A new tryptase gene haplotype in human associating alpha-triplication and beta-deletion

Introduction (contexte de la recherche)

In human, secreted α- and β-tryptase are encoded by the TPSAB1/TPSB2 genes, which frequently undergo copy number variations. For instance, Hereditary alpha-Tryptasemia (HαT) is a frequent genetic trait characterized by additional copies of the TPSAB1 gene encoding the α-tryptase allele. To date, the most frequent HαT-associated haplotypes are α-duplication (ααβ) or α-triplication (αααβ), associated with a wild-type β-allele copy at TPSB2. Very few is known regarding other tryptase haplotypes.

Objective

To investigate a rare copy number variation of the TPSAB1/TPSB2 genes, displaying 4 α-tryptase but only 1 β-tryptase encoding genes.

Methods

TPSAB1/TPSB2 copy number variations were determined by droplet digital PCR according to the reference method described by Lyons et al. (2016). Tryptase genotypes from 1335 patients recruited in care setting from more than 70 French centers were analyzed. Apparent copy numbers obtained from undigested DNA samples were analyzed to stratify individuals with identical copy numbers. Familial studies were performed when available to solve ambiguous genotypes.

Results

We hypothesized that the 4α1β copy number was associated with the ααα0:αβ genotype. Other possible genotypes (αα0:ααβ or α0:αααβ) were unlikely due to the absence of the αα0:αβ genotype (3α1β) and the α0:αβ (2α1β) in our cohort. Moreover, a subgroup of 14 subjects with 3α2β copy number displayed apparent copy number on undigested DNA samples consistent with the ααα0:ββ genotype rather than with the ααβ:αβ genotype. Finally, we were able to obtain two familial pedigrees among such individuals, which were all concordant with the ααα0 haplotype.

Conclusions

This study describes a new tryptase gene haplotype (ααα0) associating TPSAB1 triplication and TPSB2 deletion, present in 23 index cases (23/642 (4%) of HαT). This was the third more frequent HαT-associated haplotype after ααβ (86%) and αααβ (11%). This study illustrates the importance of undigested DNA samples in tryptase genotyping. In addition, the potential existence of rare homozygous individuals, thus completely devoided of β-tryptase alleles, entails that human subjects are not protected from functional mast cell tryptase deficiency.