PB0668 - Chronic Immune Thrombocytopenia in Children - elucidating the underlying genetic basis in context of primary immune deficiencies

Background: About 10% of children with immune thrombocytopenia (ITP) have primary immunodeficiency (PID), suggesting a correlation between the two conditions. PIDs are congenital disorders that result in increased susceptibility to infections as well as inflammatory, autoimmune, allergic, non-malignant lymphoproliferative, and neoplastic manifestations. These disorders are caused by defects in genes involved in the development, function, and regulation of the immune system. ITPs with PIDs are distinct from sporadic ones in that they have a predisposition towards treatment refractoriness, a chronic/relapsing course, multilineage involvement, and late start.

Aims: To detect clinical and laboratory signs of PIDs in children with chronic ITP through whole exome sequencing.

Methods: 20 children with a chronic ITP, their parents and siblings were investigated. Targeted exome sequencing with a gene panel for primary immune deficiencies, autoimmune and autoinflammatory diseases was performed. Sanger sequencing was used to confirm the findings. Classification of discovered variants was performed by ACMG criteria.

Results: In 15 of the 20 index patients examined, genetic mutations in the genes responsible for the occurrence of congenital immune deficiencies were found. The detected mutations are classified into 7 groups according to the type of immune deficiency they cause. A large proportion of the detected mutations fall into the VUS (variant of unclear significance) category. Most of the mutations are present in heterozygous state and most of them are inherited in a autosomal-dominant manner. Of special interest are the mutations detected in the MEVF gene as well as in the NOD2 gene and the CR2 gene, as in the patients with the detected mutations pathogenetic treatment was started.

Conclusion(s): The current study demonstrates that a vast proportion of the patients with chronic ITP have genetic mutations to s large extend - VUS. It is a matter of future analysis and further studies to clarify their significance for the occurrence of chronic thrombocytopenia.