Law, Brett M. Elicker, Kirk D. Jones, Sharon D. Dell, Gunnar Gudmundsson, Sif Hansdottir, Simon M. Helfgott, Stefano Volpi, Marco Gattorno, Michael R. Waterfield, Alice Y. Chan, Sharon A. Chung, Brett Ley, and Anthony K. Shum. Analysis of pulmonary features and treatment approaches in the copa syndrome. ERJ Open Research, 4:00017-2018, Apr 2018. URL: https://doi.org/10.1183/23120541.00017-2018, doi:10.1183/23120541.00017-2018. This article has 108 citations and is from a peer-reviewed journal.
(tsui2018analysisofpulmonary media 3c75068d): Jessica L. Tsui, Oscar A. Estrada, Zimu Deng, Kristin M. Wang, Christopher S. Law, Brett M. Elicker, Kirk D. Jones, Sharon D. Dell, Gunnar Gudmundsson, Sif Hansdottir, Simon M. Helfgott, Stefano Volpi, Marco Gattorno, Michael R. Waterfield, Alice Y. Chan, Sharon A. Chung, Brett Ley, and Anthony K. Shum. Analysis of pulmonary features and treatment approaches in the copa syndrome. ERJ Open Research, 4:00017-2018, Apr 2018. URL: https://doi.org/10.1183/23120541.00017-2018, doi:10.1183/23120541.00017-2018. This article has 108 citations and is from a peer-reviewed journal.
(NCT06878365 chunk 1): A Study to Test How Well BI 3000202 is Tolerated by People With Type 1 Interferonopathies. Boehringer Ingelheim. 2025. ClinicalTrials.gov Identifier: NCT06878365
(delafontaine2024heterozygousmutationsin pages 17-17): Selket Delafontaine, Alberto Iannuzzo, Tarin M. Bigley, Bram Mylemans, Ruchit Rana, Pieter Baatsen, Maria Cecilia Poli, Daisy Rymen, Katrien Jansen, Djalila Mekahli, Ingele Casteels, Catherine Cassiman, Philippe Demaerel, Alice Lepelley, Marie-Louise Frémond, Rik Schrijvers, Xavier Bossuyt, Katlijn Vints, Wim Huybrechts, Rachida Tacine, Karen Willekens, Anniek Corveleyn, Bram Boeckx, Marco Baggio, Lisa Ehlers, Sebastian Munck, Diether Lambrechts, Arnout Voet, Leen Moens, Giorgia Bucciol, Megan A. Cooper, Carla M. Davis, Jérôme Delon, and Isabelle Meyts. Heterozygous mutations in the c-terminal domain of copa underlie a complex autoinﬂammatory syndrome. The Journal of Clinical Investigation, Jan 2024. URL: https://doi.org/10.1172/jci163604, doi:10.1172/jci163604. This article has 24 citations.
(NCT06235580 chunk 1): Genotype-phenotype Characterization Study on Genetic Diseases With Immune and Neurological Dysfunctions. Imagine Institute. 2015. ClinicalTrials.gov Identifier: NCT06235580

Ask OpenScientist

OpenScientist Report

Inheritance

Subtypes

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Clinical Trials

Source YAML

References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

COPA Syndrome (MONDO:0014629) — Comprehensive Disease Characteristics Report

Executive summary

1. Disease information

1.1 What is COPA syndrome?

1.2 Key identifiers and ontology mapping

2. Etiology

2.1 Disease causal factors

2.2 Risk factors

2.3 Protective factors

2.4 Gene–environment interactions

3. Phenotypes (clinical spectrum)

3.1 Major phenotype clusters

3.2 Onset, severity, and progression

3.3 Suggested HPO terms (with frequencies where available)

4. Genetic / molecular information

4.1 Causal gene

4.2 Pathogenic variants (examples explicitly supported by retrieved evidence)

4.3 Functional consequence (current understanding)

4.4 Modifier genes / epigenetics / chromosomal abnormalities

5. Environmental information

6. Mechanism / pathophysiology

6.1 Causal chain (integrated model)

6.2 STING/type I interferon biology in COPA syndrome (key primary findings)

6.3 cGAS/STING, ER stress, and NF-κB (2024 expansion into CTD)

6.4 Immune cell involvement (suggested CL terms)

6.5 Suggested GO terms (biological process / cellular component)

6.6 Suggested UBERON anatomy terms (major affected structures)

6.7 Molecular profiling / “IFN signature” as a biomarker concept

7. Anatomical structures affected

Organ/system level

Tissue/cell level (examples)

Subcellular localization

8. Temporal development

Onset

Progression/course

9. Inheritance and population

Inheritance

Epidemiology (data availability)

10. Diagnostics

10.1 Clinical suspicion pattern (high-yield recognition)

10.2 Laboratory findings / biomarkers

10.3 Imaging / pathology

10.4 Genetic testing approach

Differential diagnosis (examples)

11. Outcome / prognosis

Key prognosis concepts