Defective neutrophil development and specific granule deficiency caused by a homozygous splice site mutation in SMARCD2.

Abstract Background SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2) has recently been shown to have a critical role in granulopoiesis in humans, mice and zebrafish. Our patient presented with delayed cord separation, failure to thrive and sepsis. Retrospective whole exome sequencing confirmed a homozygous splice site mutation in SMARCD2. Objective Here, we provide the second description of human SMARCD2 deficiency and the first functional analysis of human primary SMARCD2-deficient cells. Methods Heparinized venous blood and bone marrow were collected from the patient after obtaining informed consent. Patient leukocytes and CD34+ cells were then isolated, phenotyped and assessed functionally. Results Circulating neutrophils appeared phenotypically immature, lacking multi-lobed nuclei, and neutrophil granules lacked lactoferrin but showed normal levels of myeloperoxidase. Neutrophil oxidative burst was preserved in response to phorbol 12-myristate 13-acetate. Patient bone marrow-derived neutrophils and white blood cells showed a severely impaired chemotactic response. Furthermore, white blood cells showed defective in vitro killing of S. aureus, consistent with a specific granule deficiency. Finally, patient bone marrow-derived CD34+ cells showed markedly impaired in vitro expansion and differentiation towards the neutrophil lineage. Prior to her molecular diagnosis, our patient underwent hematopoietic stem cell transplantation (HSCT) and is well 8 years later. Conclusion This report highlights an important role for SMARCD2 in human myelopoiesis and the curative effect of HSCT for the hematopoietic features of SMARCD2 deficiency.