PB0357 - Hereditary Thrombocytopenia with Platelet Sialic acid Deficiency and Mutations in the GNE genes

Background: The inherited thrombocytopenias are a heterogenous group of disorders. While some have been well characterized, others present an enigma with regard to the underlying molecular defect

Aims: A female patient with previously unexplained inherited macrothrombocytopenia and a platelet count between 3-20 x 109/L from birth is described. There were no other associated clinical features. The aim was to identify the underlying cause.

Methods: The proposita, her two male siblings and parents were studied. Blood counts were performed using a Sysmex SP10 analyzer (Sysmex Corp, Kobe, Hyago, Japan). Whole blood citrated samples were tested in a PFA-100 analyzer (Siemens Healthcare, Deerfield, IL). Exome sequencing including nuclear and mitochondrial DNA was completed as a trio, which includes the patient’s DNA and both parents DNA for variant segregation purposes (GeneDx, Gaithersburg, MD). Flow cytometry (FC) was performed on platelet and red cell suspensions using a two-tube 3-4 color panel using a stain with no wash technique Sialic acid was identified using Sambucus Nigra Lectin (SNA) (ThermoFisher Scientific, Eugene, OR)

Results: The hematology and Flow cytometry results for the parents and siblings are shown in the table. The parents and siblings appear normal hematologically and the proposita has an isolated thrombocytopenia. Flow cytometry revealed a large decrease in platelet sialic acid (about 95%) in the proposita’s platelets but not in her red cells. Exome sequencing showed a compound heterozygous variant in the Glucosamine (UDP-N-acetyl) -2-epimerase/N-acetylmannosamine kinase gene (GNE) gene. The maternally inherited variant, c.787delA (p.M263CfsX4), is a frameshift variant that results in protein truncation at exon 4. The paternally inherited variant c.1343C>T (p.T448M) is a missense variant in exon 7, which has never been reported in individuals with GNE related disease.

Conclusion(s): This interesting case describes two novel pathogenic variants in the GNE gene which appear restricted to the megakaryocyte lineage.