{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:20:11Z","timestamp":1792790411770,"version":"4.5.0"},"reference-count":27,"publisher":"Rockefeller University Press","issue":"4","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1 R01 DK137172"],"award-info":[{"award-number":["1 R01 DK137172"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sanford Children\u2019s Genomic Medicine Consortium Collaborative Innovation Project"}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,7,6]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.70962\/jhi.20250173","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T06:22:01Z","timestamp":1775542921000},"update-policy":"https:\/\/doi.org\/10.70962\/jhi.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["X-linked SEPTIN6-related congenital neutropenia and B cell deficiency"],"prefix":"10.70962","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3170-381X","authenticated-orcid":true,"given":"Lauren M.","family":"Gunderman","sequence":"first","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute 1 , Seattle, WA,","place":["USA"]},{"name":"University of Washington School of Medicine 2 Department of Pediatrics, , Seattle, WA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3303-7032","authenticated-orcid":true,"given":"Aleksandra","family":"Petrovic","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute 1 , Seattle, WA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9008-4562","authenticated-orcid":true,"given":"Ingrid","family":"Lundgren","sequence":"additional","affiliation":[{"name":"University of Washington School of Medicine 2 Department of Pediatrics, , Seattle, WA,","place":["USA"]},{"id":[{"id":"https:\/\/ror.org\/02m0cd826","id-type":"ROR","asserted-by":"publisher"}],"name":"St. Luke\u2019s Children\u2019s Hospital 3 Pediatric Infectious Diseases, , Boise, ID,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1898-1252","authenticated-orcid":true,"given":"Karen M.","family":"Chisholm","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01njes783","id-type":"ROR","asserted-by":"publisher"}],"name":"Seattle Children\u2019s Hospital, Seattle, WA, USA 4 Department of Laboratories,"},{"id":[{"id":"https:\/\/ror.org\/00cvxb145","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Washington 5 Department of Laboratory Medicine and Pathology, , Seattle, WA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0422-4549","authenticated-orcid":true,"given":"Sandra D.","family":"Bohling","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01njes783","id-type":"ROR","asserted-by":"publisher"}],"name":"Seattle Children\u2019s Hospital, Seattle, WA, USA 4 Department of Laboratories,"},{"id":[{"id":"https:\/\/ror.org\/00cvxb145","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Washington 5 Department of Laboratory Medicine and Pathology, , Seattle, WA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2287-5284","authenticated-orcid":true,"given":"Jonathan R.","family":"Fromm","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00cvxb145","id-type":"ROR","asserted-by":"publisher"}],"name":"University of Washington 5 Department of Laboratory Medicine and Pathology, , Seattle, WA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-9104-7654","authenticated-orcid":true,"given":"Alexandra","family":"Ferrannini","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cpe7c52","id-type":"ROR","asserted-by":"publisher"}],"name":"Allen Institute 6 , Seattle, WA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3489-5036","authenticated-orcid":true,"given":"Troy R.","family":"Torgerson","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03cpe7c52","id-type":"ROR","asserted-by":"publisher"}],"name":"Allen Institute 6 , Seattle, WA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9806-4739","authenticated-orcid":true,"given":"Cullen M.","family":"Dutmer","sequence":"additional","affiliation":[{"name":"University School of Medicine 7 Department of Pediatrics Emory, , Atlanta, GA,","place":["USA"]},{"name":"Children\u2019s Healthcare of Atlanta 8 Division of Allergy and Immunology, , Atlanta, GA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3969-6597","authenticated-orcid":true,"given":"Elena W.Y.","family":"Hsieh","sequence":"additional","affiliation":[{"name":"University of Colorado, School of Medicine 9 Department of Pediatrics, Section of Allergy and Immunology, , Aurora, CO,","place":["USA"]},{"name":"University of Colorado, School of Medicine 10 Department of Immunology and Microbiology, , Aurora, CO,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6676-7912","authenticated-orcid":true,"given":"Safa F.","family":"Mohamad","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00dvg7y05","id-type":"ROR","asserted-by":"publisher"}],"name":"Boston Children\u2019s Hospital, Harvard Medical School 11 Division of Hematology\/Oncology, Department of Pediatrics, , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7057-6863","authenticated-orcid":true,"given":"David A.","family":"Williams","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00dvg7y05","id-type":"ROR","asserted-by":"publisher"}],"name":"Boston Children\u2019s Hospital, Harvard Medical School 11 Division of Hematology\/Oncology, Department of Pediatrics, , Boston, MA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7346-5835","authenticated-orcid":true,"given":"Eric J.","family":"Allenspach","sequence":"additional","affiliation":[{"name":"Center for Immunity and Immunotherapies, Seattle Children\u2019s Research Institute 1 , Seattle, WA,","place":["USA"]},{"name":"University of Washington School of Medicine 2 Department of Pediatrics, , Seattle, WA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"2026050409182391500_bib1","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1515\/hsz-2013-0233","article-title":"Septin functions in organ system physiology and pathology","volume":"395","author":"Dolat","year":"2014","journal-title":"Biol. Chem."},{"key":"2026050409182391500_bib2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.202203016","article-title":"Human septins organize as octamer-based filaments and mediate actin-membrane anchoring in cells","volume":"222","author":"Martins","year":"2023","journal-title":"J. Cell Biol."},{"key":"2026050409182391500_bib3","doi-asserted-by":"publisher","first-page":"765085","DOI":"10.3389\/fcell.2021.765085","article-title":"The structural biology of septins and their filaments: An update","volume":"9","author":"Cavini","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"2026050409182391500_bib4","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.exphem.2017.07.005","article-title":"Septin 6 regulates engraftment and lymphoid differentiation potential of murine long-term hematopoietic stem cells","volume":"55","author":"Senger","year":"2017","journal-title":"Exp. Hematol."},{"key":"2026050409182391500_bib5","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1002\/ajh.26382","article-title":"Congenital X-linked neutropenia with myelodysplasia and somatic tetraploidy due to a germline mutation in SEPT6","volume":"97","author":"Renella","year":"2022","journal-title":"Am. J. Hematol."},{"key":"2026050409182391500_bib6","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.cancergencyto.2006.02.020","article-title":"MLL-SEPT6 fusion transcript with a novel sequence in an infant with acute myeloid leukemia","volume":"168","author":"Kadkol","year":"2006","journal-title":"Cancer Genet. Cytogenet."},{"key":"2026050409182391500_bib7","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.3324\/haematol.12594","article-title":"Molecular characterization of the MLL-SEPT6 fusion gene in acute myeloid leukemia: Identification of novel fusion transcripts and cloning of genomic breakpoint junctions","volume":"93","author":"Cerveira","year":"2008","journal-title":"Haematologica"},{"key":"2026050409182391500_bib8","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1182\/blood.2024024006","article-title":"new frameworks for hematopoiesis derived from single-cell genomics","volume":"144","author":"Safina","year":"2024","journal-title":"Blood"},{"key":"2026050409182391500_bib9","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1182\/blood.2023019721","article-title":"IL-7 receptor signaling drives human B-cell progenitor differentiation and expansion","volume":"142","author":"Kaiser","year":"2023","journal-title":"Blood"},{"key":"2026050409182391500_bib10","doi-asserted-by":"publisher","first-page":"2928","DOI":"10.1182\/blood-2016-11-745638","article-title":"Reticular dysgenesis: International survey on clinical presentation, transplantation, and outcome","volume":"129","author":"Hoenig","year":"2017","journal-title":"Blood"},{"key":"2026050409182391500_bib11","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1016\/j.jaci.2010.10.013","article-title":"Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-Cell lymphopenia","volume":"127","author":"Accetta","year":"2011","journal-title":"J. Allergy Clin. Immunol."},{"key":"2026050409182391500_bib12","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1006\/clin.1996.0188","article-title":"Neutropenia in X-Linked agammaglobulinemia","volume":"81","author":"Farrar","year":"1996","journal-title":"Clin. Immunol. Immunopathol."},{"key":"2026050409182391500_bib13","doi-asserted-by":"publisher","first-page":"916","DOI":"10.1182\/bloodadvances.2023011371","article-title":"Choosing the right mouse model: Comparison of humanized NSG and NBSGW mice for in vivo HSC gene therapy","volume":"8","author":"Choo","year":"2024","journal-title":"Blood Adv."},{"key":"2026050409182391500_bib14","doi-asserted-by":"publisher","first-page":"1465","DOI":"10.1038\/mt.2015.113","article-title":"MiRNA-embedded shRNAs for lineage-specific BCL11A knockdown and hemoglobin F induction","volume":"23","author":"Guda","year":"2015","journal-title":"Mol. Ther. J. Am. Soc. Gene Ther."},{"key":"2026050409182391500_bib15","doi-asserted-by":"publisher","first-page":"166889","DOI":"10.1016\/j.jmb.2021.166889","article-title":"Orientational ambiguity in septin coiled coils and its structural basis","volume":"433","author":"Leonardo","year":"2021","journal-title":"J. Mol. Biol."},{"key":"2026050409182391500_bib16","doi-asserted-by":"publisher","first-page":"244","DOI":"10.1038\/nature24265","article-title":"Landscape of X chromosome inactivation across human tissues","volume":"550","author":"Tukiainen","year":"2017","journal-title":"Nature"},{"key":"2026050409182391500_bib17","doi-asserted-by":"publisher","first-page":"109182","DOI":"10.1016\/j.clim.2022.109182","article-title":"Natural history of infants with non-SCID T cell lymphopenia identified on newborn screen","volume":"245","author":"Kubala","year":"2022","journal-title":"Clin. Immunol."},{"key":"2026050409182391500_bib18","doi-asserted-by":"publisher","first-page":"1524","DOI":"10.1182\/blood.2022017764","article-title":"The spectrum of GATA2 deficiency syndrome","volume":"141","author":"Calvo","year":"2023","journal-title":"Blood"},{"key":"2026050409182391500_bib19","doi-asserted-by":"publisher","first-page":"2794","DOI":"10.1182\/bloodadvances.2024015106","article-title":"Hematological phenotypes in GATA2 deficiency syndrome arise from aging, maladaptation to proliferation, and somatic events","volume":"9","author":"Fernandez-Orth","year":"2025","journal-title":"Blood Adv."},{"key":"2026050409182391500_bib20","doi-asserted-by":"publisher","first-page":"707","DOI":"10.3324\/haematol.2015.137711","article-title":"Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome","volume":"101","author":"Nov\u00e1kov\u00e1","year":"2016","journal-title":"Haematologica"},{"key":"2026050409182391500_bib21","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1182\/bloodadvances.2025016507","article-title":"Germline LCP1 mutations cause immunodeficiency with neutropenia, monocytopenia, lymphopenia and defective cytokinesis","volume":"10","author":"Van Bergen","year":"2026","journal-title":"Blood Adv."},{"key":"2026050409182391500_bib22","doi-asserted-by":"publisher","first-page":"767","DOI":"10.1016\/j.jaci.2024.05.001","article-title":"L-plastin associated syndrome of immune deficiency and hematologic cytopenia","volume":"154","author":"Hernandez","year":"2024","journal-title":"J. Allergy Clin. Immunol."},{"key":"2026050409182391500_bib23","doi-asserted-by":"publisher","first-page":"2581","DOI":"10.1182\/bloodadvances.2021006398","article-title":"Lymphocyte cytosolic protein 1 (L-plastin) I232F mutation impairs granulocytic proliferation and causes neutropenia","volume":"6","author":"Mahat","year":"2022","journal-title":"Blood Adv."},{"key":"2026050409182391500_bib24","doi-asserted-by":"publisher","first-page":"630","DOI":"10.1002\/pbc.21094","article-title":"Mosaic tetraploidy and transient GFI1 mutation in a patient with severe chronic neutropenia","volume":"50","author":"Hochberg","year":"2008","journal-title":"Pediatr. Blood Cancer"},{"key":"2026050409182391500_bib25","doi-asserted-by":"publisher","first-page":"2213","DOI":"10.1084\/jem.20062324","article-title":"Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia","volume":"204","author":"Moulding","year":"2007","journal-title":"J. Exp. Med."},{"key":"2026050409182391500_bib26","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1093\/bib\/bbs017","article-title":"Integrative genomics viewer (IGV): High-performance genomics data visualization and exploration","volume":"14","author":"Thorvaldsd\u00f3ttir","year":"2013","journal-title":"Brief. Bioinform."},{"key":"2026050409182391500_bib27","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1026","article-title":"standR: Spatial transcriptomic analysis for GeoMx DSP data","volume":"52","author":"Liu","year":"2024","journal-title":"Nucleic Acids Res."}],"container-title":["Journal of Human Immunity"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jhi\/article-pdf\/doi\/10.70962\/jhi.20250173\/2032593\/jhi_20250173.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jhi\/article-pdf\/doi\/10.70962\/jhi.20250173\/2032593\/jhi_20250173.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T13:18:28Z","timestamp":1777900708000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jhi\/article\/2\/4\/e20250173\/282069\/X-linked-SEPTIN6-related-congenital-neutropenia"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,4]]},"references-count":27,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,7,6]]}},"URL":"https:\/\/doi.org\/10.70962\/jhi.20250173","relation":{},"ISSN":["3065-8993"],"issn-type":[{"value":"3065-8993","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,4]]},"article-number":"e20250173"}}