Genetically defined individual reference ranges for tryptase limit unnecessary procedures and unmask myeloid neoplasms

Author:

Chovanec Jack1ORCID,Tunc Ilker2,Hughes Jason3,Halstead Joseph4,Mateja Allyson5,Liu Yihui1,O’Connell Michael P.1,Kim Jiwon1,Park Young Hwan1,Wang Qinlu6,Le Quang7,Pirooznia Mehdi2ORCID,Trivedi Neil N.89,Bai Yun10,Yin Yuzhi10,Hsu Amy P.11ORCID,McElwee Joshua12,Lassiter Sheryce13,Nelson Celeste1,Bandoh Judy1,DiMaggio Thomas14ORCID,Šelb Julij15,Rijavec Matija15,Carter Melody C.10,Komarow Hirsh D.10,Sabato Vito16,Steinberg Joshua17ORCID,Hafer Kurt M.18,Feuille Elizabeth19,Hourigan Christopher S.20ORCID,Lack Justin21,Khoury Paneez22ORCID,Maric Irina23,Zanotti Roberta24,Bonadonna Patrizia25,Schwartz Lawrence B.7,Milner Joshua D.26,Glover Sarah C.27ORCID,Ebo Didier G.16ORCID,Korošec Peter15,Caughey George H.89ORCID,Brittain Erica H.28,Busby Ben29,Metcalfe Dean D.10ORCID,Lyons Jonathan J.1ORCID

Affiliation:

1. 1Translational Allergic Immunopathology Unit, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD

2. 2Bioinformatics and Computational Biology Core, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD

3. 3Foundation Medicine, Cambridge, MA

4. 4Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom

5. 5Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD

6. 6Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, NIAID, NIH, Bethesda, MD

7. 7Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA

8. 8Cardiovascular Research Institute and Department of Medicine, University of California San Francisco, San Francisco, CA

9. 9Veterans Affairs Medical Center, San Francisco, CA

10. 10Mast Cell Biology Section, Laboratory of Allergic Diseases, NIAID, NIH, Bethesda, MD

11. 11Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD

12. 12Nimbus Therapeutics, Cambridge, MA

13. 13Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD

14. 14Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD

15. 15University Clinic of Respiratory and Allergic Diseases Golnik, Golnik, Slovenia

16. 16Department of Immunology, Allergology, and Rheumatology, Infla-Med Centre of Excellence, Antwerp University Hospital, University of Antwerp, Antwerp, Belgium

17. 17Division of Allergy and Clinical Immunology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI

18. 18Department of Medicine, Stanford University, Stanford, CA

19. 19Division of Allergy and Clinical Immunology, Department of Pediatrics, Weill Cornell Medical College, Cornell University, New York, NY

20. 20Myeloid Malignancies Section, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD

21. 21NIAID Collaborative Bioinformatics Resource, NIAID, NIH, Bethesda, MD

22. 22Human Eosinophil Section, Laboratory of Parasitic Diseases, NIAID, NIH, Bethesda, MD

23. 23Hematology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, MD

24. 24Department of Medicine, Section of Hematology, Verona University Hospital, Verona, Italy

25. 25Allergy Unit, Verona University Hospital, Verona, Italy

26. 26Division of Allergy, Immunology and Rheumatology, Columbia University, New York, NY

27. 27Division of Digestive Diseases, Department of Medicine, University of Mississippi Medical Center, Jackson, MS

28. 28Biostatistics Research Branch, NIAID, NIH, Bethesda, MD

29. 29National Library of Medicine, National Center for Biotechnology Information, NIH, Bethesda, MD

Abstract

Abstract Serum tryptase is a biomarker used to aid in the identification of certain myeloid neoplasms, most notably systemic mastocytosis, where basal serum tryptase (BST) levels >20 ng/mL are a minor criterion for diagnosis. Although clonal myeloid neoplasms are rare, the common cause for elevated BST levels is the genetic trait hereditary α-tryptasemia (HαT) caused by increased germline TPSAB1 copy number. To date, the precise structural variation and mechanism(s) underlying elevated BST in HαT and the general clinical utility of tryptase genotyping, remain undefined. Through cloning, long-read sequencing, and assembling of the human tryptase locus from an individual with HαT, and validating our findings in vitro and in silico, we demonstrate that BST elevations arise from overexpression of replicated TPSAB1 loci encoding canonical α-tryptase protein owing to coinheritance of a linked overactive promoter element. Modeling BST levels based on TPSAB1 replication number, we generate new individualized clinical reference values for the upper limit of normal. Using this personalized laboratory medicine approach, we demonstrate the clinical utility of tryptase genotyping, finding that in the absence of HαT, BST levels >11.4 ng/mL frequently identify indolent clonal mast cell disease. Moreover, substantial BST elevations (eg, >100 ng/mL), which would ordinarily prompt bone marrow biopsy, can result from TPSAB1 replications alone and thus be within normal limits for certain individuals with HαT.

Publisher

American Society of Hematology

Subject

Hematology

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