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

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.

• Authors: Jack Chovanec, Ilker Tunc, Jason Hughes, Joseph Halstead, Allyson Mateja, Yihui Liu, Michael P O'Connell, Jiwon Kim, Young Hwan Park, Qinlu Wang, Quang Le, Mehdi Pirooznia, Neil N Trivedi, Yun Bai, Yuzhi Yin, Amy P Hsu, Joshua McElwee, Sheryce Lassiter, Celeste Nelson, Judy Bandoh, Thomas DiMaggio, Julij Šelb, Matija Rijavec, Melody C Carter, Hirsh D Komarow, Vito Sabato, Joshua Steinberg, Kurt M Hafer, Elizabeth Feuille, Christopher S Hourigan, Justin Lack, Paneez Khoury, Irina Maric, Roberta Zanotti, Patrizia Bonadonna, Lawrence B Schwartz, Joshua D Milner, Sarah C Glover, Didier G Ebo, Peter Korošec, George H Caughey, Erica H Brittain, Ben Busby, Dean D Metcalfe, Jonathan J Lyons
• Journal: Blood advances (Blood Adv) Vol. 7 Issue 9 Pg. 1796-1810 (05 09 2023) ISSN: 2473-9537 [Electronic] United States
• PMID: 36170795 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution.

Chemical References

• Tryptases

Topics

• Humans
• Tryptases (genetics)
• Mast Cells
• Reference Values
• Unnecessary Procedures
• Mastocytosis (diagnosis)
• Myeloproliferative Disorders (pathology)