Multiple etiological variants in the NBEAL2 gene involved in the rare hematologic disease gray platelet syndrome (GPS) have been identified, the findings for which have been published in Blood.

In this international study, DNA samples were extracted from patients and subjected to sequencing. Those patients who showed etiological variants in NBEAL2 were included in this analysis. Healthy control participants were also included for some analyses. Etiological genetic variants were categorized as pathogenic (PV), likely pathogenic (LPV), and variants of uncertain significance (VUS). Patient phenotypes were assessed using clinical information, analyses of bloodwork, and, in some cases, bone marrow biopsy, RNA-seq, flow cytometry, and/or mass spectrometry analyses.

From 47 patients, 70 etiological variants in NBEAL2 were found; 32 of these variants were considered novel. A total of 56 variants were unique, with 64% of the unique variants considered PV or LPV.

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Nearly half (49%) of the variants found in this study were based on missense mutations, and, among variants, the highly conserved BEACH domain of the Nbeal2 protein was found to be enriched in missense mutations.

In phenotype analysis, the researchers identified features previously associated with GPS, such as macrothrombocytopenia, bone marrow fibrosis, splenomegaly, increased vitamin B12 concentrations, and possible engulfment of neutrophils by megakaryocytes. Bleeding symptoms were apparent in some patients, but this feature was heterogeneous in the population.

Previously unknown phenotypes were also identified in patients with GPS, including lower leukocyte counts and an increased tendency toward autoimmune disease. Positive autoantibodies were found in many evaluated patients, and 26% of the patients showed a range of autoimmune disease diagnoses.

Proteins linked to inflammation and immunity also appeared to be more abundant in the plasma of patients with GPS. In addition, proteins associated with granules were reduced across platelets, neutrophils, and monocytes in patients with GPS.

“Our study gives further evidence for the role of Nbeal2 in the granule and cell biology of platelets and immune cells and highlights the prevalence of immune dysregulation not previously associated with this rare bleeding disorder,” the researchers wrote.


Sims MC, Mayer L, Collins JH, et al. Novel manifestations of immune dysregulation and granule defects in gray platelet syndrome. Blood. Published online July 21, 2020. doi:10.1101/2020.03.23.20041467