Researchers have identified a genetic variant associated with inherited elevated basal serum tryptase levels and linked to a distinct group of comorbid multisystem complaints.
These features, including cutaneous flushing, certain chronic pain disorders, autonomic dysfunction, and gastrointestinal dysmotility, have been reported in association with genetic disorders or joint hypermobility syndromes such as Ehlers-Danlos syndrome type III (hypermobility type, EDS III) and often follow a dominant inheritance pattern in affected families, providing a reason to look into a genetic basis for these patient characteristics, according to Jonathan J. Lyons, MD, of the National Institute of Allergy and Infectious Diseases, and his coauthors. The researchers reported their findings Oct. 17 in Nature Genetics.
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The researchers recruited 96 individuals from 35 families with a syndrome of elevated basal serum tryptase levels and multiple comorbid symptoms following an autosomal dominant pattern of inheritance.
These symptoms included gastrointestinal dysmotility such as irritable bowel syndrome or chronic gastroesophageal reflux, connective tissue abnormalities such as joint hypermobility, congenital skeletal abnormalities, retained primary dentition, symptoms suggestive of autonomic dysfunction such as postural orthostatic tachycardia syndrome, and elevated composite autonomic symptom scores. Other symptoms included recurrent cutaneous flushing and pruritus – often associated with urticaria and complaints of sleep disruption – and systemic reaction to stinging insects.
Using exome and genome sequencing followed by linkage analysis, researchers identified duplications and triplications within the TPSAB1 gene encoding alpha-tryptase (Nat Genet. 2016 Oct 17. doi: 10.1038/ng.3696). Further analysis found elevated alpha-tryptase/beta-tryptase ratios among affected family members and suggested that multiple copies of the alpha-tryptase sequence were inherited together.
To confirm the finding, researchers examined genetic data from a cohort of healthy unrelated volunteers in the National Human Genome Research Institute ClinSeq cohort, which identified 125 samples with partially enriched duplication of alpha tryptase–encoding sequence using a common haplotype.
Of these, three individuals had single-allele duplications of the alpha tryptase–encoding sequence and also presented with similar symptoms to the original cohort: cutaneous flushing, itching, or hives, systemic venom reactions, irritable bowel syndrome, retained primary dentition, and elevated autonomic symptom scores.
“We have found that this phenotype is most frequently inherited in an autosomal dominant manner and that, when this occurs, it is exclusively associated with increased copy number on a single allele of alpha tryptase–encoding sequence in the TPSAB1 gene, a genetic trait we have termed hereditary alpha-tryptasemia,” the researchers reported. “The families studied in our initial cohort likely represent the most severe phenotypes among individuals affected with hereditary alpha-tryptasemia, owing in part to the lack of detection of triplication of alpha tryptase–encoding sequence in unselected populations, which we have tentatively designated as hereditary alpha-tryptasemia syndrome.”
The authors suggested that part of the clinical presentation of this syndrome included symptoms that may be associated clinically with mast cell mediator release. In the context of elevated basal serum tryptase levels, this might prompt a doctor to investigate for clonal mast cell disease, which would include bone-marrow biopsy.
However, given that such an investigation would be challenging, and given that elevated tryptase levels are not uncommon in the generally population, they suggested tryptase genotyping may be warranted.
The study was supported by the National Institute of Allergy and Infectious Diseases, the ARTrust/the Mastocytosis Society, and the National Human Genome Research Institute. One author declared royalties associated with the tryptase UniCAP assay, and consulting fees from Genentech. Another author declared an advisory position and royalties from private industry.