SEPTIN6-Related Congenital Neutropenia and B Cell Deficiency

• DOI: 10.70962/cis2025abstract.15
• Publication Date: 2025-04-25T20:15:14Z
• Authors: Lauren Gunderman; Aleksandra Petrovic; Ingrid Lundgren; Elena Hsieh; Karen Chisholm; Sandra Bohling; Eric Allenspach
• Keywords: Congenital Neutropenia

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