To the Editor:
COPA syndrome is a rare genetic disorder of vesicle trafficking that typically affects lungs, joints, and kidneys in infants, though rare adult cases exist. Pathogenic variants are usually missense mutations in the N-terminal WD40 domain of the COPA gene, but other regions may also be implicated in autoinflammatory phenotypes. We describe a case of adult-onset autoinflammatory syndrome with cardiac involvement and a novel variant of uncertain significance (VUS), p.(Thr647Ile), located outside the canonical domain of the COPA gene. Its uncertain significance precludes a definitive diagnosis. This case underscores the need to further investigate noncanonical COPA variants in autoinflammatory diseases.
A 60-year-old White male individual, with a previous history of smoking and no other personal or familial history, developed a 4-week clinical picture of dyspnea, pleuritic chest pain, constitutional symptoms, and low-grade fever in the context of myopericarditis. Polyarthritis of the small joints of both hands and the left knee and polymyalgia rheumatica–like pain and stiffness were observed. Physical examination revealed hypophonesis of lung bases and hepatosplenomegaly, without other physical abnormalities.
The Table summarizes laboratory findings, highlighting positivity for multiple antibodies and normality of muscle inflammation markers. Urinalysis revealed 180 mg of proteinuria in 24-hour collection with maintained kidney function.
Baseline laboratory characteristics of the patient.
Chest radiograph revealed pleural effusion and a pulmonary nodule in the left upper lobe, confirmed by thoracic computed tomography and positron emission tomography. These exhibited the presence of 2 more pulmonary nodules, inflammatory condensations in lower lobes, and hiliomediastinal adenopathies (Figure 1 and Figure 2).
(A) Chest radiograph (March 2024) showing bilateral pleural effusion, most significantly in the right hemithorax (white arrows). (B) PET/CT scan (March 2024) showing main LUL pulmonary nodule (white arrow). CT: computed tomography; LUL: left upper lobe; PET: positron emission tomography.
Evolution of pleural (white arrows) and pericardial (gray arrows) effusions. (A) Thoracic CT (March 2024) showing small bilateral pleural effusion, with thickening and enhancement of the pleural layers suggesting exudative effusion, and minimal pericardial thickening. (B) Thoracic CT angiography (April 2024) showing increased volume of the right pleural effusion, with a loculated appearance, and the presence of a pericardial effusion. (C) Thoracic CT scan (June 2024) showing resolution of the pleural and pericardial effusions, with minimal pericardial thickening persisting. (D) Normal thoracic CT scan (July 2025). CT: computed tomography.
No data suggestive of malignancy or thromboembolism were evident. All microbiological studies were negative, including bronchoalveolar lavage (BAL) extended to mycobacteria and fungi. The anatomopathological study of BAL showed no evidence of alveolar hemorrhage. Biopsy was not performed.
After reasonably ruling out microbial etiology, malignancy, or other complications requiring specific management, and in view of progressive deterioration despite progressive escalation of antibiotic coverage, management with pulses of methylprednisolone was decided upon. The initial response was excellent, but there was relapse of symptoms with dose reduction (fever, inflammatory arthromyalgias, and pericarditis). Colchicine 1 mg daily was added, with favorable response.
Adult-onset Still disease (AOSD) was proposed. Although the patient presented with hyperferritinemia, it was not extreme and no high or evening fevers were observed. There was also no evidence of an evanescent rash or other cutaneous alterations, leukocytosis, and/or neutrophilia, nor a sore throat preceding the clinical picture. The presence of pulmonary abnormalities (but not interstitial lung disease), a multipositive autoimmunity profile, and normal lactate dehydrogenase levels helped to discard the possibility of an AOSD diagnosis. Antineutrophil cytoplasmic antibody–associated vasculitis (AAV) was also suspected but was ruled out in the absence of significant renal involvement, cutaneous lesions, or polyneuropathy, and given that the broader autoimmune profile identified—beyond ANCA positivity—was not consistent with AAV. Additionally, the favorable response to colchicine is inconsistent with AAV, since this condition does not typically respond to such treatment.
In suspicion of an adult-onset autoinflammatory syndrome, genetic analysis was performed. A heterozygous missense variant in exon 19 of the COPA gene leading to a threonine-to-isoleucine change at position 647, p.(Thr647Ile), was observed, with a variant allele frequency of 51%. This variant, located in the coatomer WD-associated region, was considered a VUS, but identified as likely pathogenic by in silico predictor models (6 out of 8) with a Rare Exome Variant Ensemble Learner (REVEL) value of 0.588, and has not been described previously in reference databases such as the Genome Aggregation Database (gnomAD) or ClinVar ID (American College of Medical Genetics and Genomics criteria PM2 and PP2). Segregation was not examined in family members owing to laboratory restrictions.
Baricitinib was started (4 mg/day). The patient showed laboratory, clinical, and radiological improvement, with normalization of inflammatory markers, resolution of pulmonary condensations, and disappearance of nodules without symptom recurrence (Figure 3). This response has continued for more than 18 months after glucocorticoid withdrawal.
Evolution of the main LUL pulmonary nodule image showing a tendency toward resolution over time: (A) Thoracic CT (March 2024) and (B) CT angiography (April 2024) before the start of specific treatment; and (C) thoracic CT (June 2024) and (D) thoracic CT (July 2025) after the start of specific treatment. CT: computed tomography; LUL: left upper lobe.
This report describes an adult-onset autoinflammatory syndrome with a novel mutation in the coatomer WD-associated region of the COPA gene, which, according to the current definition, can only be classified as VUS. However, considering the clinical picture of an adult-onset autoinflammatory syndrome, the high probability of this VUS being deleterious according to in silico predictor models, as well as the location of the mutation—a highly conserved domain—we propose that p.(Thr647Ile) may represent the first disease-causing variant identified in adults within the coatomer WD-associated region of the COPA gene.
Further, missense mutations in the COPA gene have been described as pathogenic or possibly pathogenic,1 and fewer variants than expected have a neutral or nondeleterious effect (gnomAD Z score of 4.8). Since the affected region is involved in the assembly of the coat protein complex I (COPI) and its interaction with other subunits,2 it seems plausible that mutations at this site could lead to a less stable COPI assembly, a hypothesis that should be tested in larger cohorts.
COPA syndrome is an autosomal dominant interferonopathy affecting intracellular protein trafficking that was first reported in 2015; it is characterized by heterogeneous lung disease, musculoskeletal inflammation, and immune-mediated glomerulopathy.3 At present, COPA syndrome is the only known disease affecting the COPA gene, and typically affects infants before age 12 (89%).4 All pathogenic variants consistent with COPA syndrome described are heterozygous missense mutations clustered within the N-terminal WD40 domain4; nevertheless, other autoinflammatory phenotypes have been identified as well in the C-terminal region5 and coatomer WD-associated region.6
To summarize, the clinical presentation of our patient was characterized by adult-onset disease, cardiac involvement, and a mutation located outside the canonical WD40 domain of the COPA gene. Given this presentation and the inability to establish the inheritance pattern or determine the functional consequences of this VUS, the patient cannot be definitively diagnosed with COPA syndrome at present. Nonetheless, this case may be regarded as an adult-onset autoinflammatory syndrome in a patient that possesses a novel missense variant in the COPA gene, p.(Thr647Ile), the pathogenic role of which warrants further clinical, functional, and prognostic investigation. Further studies are needed to clarify the effect of variants in this domain on autoinflammatory diseases.
Footnotes
CONTRIBUTIONS
Writing – original draft: PGE; writing – review & editing: PGE, AIdE, SBdOG, MLIG.
FUNDING
No specific funding was received from public, private, or nonprofit sectors to carry out the work described in this article.
COMPETING INTERESTS
The authors declare no competing interests relevant to this manuscript.
ETHICS AND PATIENT CONSENT
Ethical approval was not required for this case report. Written informed consent was obtained from the patient for the publication of this article.
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