(A) Localization and consequence of the 9 distinct rare variants identified in GP1BB (shown above the diagram) in the context of all 39 variants published previously, excluding the 22q11.2 deletion. Novel variants are shown in red. Known variants were obtained from a recent review,8 2 publications on BSS published since the review,26,27 and an article reporting a single case with dominant macrothrombocytopenia possibly because of a heterozygous variant encoding R42C.12 The variant encoding T68M was observed in an unaffected relative of a patient with non-BPD rare disease for whom a complete blood count was unavailable. Only the variant encoding G43W is present (in 1 individual) in the ExAC database. The domains shown in colors, from left to right, are signal peptide (1–25), LRR N-terminal (27–55), LRR (60–83), LRR C-terminal (89–143), transmembrane domain (148–172), and cytoplasmic domain (173–206). (B) Gender-stratified histograms of platelet count measurements obtained using a Sysmex hematology analyzer from 48 345 blood donors from the INTERVAL randomized controlled trial28 after adjustment for technical artifacts. The red arrows superimposed on the histograms indicate the gender and values for patients with 1 of the variants in GP1BB reported herein. For individuals I-3 and L-3, with a range of platelet counts, the midpoints were used. The green arrow indicates the gender and value for individual E-1, who is homozygous for the wild-type allele. Any superimposed arrows have been nudged slightly along the vertical axis so they can be distinguished. (C) Images of blood films from cases E-5, F-5, and H-7, with different variants in GP1BB (encoding W46*, T68M, and A150Rfs*43). Original magnification, ×100; May-Grünwald-Giemsa stain. (D) Images show representative electron micrographs of platelets from patient B-3, a patient with BSS (homozygous for a variant encoding Y131C) and an unaffected control, whereas the dot plot shows area measurements of 30 randomly selected platelets from a patient with BSS, 30 from case B-3, and 88 from 3 controls (30+30+28 platelets) with similar distributions. There was a significant difference among the means of the 3 groups (P < .0001, one-way analysis of variance). There was a significant difference between the mean area of platelets from the BSS case and patient B-3 (P = .0021), between the BSS case and controls (P < .0001), and between B-3 and controls (P = .004; Tukey’s method for multiple comparisons).
