Severe congenital neutropenia (CN) is a rare heterogeneous bone marrow syndrome characterized by maturation arrest of granulopoiesis at the level of promyelocytes/myelocytes, resulting in an absence of mature granulocytes in peripheral blood (neutropenia) and severe recurrent bacterial infections. So far, more than 20 different genes have been identified to be associated with CN, including ELANE, HAX1, and JAGN1; however,their pathophysiological mechanisms are not fully understood. Moreover, almost 25% of CN patients remain without a genetic diagnosis.
In collaboration with the Severe Chronic Neutropenia International Registry (SCNIR), our group aims to identify and characterize novel gene mutations in patients with genetically unclassified CN. First, a comprehensive analysis of the genome using a next-generation sequencing pipeline for genetic diagnosis is completed. If a candidate gene variant is identified, the pathogenesis of the mutation is investigated using different experimental models. These models include studies in i) human hematopoietic stem cells, ii) induced pluripotent stem cell (iPSC) derived from healthy individuals and CN patients, and iii) zebrafish. Overall, these studies allow us to determine whether the new variant is responsible of the maturation arrest of granulopoiesis and to further uncover downstream mechanisms involved in the pathogenesis. Then, we further work to define the pathomechanisms of CN-associated genes in disease development in order to better understand disease development and define therapeutic targets.