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Expanding the phenotype of COPA syndrome: a kindred with typical and atypical features
  1. Angelo M Taveira-DaSilva1,
  2. Thomas C Markello2,
  3. David E Kleiner3,
  4. Amanda M Jones1,
  5. Catherine Groden2,
  6. Ellen Macnamara2,
  7. Tadafumi Yokoyama4,
  8. William A Gahl2,4,
  9. Bernadette R Gochuico4,
  10. Joel Moss1
  1. 1Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
  2. 2NIH Undiagnosed Diseases Program, Bethesda, Maryland, USA
  3. 3Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
  4. 4Medical Genetics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA
  1. Correspondence to Dr Bernadette R Gochuico, Medical Genetics Branch, National Human Genome Research Institute, Bethesda, MD 20892-1851, USA; gochuicb{at}


Background Copa syndrome is a rare autosomal dominant disorder with abnormal intracellular vesicle trafficking. The objective of this work is to expand the knowledge about this disorder by delineating phenotypic features of an unreported COPA family.

Methods and results A heterozygous missense variant (c.698 G>A, p.Arg233His) in COPA was identified in four members of a three-generation kindred with lung, autoimmune and malignant disease of unknown aetiology. Ages of onset were 56, 26, 16 and 1 year, with earlier age of onset in successive generations. Presenting symptoms were cough and dyspnoea. Findings included small lung cysts, follicular bronchiolitis, interstitial lung disease, neuroendocrine cell hyperplasia, rheumatoid arthritis, avascular necrosis and select abnormal autoimmune serologies. Neither alveolar haemorrhage nor glomerular disease were present. Features not previously associated with Copa syndrome included neuromyelitis optica, pulmonary carcinoid tumour, clear cell renal carcinoma, renal cysts, hepatic cysts, nephrolithiasis, pyelonephritis and meningitis. Longitudinal evaluations demonstrated slow progression of lung disease and extrapulmonary cysts.

Conclusions Worsening severity with successive generations may be observed in Copa syndrome. Extrapulmonary cysts, malignancies, autoimmune neurological disorders and infections are clinical features that may be associated with Copa syndrome. Further studies are indicated to fully define the phenotypic spectrum of this disorder.

  • arthritis
  • follicular bronchiolitis
  • lung cysts
  • neuromyelitis optica
  • renal cell carcinoma

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  • BRG and JM contributed equally.

  • AMT-DS and TCM contributed equally.

  • Contributors All authors contributed to the acquisition, analysis or interpretation of data, revised the manuscript critically for important intellectual content and approved the version to be published. AMT-DS, TCM, WAG, BRG and JM contributed to the conception of this work. AMT-DS, TCM, BRG and JM drafted the manuscript and are responsible for the overall content as guarantor(s).

  • Funding This research was supported by the Intramural Research Programs of the National Heart, Lung and Blood Institute, the Office of the Director, the National Cancer Institute and the National Human Genome Research Institute, National Institutes of Health.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval National Heart, Lung, and Blood Institute or National Human Genome Research Institute.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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