Clinical relevance of inherited genetic differences in human tryptases

Glover, Sarah C.; Carter, Melody C.; Korošec, Peter; Bonadonna, Patrizia; Schwartz, Lawrence B.; Milner, Joshua D.; Caughey, George H.; Metcalfe, Dean D.; Lyons, Jonathan J.

doi:10.1016/j.anai.2021.08.009

Cited by 38 publications

(48 citation statements)

References 74 publications

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“…Although this remains a matter of scientific debate, some associated symptoms have been validated in at least one unselected cohort including: cutaneous flushing/ pruritus, irritable bowel syndrome-like symptoms, retained primary dentition, and systemic immediate hypersensitivity reactions to stinging insects [21]. Other symptoms that have been reported to be associated with HaT but that have not been validated in other cohorts include congenital skeletal abnormality, arthralgia, body pain and headaches, sleep disruption, and chronic gastroesophageal reflux [12,37].…”

Section: Andandmentioning

confidence: 99%

“…However, it is likely that some of these findings were related to recruitment and/or ascertainment biases. Moreover, in the landmark study that defined HaT, and in subsequent studies, it has been demonstrated that many, if not the majority of individuals with HaT, report few symptoms, raising the question as to whether HaT is causative of some associated phenotypes or rather only a modifier of other conditions [12,21,23,25]. Although this remains a matter of scientific debate, some associated symptoms have been validated in at least one unselected cohort including: cutaneous flushing/ pruritus, irritable bowel syndrome-like symptoms, retained primary dentition, and systemic immediate hypersensitivity reactions to stinging insects [21].…”

Section: Andandmentioning

confidence: 99%

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Resolving the genetics of human tryptases: implications for health, disease, and clinical use as a biomarker

O’Connell

Lyons

2022

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of reviewTo discuss our evolving understanding of the genetic variation in human tryptases and recent advances in associated clinical phenotypes. Recent findingsSerum tryptase levels have long been used as biomarkers in clinical practice to diagnose mast cellassociated disorders and mast cell-mediated reactions but the contribution of specific secreted isoforms of human tryptases and their role(s) in health and disease has only recently begun to be illuminated. It is now recognized that hereditary alpha-tryptasemia (HaT) is a common genetic trait and the commonest cause for elevated basal serum tryptase (BST), where it can both contribute to mast cell-associated phenotypes, and potentially confound their correct diagnosis. Expression of different tryptase isoforms is now recognized to be associated with specific clinical phenotypes including clonal and nonclonal mast cell-associated disorders as well as certain asthma endotypes. These disparate impacts on clinical disorders may result from differences in enzymatic activities of mature a-tryptases and b-tryptases, and the unique substrate profile and stability of heterotetrameric mature a/b-tryptases recently described to naturally occur.

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Section: Andandmentioning

confidence: 99%

Section: Andandmentioning

confidence: 99%

Resolving the genetics of human tryptases: implications for health, disease, and clinical use as a biomarker

O’Connell

Lyons

2022

Current Opinion in Allergy &Amp; Clinical Immunology

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“…Approximately two-thirds of people have a-tryptase, encoded at TPSAB1 on one or both alleles, whereas everyone has btryptase encoded at one or both TPSB2 alleles, as well as at non-a-tryptase encoding TPSAB1 loci (1)(2)(3). Copy number gain and loss of tryptase gene sequences encoding both aand b-tryptases have also been reported (4). However, the structures of such copy number variants (CNV) remain unknown.…”

Section: Introductionmentioning

confidence: 99%

“…HaT has a BST level >20 ng/mL, representing an estimated 7.5 million people in the U.S. alone (4,15). Because HaT has been shown to augment immediate hypersensitivity symptoms in a number of conditions (7,8), many of these individuals are likely to undergo unwarranted invasive work-up for SM, including bone marrow biopsy, if tryptase genotype is not taken into account.…”

Section: Introductionmentioning

confidence: 99%

Genetically determining individualized clinical reference ranges for the biomarker tryptase can limit unnecessary procedures and unmask myeloid neoplasms

Chovanec

Tunc

Hughes³

et al. 2022

Preprint

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Serum tryptase is a biomarker used to aid in the identification of certain myeloid neoplasms, most notably systemic mastocytosis, where baseline (BST) levels >20 ng/mL are a minor criterion for diagnosis. Whereas clonal myeloid neoplasms are rare, the common cause for elevated BST is the genetic trait hereditary alpha-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 over-expression of replicated TPSAB1 loci encoding wild-type α-tryptase due to co-inheritance of a linked over-active promoter element. Modeling BST levels based upon 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 (e.g., >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.

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“…5 Lastly, the increased b-tryptase-encoding copy number reported in Chollet and Akin 1 has been described. 2 However, the structural complexity of the human tryptase locus remains incompletely understood; relevant paralogous loci (TPSAB1 and TPSB2) encode any of 3 identified b-tryptase isoforms (b1, b2, and b3), whereas the 6 known a-tryptase isoforms are encoded at TPSAB1. More complicated structural variation has also been reported (eg, TPSB2 c.980_981insC, p.M123Dfs*14) and observed by us (Fig 1, B).…”

mentioning

confidence: 99%