Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis

Mastocytosis is a hematopoietic neoplasm characterized by expansion of KIT D816V-mutated clonal mast cells in various organs and severe or even life-threatening anaphylactic reactions. Recently, hereditary alpha-tryptasemia (H alpha T) has been described as a common genetic trait with increased copy numbers of the alpha-tryptase encoding gene, TPSAB1, and associated with an increased basal serum tryptase level and a risk of mast cell activation. The purpose of our study was to elucidate the clinical relevance of H alpha T in patients with mastocytosis. TPSAB1 germline copy number variants were assessed by digital polymerase chain reaction in 180 mastocytosis patients, 180 sex-matched control subjects, 720 patients with other myeloid neoplasms, and 61 additional mastocytosis patients of an independent validation cohort. alpha-Tryptase encoding TPSAB1 copy number gains, compatible with H alpha T, were identified in 17.2% of mastocytosis patients and 4.4% of the control population (P < .001). Patients with H alpha T exhibited higher tryptase levels than patients without H alpha T (median tryptase in H alpha T+, cases: 49.6 ng/mL vs H alpha T- cases: 34.5 ng/mL, P = .004) independent of the mast cell burden. Hymenoptera venom hypersensitivity reactions and severe cardiovascular mediator-related symptoms/anaphylaxis were by far more frequently observed in mastocytosis patients with H alpha T than in those without H alpha T. Results were confirmed in an independent validation cohort. The high prevalence of H alpha T in mastocytosis hints at a potential pathogenic role of germline alpha-tryptase encoding TPSAB1 copy number gains in disease evolution. Together, our data suggest that H alpha T is a novel emerging robust biomarker in mastocytosis that is useful for determining the individual patient's risk of developing severe anaphylaxis.

Automated summary

The study showed that in patients with mastocytosis, those with HαT had higher levels of tryptase and were more likely to experience hymenoptera venom hypersensitivity reactions and severe cardiovascular mediator-related symptoms/anaphylaxis. This suggests that HαT could be a novel emerging robust biomarker in mastocytosis.