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NAPDH Oxidase-Specific Flow Cytometry Allows for Rapid Genetic Triage and Classification of Novel Variants in Chronic Granulomatous Disease.

Authors
  • Sacco, Keith A1, 2
  • Smith, Matthew J3
  • Bahna, Sami L4
  • Buchbinder, David5
  • Burkhardt, Joshua4
  • Cooper, Megan A6
  • Hartog, Nicholas L7, 8
  • Kobrynski, Lisa9
  • Patel, Kiran P9
  • Abraham, Roshini S10, 11
  • 1 Department of Medicine, Mayo Clinic, Jacksonville, FL, USA.
  • 2 Allergy/Immunology Program, National Institutes of Health, Bethesda, MD, USA.
  • 3 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • 4 Section of Allergy and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA, USA.
  • 5 Department of Pediatric Hematology, Children's Hospital, County, Orange, CA, USA.
  • 6 Department of Pediatrics, Division of Rheumatology and Department of Pathology and Immunology, Washington University, St. Louis, MO, USA.
  • 7 Division of Allergy and Immunology, Michigan State College of Human Medicine, Grand Rapids, MI, USA.
  • 8 Spectrum Health Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
  • 9 Division of Allergy and Immunology, Emory University, Atlanta, GA, USA.
  • 10 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA. [email protected]
  • 11 Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, 43205, USA. [email protected]
Type
Published Article
Journal
Journal of Clinical Immunology
Publisher
Springer-Verlag
Publication Date
Dec 08, 2019
Identifiers
DOI: 10.1007/s10875-019-00712-6
PMID: 31813112
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Chronic granulomatous disease (CGD) is an innate immune deficiency, primarily affecting the phagocytic compartment, and presenting with a diverse phenotypic spectrum ranging from severe childhood infections to monogenic inflammatory bowel disease. Dihydrorhodamine (DHR) flow cytometry is the standard diagnostic test for CGD, and correlates with NADPH oxidase activity. While there may be genotype correlation with the DHR flow pattern in some patients, in several others, there is no correlation. In such patients, assessment by flow cytometric evaluation of NADPH oxidase-specific (NOX) proteins provides a convenient and rapid means of genetic triage, though immunoblotting has long been used for this purpose. We describe the clinical utility of the NOX flow cytometry assay through assessment of X-linked and autosomal recessive CGD patients and their first-degree relatives. The assessment of specific NOX proteins was correlated with overall NADPH oxidase function (DHR flow), clinical phenotype and genotype. NOX-specific protein assessment is a valuable adjunct to DHR assessment and genotyping to classify and characterize CGD patients. The atypical clinical presentation of some CGD patients can make genotype-phenotype correlation with DHR flow data challenging. Genetic testing, while useful for confirmation of diagnosis, can take several weeks, and in some patients does not provide a conclusive answer. However, NADPH-oxidase-specific protein flow assessment offers a rapid alternative to identification of the underlying genetic defect in cellular subsets, and can be utilized as a reflex test to an abnormal DHR flow. Further, it can provide insight into correlation between oxidative burst relative to protein expression in granulocytes and monocytes.

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