Genetic Variants Associated with Inborn Errors of Immunity in Pediatric Immune Thrombocytopenia

Inborn errors of immunity (IEI) represent a large and expanding group of disorders caused by genetic defects that affect various pathways of the immune system, leading to a broad spectrum of phenotypes. Immune thrombocytopenia (ITP) is the most common form of immune cytopenia in children and is a frequent manifestation among IEI. The phenotypic heterogeneity of ITP is partly attributed to underlying genetic alterations, particularly in genes associated with immune dysregulation.This study aimed to assess pediatric patients with established diagnosis of primary ITP who presented phenotypic characteristics of IEI. These patients were evaluated for the presence of variants in genes previously associated with IEI by targeted next generation sequencing (NGS). Among the patients evaluated, four harbored genetic variants classified as of uncertain significance (VUS). These variants were identified in the JAK3 (p.Ala32Thr), LRBA (p.Ser1335Gly, p.Tyr227Ala), BACH2 (p.Pro772Leu), STXBP2 (c.1389+4C>T), and PRF1 (p.Ala91Val) genes. The patients had recurrent infections, altered immunoglobulin levels, other autoimmunity, or low TRECs copies number. Conclusion: Despite the presence of clinical and laboratory features indicative of underlying IEI in the ITP patients analyzed in this study, a definitive diagnosis could not be established. Nevertheless, we identified genetic variants that may affect specific phenotypic characteristics exhibited by the patients. This suggests that a comprehensive understanding of the non-infectious manifestations of IEI is crucial for enhancing awareness of the diverse spectrum associated with the diagnosis of ITP, which could be instrumental in guiding the development of targeted therapies.