SLFN14-related thrombocytopenia: Identification within a large series of patients with inherited thrombocytopenia

Inherited thrombocytopenias (ITs) are a group of disorders characterized by different degrees of complexity and severity, which, in turn, result from a wide genetic heterogeneity. To date, at least 25 genes responsible for ITs have been identified. Moreover, known genetic defects account for only 50% of patients, indicating that not all the existing forms have yet been recognized. The development of next generation sequencing is favoring the discovery of novel genes causative for IT, and characterization of these “new” forms is important for improving patients’ management as well as for gaining novel information on mechanisms of platelet production. Recently, Fletcher and colleagues identified by exome analysis monoallelic mutations in the SLFN14 gene as a novel cause of IT. SLFN14-related thrombocytopenia (SLFN14-RT) was described in three pedigrees as a non-syndromic thrombocytopenia associated with excessive bleeding phenotype and defective platelet ATP secretion. The reported families carried three different mutations predicted to result in substitutions hitting consecutive residues (Lys218, Lys219, and Val220) within the ATPase-AAA-4 domain of the SLFN14 protein. The function of SLFN family of proteins is poorly known: they have been associated with regulation of cell proliferation and differentiation, and recently SLFN14 has been shown to have endoribonuclease activity in rabbit reticulocytes. However, the role of SLFN14 in platelet biogenesis or survival is completely unknown. Here we report a fourth family with IT caused by a novel SLFN14 mutation.