D1.98 - Comparative Evaluation of Basal Serum Tryptase Determinants: Differential Impact of KIT D816V Allelic Load and HaT Gene Copy Number

Hereditary α-Tryptasemia (HaT) is caused by an increased copy number of the TPSAB1/TPSB2 genes, leading to elevated basal serum tryptase (BST) levels. In addition, the KIT D816V mutation in systemic mastocytosis is also associated with increased BST. Therefore, the purpose of this study is to investigate the association of the HaT genotype, KIT D816V allelic load (%VAF) and BST levels.

HaT genotyping and quantification of KIT D816V allelic load (%VAF) using digital PCR were performed in 42 patients. BST levels were measured using ImmunoCAP and the data were analyzed with multivariate regression and correlation models.

In the overall cohort (mean age 37,6 years, 64,3% male), KIT D816V allelic load emerged as the strongest independent factor influencing BST (r=0.67, p<0.05), while α-tryptase copy number showed marginal significance (p=0.06). In contrast, analysis restricted to the HaT subgroup (n=23) revealed a different pattern: the regression model explained 83.8% of BST variability (R²=0.838). Within this subgroup, α-tryptase copy number was the dominant determinant (p<0.0001), with a significant contribution from β-copy number (p=0.0014). The nonlinear association between α-tryptase copy number and BST suggests that a simple linear model is not sufficient to fully explain this relationship.

The study suggests that the determinants of BST differ by condition. In mastocytosis, allelic load appears to predominate, whereas in HaT, BST is a direct reflection of gene dosage. It is suggested to establish individualized reference limits based on genotype instead of the fixed population limits (11.0 ng/mL). Estimating expected BST according to alpha/beta copies can be a critical tool and contribute to avoiding unnecessary invasive procedures and improving differential diagnosis.