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FeedbackDroplet Digital PCR (ddPCR)
Hereditary alpha-tryptasemia (HαT) is an autosomal dominant genetic trait that is caused by germline amplification of the alpha-tryptase isoform at the TPSAB1 locus on chromosome 16. This test uses droplet digital PCR (ddPCR) to assess for the presence of TPSAB1 copy number variants (CNVs) and can be used in the diagnosis of HαT in individuals with consistent signs and symptoms.
Testing for TPSAB1 CNVs may also be considered in individuals with confirmed or suspected systemic mastocytosis, Ehlers-Danlos syndrome or other connective tissue abnormalities, recurrent anaphylaxis, severe postural orthostatic tachycardia syndrome, irritable bowel syndrome, systemic venom reactions, or other systemic immediate hypersensitivity reactions.
Disease Overview
Individuals with HαT may present with increased basal serum tryptase (≥8 ng/mL) and symptoms such as anaphylaxis, connective tissue abnormalities, dysautonomia, gastrointestinal problems, pain, and skin flushing and pruritus. , , , HαT may present on its own or in conjunction with mastocytosis. , Furthermore, HαT is enriched in individuals with mastocytosis. ,
An elevated serum tryptase level is a minor diagnostic criterion for systemic mastocytosis according to both the World Health Organization (WHO) and International Consensus Classification (ICC), however, the WHO recommends that measurements be adjusted in individuals with HαT to properly apply the criteria. There are multiple suggested methods for this adjustment; refer to the National Comprehensive Cancer Network (NCCN) guidelines for more information.
Genetics
Genes
TPSAB1, TPSB2
HαT is defined by a sum of five or more total TPSAB1/TPSB2 copies with at least two alpha-tryptase encoding copies of TPSAB1. Refer to the Possible TPSAB1/TPSB2 Genotypes section for possible genetic configurations.
Inheritance
Autosomal dominant
Structure/Function
The human tryptase locus maps to 16p13.3. There are four paralogous tryptase genes (TPSG1, TPSB2, TPSAB1, and TPSD1) that code for tryptase, however, the primary secreted tryptase proteins are α-tryptase (encoded by TPSAB1) and β-tryptase (encoded by TPSAB1 and TPSB2). , Duplication and triplication of the TPSAB1 gene (as in HαT) can result in the elevation of basal serum tryptase levels and associated risk of severe mediator symptoms (eg, anaphylaxis). ,
Possible TPSAB1/TPSB2 Genotypes
| Allele 1 of TPSB2 and TPSAB1 | Allele 2 of TPSB2 and TPSAB1 | α-tryptase Copies | β-tryptase Copies | Total α + β | Rarity | Tryptase Concentration |
|---|---|---|---|---|---|---|
| β,β | β,β | 0 | 4 | 4 | Common | Normal |
| β,α | β,β | 1 | 3 | 4 | Common | Normal |
| β,α | β,α | 2 | 2 | 4 | Common | Normal |
| β,-* | β,α | 1 | 2 | 3 | Uncommon | Normal |
| β,-* | β,β | 0 | 3 | 3 | Uncommon | Normal |
| β,β | β,ββ | 0 | 5 | 5 | Uncommon | Normal |
| β,αα | β,β | 2 | 3 | 5 | Common | Increased |
| β,αα | β,α | 3 | 2 | 5 | Common | Increased |
| β,αα | β,βα | 3 | 3 | 6 | Common | Increased |
| β,αα | -,αα | 4 | 1 | 5 | Uncommon | Increased |
| β,αα | β,αα | 4 | 2 | 6 | Uncommon | Increased |
| β,ααα | β,ααα | 6 | 2 | 8 | Uncommon | Increased |
*This assay quantifies the absolute copy numbers of α- and β-tryptase. It cannot determine whether a deletion is from the TPSB2 or TPSAB1 locus. | ||||||
Test Interpretation
Sensitivity and Specificity
Results
| Result Reported | Possible CNVs | Result Interpretation |
|---|---|---|
| Not increased | TPSAB1 (0)/TPSB2 (≤5) TPSAB1 (1)/TPSB2 (≤3) TPSAB1 (2)/TPSB2 (=2) | There is no increase in copy number of TPSAB1 (alpha-tryptase). Calculations are based on the allelic ratio of TPSAB1 to AP3B1 and TPSB2 to AP3B1 genes. |
| Increased | TPSAB1 (≥2)/TPSB2 (≥3) TPSAB1 (≥3)/TPSB2 (≥2) TPSAB1 + TPSB2 (≥5) AND TPSAB1 (≥2) | There is an increase in copy number of TPSAB1 (alpha-tryptase), which is reported in HαT. Calculations are based on the allelic ratio of TPSAB1 to AP3B1 and TPSB2 to AP3B1 genes. |
Limitations
- Diagnostic errors may occur due to rare sequence and CNVs.
- Single base pair substitutions, small deletions/duplications, and regulatory regions are not detected.
- This test is unable to determine chromosomal phase of TPSAB1 and TPSB2 genes, ie:
- Whether TPSAB1 copies are on the same or opposite chromosomes
- Whether TPSAB1 and TPSB2 copies are on the same or opposite chromosomes
- This assay detects only the total number of TPSAB1 and TPSB2 gene copies by normalizing to a reference gene (AP3B1). Therefore, rare CNVs that affect TPSAB1 allelic/chromosomal distribution are not detected by this assay.
References
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27749843
Lyons JJ, Yu X, Hughes JD, et al. Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number. Nat Genet. 2016;48(12):1564-1569.
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34896311
Glover SC, Carlyle A, Lyons JJ. Hereditary alpha-tryptasemia despite normal tryptase-encoding gene copy number owing to copy number loss in trans. Ann Allergy Asthma Immunol. 2022;128(4):460-461.
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NCCN - systemic mastocytosis v2.2024
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: systemic mastocytosis. Version 2.2024. Published Mar 2024; accessed Mar 2024.
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32777817
Greiner G, Sprinzl B, Górska A, et al. Hereditary α tryptasemia is a valid genetic biomarker for severe mediator-related symptoms in mastocytosis. Blood. 2021;137(2):238-247.
Use to confirm a suspected diagnosis of hereditary alpha-tryptasemia (HαT), rule out HαT in individuals with symptoms of mast cell activation, or as an aid in the diagnosis of systemic mastocytosis.