The Lynx Group

Genetic Testing for Hereditary Alpha-Tryptasemia in Patients Presenting with Mast-Cell Mediator Symptoms in the Absence of Symptoms of Mastocytosis

Conference Correspondent

Systemic mastocytosis (SM) is a condition in which mast cells are overactivated and accumulate in various organs. Evidence suggests that hereditary alpha-tryptasemia (HαT) may promote development of SM. Those who inherit HαT have extra copies of the alpha tryptase gene (TPSAB1), which leads to increased levels of tryptase protein in the blood. Prevalence of HαT in patients with SM is 4 times higher than in the general population (20% vs 5%, respectively). In addition, HαT is associated with higher occurrence of mast-cell mediator symptoms (MC-MSs) in patients with SM. Testing for TPSAB1 copy number is performed in only a few centers because of the high homology between α and β encoding isoforms and the presence of duplicate genes in a single locus. Consequently, the precise frequency of HαT in SM has not been determined. The current study examines the prevalence of HαT in patients in 2 cohorts: (1) with evidence of mast-cell activation including MC-MSs and increased serum tryptase but no evidence of SM; and (2) those diagnosed with mastocytosis as defined by World Health Organization-2016 criteria. Variations in TPSAB1 copy number were measured by analyzing 10 samples in triplicate in 3 separate experiments using droplet digital polymerase chain reaction (ddPCR).

Patients with MC-MSs and elevated blood tryptase (n = 41) had a median age of 64.7 years, had serum tryptase 15.3 (range, 12.3-21 mcg/L), and 29% had a history of anaphylactic episodes. HαT was detected in 65.9% of patients in this cohort, with 3α-tryptase copy number observed most frequently (59.2%). Patients positive for HαT had significantly higher serum tryptase compared with patients who lacked HαT (17.1 vs 12.05 mcg/L; P <.001) but the occurrence of mediator-related symptoms and anaphylaxis were comparable.

In patients diagnosed with mastocytosis (n = 150), median age was 49 years, 41.7% had previous anaphylaxis, and 89.3% had SM, whereas 8.6% had cutaneous mastocytosis. Among SM patients, 84.3% presented with non-advanced SM variants. Advanced forms of SM identified included aggressive SM (4.5%) and SM with an associated hematologic neoplasm (6%). In this cohort, HαT was observed in 9.3% of patients. In this group, the most frequent isoforms detected were 3α- and 2α-tryptase (42.8%). There was no difference in serum tryptase levels and episodes of anaphylaxis between HαT-positive and HαT wild-type patients. However, more patients positive for HαT presented with a lower prevalence of KIT 816V mutation compared with those who were negative for HαT (71.4% vs 89.5%, respectively).

Although the clinical impacts of HαT in SM remain to be fully ascertained, the current study suggests ddPCR may be an effective method to analyze copy number variation of TPSAB1. In conclusion, genetic testing for HαT may be useful in patients presenting with mast-cell mediator-related symptoms but without evidence of SM development.

Vanderwert FI, Sordi B, Manelli F, et al. Screening for hereditary alpha-tryptasemia in subjects with systemic mastocytosis (SM) and non-SM mast cell activation symptoms. American Society of Hematology Annual Meeting and Exposition; December 11-14, 2021. Abstract 1500.

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