X-linked SEPTIN6-related congenital neutropenia and B cell deficiency.

Septins are a conserved family of hematopoietic cytoskeletal regulators. We report two full-term male siblings with a stop-loss variant in the X-linked SEPTIN6 gene who tested positive on SCID newborn screening and presented with myeloid tetraploidy, congenital neutropenia, absent circulating B cells, and variable T cell lymphopenia despite a normal percentage of naive T cells. In the proband, neutropenia was unresponsive to G-CSF with undetectable antineutrophil antibody. Both siblings had hypersegmented myeloid forms and tetraploidy with subsequent development of trisomy 8. One sibling had monosomy 7. Mature and progenitor B cells were markedly decreased to absent; rare plasma cells were present. Mature myeloid forms and plasma cells accumulated in the marrow leading to peripheral neutropenia and B cell lymphopenia. Matched sibling myeloablative HSCT resulted in full disease correction and minimal-to-no GVHD. In xenograft studies, altered SEPTIN6 function led to reduced early lymphoid progenitor cells, demonstrating that SEPTIN6 plays a critical role in lymphocyte development, representing a new inborn error of immunity.