SEPTIN6-Related Congenital Neutropenia and B Cell Deficiency

Septins, a highly conserved family of GTP-binding, filament-forming proteins, serve as scaffolds and diffusion barriers in various cellular processes. SEPTIN6 is involved in hematopoiesis, assisting in cell division and cytokinesis. We present the second reported case of SEPTIN6-related disease with X-linked congenital neutropenia, tetraploid precursors, and multinucleated myeloid cells associated with the unique finding of B cell deficiency and abnormal initial NBS. A full-term male infant with uncomplicated delivery screened positive on NBS for SCID. Labs showed moderate T cell deficiency (CD3+ 548 cells/µL) enumerated as 90% CD45RA+, persistent profound B cell deficiency (CD19+ 8 cells/µL), and severe neutropenia (ANC < 200). NK cells were normal in range. ADA testing was also normal. Repeat TRECs and T cell quantitation normalized by 2 months. Given absent circulating B cells (CD19+ < 1%), immunoglobulin replacement was started. Peripheral smear showed decreased neutrophils with intermittently abnormal multi-lobation and normal granulation. Anti-neutrophil antibodies were negative. Bone marrow (BM) biopsy at 2 months was normocellular with maturing trilineage hematopoiesis with hypersegmentation of myeloid forms (neutrophils, monocytes, and eosinophils), neutropenia, and decreased lymphoid cells. Neutropenia was unresponsive to G-CSF and vitamin B12 supplementation. At 4 months, BM showed enlarged, hypersegmented myeloid cells (up to 80% tetraploidy), absent B cells (<1%), and rare CD79a+ cells (plasma cells). A primary immunodeficiency genetic panel returned negative. Research trio whole genome sequencing identified an X-linked maternally inherited variant in SEPT6 c.1282T>A (p.*428Lysext*9). Sequential BMs identified increased reticular fibrosis, trisomy 8 without overt dysplasia, and markedly decreased PAX5+CD20+ B cells (<<1%) with continued rare CD79a+ cells (<1%) morphologically similar to plasma cells; a matched-related donor BM transplant resulted in full donor chimerism and no acute or chronic GVHD 3 years post-transplant. Maternal cells demonstrated skewed X-inactivation at the SEPTIN6 locus. Mechanistic studies, including RNA-seq on BM and B cell development assays, explore the role of SEPTIN6 in B cell development. Overall, we identified a novel germline defect in SEPTIN6 in a male with congenital neutropenia, B cell aplasia, and rare plasma cells. We present the case, successful transplant outcome, and remarkable similarity to the initial report of SEPTIN6-related disease.