Hereditary Alpha-Tryptasemia (HaT) [2 genes]

Hereditary alpha tryptasemia (HαT) is an autosomal dominant genetic disorder characterized by elevated basal serum tryptase (BST) levels due to the presence of an increased copy number of the TPSAB1 gene. The prevalence of HαT in the European population is estimated at 4-6%. Individuals carrying HαT show complete penetrance for BST levels >8 ng/ml. However, phenotype expressivity and severity is variable even within families and is gene dosage-dependent for TPSAB1 [PMID: 34400315]. A correlation has been established between the TPSAB1/TPSB2 genotype and mean basal serum tryptase levels, with five levels described corresponding to the following values according to Glover et al. (2021; PMID: 34400315):

• Level 0: 4.1 (0-10.4) ng/mL
• Level 1: 13.6 (6.5–33.9) ng/mL
• Level 2: 22.5 (10.5–39.5) ng/mL
• Level 3: 27.3 (23.4–40) ng/mL
• Level 4: 37 (25.5–62.7) ng/mL

However, mean BST levels can be altered by several factors, including the moment of sample collection, the patient’s health condition, and the presence of other genetic factors such as variants in the KIT gene, among others.

Among HαT patients, 100% show BST levels >8 ng/mL and >50% show gastroesophageal reflux, while arthralgia, skin manifestations (flushing, itching), and headache are observed in approximately 50% of them. Other less common manifestations are inflammatory bowel disease and sleep disorders, present in 25-50% of patients; hypersensitivity reactions, retention of primary teeth, and skeletal abnormalities, found in 25% of patients. Other less common alterations may be present. It is worth mentioning that around 15% of patients with mastocytosis show HαT and that this group of patients are at a higher risk of severe anaphylaxis [PMID: 37633651; PMID: 34400315; PMID: 30007465].

• Estimated prevalence of HαT in the European population: 4-6%
• Estimated prevalence of HαT in patients with mastocytosis: ~15%

This genetic test allows for the molecular diagnosis of the disease in this group of patients, usually identified upon examination by manifested or suspected mastocytosis. Due to the different HαT levels and risk of severe anaphylactic reactions, it is important to establish these patients’s genotypes in order to stratify them correctly. On the other hand, this being a hereditary disease, early diagnosis allows establishing follow-up measures in those patients carrying pathogenic genotypes that do not manifest symptoms.

This test is indicated for patients with suspected HαT and in patients with mast cell activation syndrome, especially those with systemic mastocytosis.