Beyond HaT: Is there room for hereditary beta-tryptasemia?

Hereditary alpha-tryptasemia (HaT) corresponds to additional copies of the alpha-tryptase allele encoded by the TPSAB1 gene. HaT is the most frequent tryptase haplotypic variation, affecting around 6% of general population. HaT has been associated with higher basal serum tryptase (bST) values and higher risk of severe anaphylaxis among subjects with clonal mast cell disease, or idiopathic or venom-induced anaphylaxis. Besides HaT, other tryptase haplotypic variations have been described, such as rare beta-allele duplication. The potential biological and clinical correlate of beta-duplications is still unknown. To describe biological and clinical features of beta-tryptase allele duplication. Tryptase genotypes determined by ddPCR at the platform of molecular analysis for mastocytosis and MCAS (St-Antoine/Trousseau hospital) were examined. Clinical and biological data from all cases of beta-allele duplications were collected from medical charts. From 620 tryptase genotyping, 8 cases of beta-duplication were found, including 6 index cases and 2 asymptomatic relatives. The most frequent haplotype was βββ, but we discovered the previously undescribed αββ haplotype in one familial study. In addition, a puzzling genotype with 2 additionnal α-copies (HaT) and 1 additionnal β-copies was found (αααββ:ββ or fortuitous αααβ:βββ), associated with bST = 28 μg/L possibly related to HaT. One case presented with urticaria pigmentosa and mastocytoma with bST = 9.6 μg/L but without detectable KIT D816 V mutation in peripheral blood. In other 4 HaT- index cases, bST were slightly increased, ranging for 5 to 10 μg/L. Two subjects presented with severe anaphylaxis, one to cow milk proteins, the other to plasma. Two other subjects presented with mast-cell activation syndrome-like features. This is the largest series of beta-tryptase allele duplication to date. We described one novel tryptase haplotype. This study and systematic review of literature advocate for the existence of biological “hereditary beta-tryptasemia”, likely associated with higher bST values, though to a lesser extent than HaT.