To the Editor: COPA syndrome is a recently described monogenic immunodysregulatory syndrome. The COPA gene encodes for the α subunit of coatomer complex I (COPI), which is expressed in all cell types and is involved in trafficking from the Golgi complex to the endoplasmic reticulum (ER)[1]. The most common clinical features of COPA syndrome are pulmonary hemorrhage, interstitial lung disease, arthritis, glomerular disease, and autoantibody development [2, 3]. Atypical features of COPA syndrome identified thus far include extrapulmonary cysts in the liver and kidney, renal and neuroendocrine malignancies, autoimmune neurological disorders such as neuromyelitis optica, and infections, such as meningitis [4]. We present a case of a 2-year-old male with COPA syndrome manifesting as lymphocytic interstitial pneumonitis, peripheral blood B cell lymphocytosis, mediastinal lymphadenopathy and persistent, unexplained transaminitis. Our patient initially presented at age 9 months with persistent nasal congestion, nonproductive cough, post-tussive emesis, and poor weight gain. He had no other past medical history. Family history was notable for myotonia congenita in the father and paternal aunt, and hypophosphatasia in the maternal grandfather and maternal siblings. Physical exam was remarkable for prominent digital clubbing, a dry cough, and tachypnea with mild retractions. Initial work-up demonstrated leukocytosis with B cell predominance and presumed reactive thrombocytosis, along with elevated transaminases. Highresolution CT of the chest showed extensive lower lobe predominant bilateral parenchymal changes with mediastinal and hilar adenopathy. Open lung biopsy demonstrated interstitial pneumonitis and lymphocytic alveolitis with mild lymphoid hyperplasia (Fig. 1A). Immunohistochemistry of the lung biopsy for CD3 and CD20 showed a B cell predominance (not shown). Additional findings included reduced CD8+ memory and NKT cells, pan-hypergammaglobulinemia, elevated soluble interleukin 2 receptor alpha (sIL2Rα), and low-titer positive anti-proteinase 3 antibody and rheumatoid factor but no other markers of autoimmune disease. Genetic testing revealed a previously unreported de novo heterozygous variant in COPA c. 715G> C (p. Ala239Pro). Initial testing was done using a targeted next-generation sequencing panel and variant confirmed by Sanger sequencing. This sequence change replaces alanine with proline at codon 239 of the COPA protein. This highly conserved residue is located in exon 9, which encodes the C-terminal portion of the WD40 domain of the protein and is the domain in which all previously reported variants causing COPA syndrome have been located [4]. This variant is not present in population databases (ExAC/gnomAD no frequency). In silico prediction algorithms agree on the damaging impact of this missense change (SIFT: Damaging; PolyPhen-2: Probably Damaging; CADD score: 27.2). Flow cytometric assays were performed using peripheral blood lymphocytes isolated from patient and both parents (who were both negative for this variant) to evaluate phenotypic changes caused by his COPA mutation. These assays confirmed increased expression of binding immunoglobulin protein (BiP), a heat shock protein 70 family protein that is upregulated as part of the unfolded protein response and serves as a marker of increased ER stress (Fig. 1B). Additionally, there was increased expression of microtubule-associated protein 1A/1B-light chain 3 (LC3), a marker of autophagy, consistent with prior reports of patients with COPA syndrome (Fig. 1B)[2]. Although this new