Supplementary Figure 1: Study design for identification of hereditary α-tryptasemia, characterization of associated clinical features, and confirmation of the genetic and clinical features in additional populations. | Nature Genetics

Supplementary Figure 1: Study design for identification of hereditary α-tryptasemia, characterization of associated clinical features, and confirmation of the genetic and clinical features in additional populations.

From: Elevated basal serum tryptase identifies a multisystem disorder associated with increased TPSAB1 copy number

Supplementary Figure 1

(a) Schematic for evaluation of the referral α-tryptasemia cohort. Families were referred for symptomatic elevation of basal serum tryptase levels without mastocytosis or for familial connective tissue abnormalities in the context of atopy and/or symptoms often associated with mast cell mediators. (b) Schematic for evaluation of the NIAID/NIAMS (left) and ClinSeq (right) cohorts. To enrich for individuals with elevated tryptase levels, exome data were reviewed in the 951 individuals enrolled in ClinSeq. Limited coverage of the 16p13.3 locus permitted the selection of 33 individuals with single-nucleotide variants (SNVs) in genes adjacent to TPSAB1 (TPSG1 (rs113856625[G>A]) and CACNA1H (rs58124832[G>A]) out of 513 with ≥10× coverage at these loci. These SNVs were observed to segregate in 8 of 12 families sequenced with hereditary α-tryptasemia syndrome. Neither SNV has been reported to cause disease; the SNV in CACNA1H in combination with another variant has been reported in association with autism spectrum disorders, which were not seen in this cohort (J. Biol. Chem. 281, 22085–22091, 2006). Given that the minor allele frequency (MAF) of these SNVs in Caucasians is approximately 0.06, enrichment was estimated to be between two- and fourfold. An additional 92 patients without these SNVs were selected at random. A cutoff basal serum tryptase level of ≥8 ng/ml was established for further genetic testing based on the range of tryptase levels in the 96 individuals identified with hereditary α-tryptasemia syndrome and the additional 8 individuals identified with hereditary α-tryptasemia in the first and second cohorts, respectively (8–39.5 ng/ml). Of the 25 individuals with basal serum tryptase concentration ≥8 ng/ml, sufficient exome sequence was captured within the TPSAB1 locus itself to perform bioinformatic genotyping in 16 individuals; the remaining 9 samples had to be excluded. A total of nine individuals were identified with TPSAB1 duplication of α-tryptase–encoding sequences, seven of whom carried the CACNA1H and TPSG1 variants and two of whom did not. Absence of TPSAB1 duplication was confirmed by bioinformatic analysis in all 65 individuals with basal serum tryptase concentration <8 ng/ml for whom capture of TPSAB1 sequence permitted analysis.

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