Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations
WHIM syndrome is typically caused by C-terminal gain-of-function variants in CXCR4, yet clinical heterogeneity suggests additional genetic modifiers. We investigated a family in which the 22-year-old proband harbored two heterozygous variants: a novel CXCR4 missense variant, c.1022C>A (p.S341...
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Frontiers Media S.A.
2025-08-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1641122/full |
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| author | Melis Yilmaz Katarina Zmajkovicova Rahim Z. Miller Rahim Z. Miller Grace Blair Maryssa Ellison Boglarka Ujhazi Maria Chitty Lopez Maria Chitty Lopez Joseph F. Dasso Jacob R. Bledsoe Krisztian Csomos Barbara Maierhofer Adriana Badarau Joao P. Pereira Henry Kanarek Christoph B. Geier Christoph B. Geier Jolan E. Walter Jolan E. Walter |
| author_facet | Melis Yilmaz Katarina Zmajkovicova Rahim Z. Miller Rahim Z. Miller Grace Blair Maryssa Ellison Boglarka Ujhazi Maria Chitty Lopez Maria Chitty Lopez Joseph F. Dasso Jacob R. Bledsoe Krisztian Csomos Barbara Maierhofer Adriana Badarau Joao P. Pereira Henry Kanarek Christoph B. Geier Christoph B. Geier Jolan E. Walter Jolan E. Walter |
| author_sort | Melis Yilmaz |
| collection | DOAJ |
| description | WHIM syndrome is typically caused by C-terminal gain-of-function variants in CXCR4, yet clinical heterogeneity suggests additional genetic modifiers. We investigated a family in which the 22-year-old proband harbored two heterozygous variants: a novel CXCR4 missense variant, c.1022C>A (p.S341Y), and a frameshift variant in NFKB1, c.980dup (p.A328Sfs*12). Functionally, CXCR4 p.S341Y substitution - located two residues upstream of the known pathogenic p.E343K variant - increased CXCL12-induced chemotaxis and ERK/AKT signaling while minimally affecting receptor internalization, supporting a partial CXCR4 gain-of-function. The CXCR4 variant co-segregated with mild neutropenia, recurrent respiratory infections, and cutaneous warts in the paternal lineage. In contrast, the maternal NFKB1 variant was associated with agammaglobulinemia and autoimmunity. Their co-inheritance in the proband resulted in a blended WHIM/CVID phenotype characterized by myelokathexis, B-cell maturation arrest and T-cell dysregulation. This case expands the phenotypic spectrum of CXCR4 variants and highlights how multilocus inheritance can obscure classical diagnostic boundaries and guide individualized therapy. |
| format | Article |
| id | doaj-art-c7ea4d428a404fef890bcbe8b385f26c |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-c7ea4d428a404fef890bcbe8b385f26c2025-08-20T05:32:31ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.16411221641122Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestationsMelis Yilmaz0Katarina Zmajkovicova1Rahim Z. Miller2Rahim Z. Miller3Grace Blair4Maryssa Ellison5Boglarka Ujhazi6Maria Chitty Lopez7Maria Chitty Lopez8Joseph F. Dasso9Jacob R. Bledsoe10Krisztian Csomos11Barbara Maierhofer12Adriana Badarau13Joao P. Pereira14Henry Kanarek15Christoph B. Geier16Christoph B. Geier17Jolan E. Walter18Jolan E. Walter19Division of Allergy and Immunology, Department of Pediatrics and Medicine, Morsani College of Medicine, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesResearch Department, Formerly X4 Pharmaceuticals (Austria) GmbH, Vienna, AustriaDivision of Allergy and Immunology, Department of Pediatrics and Medicine, Morsani College of Medicine, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesDivision of Allergy and Immunology, Department of Pediatrics, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesDivision of Allergy and Immunology, Department of Pediatrics and Medicine, Morsani College of Medicine, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesDivision of Allergy and Immunology, Department of Pediatrics and Medicine, Morsani College of Medicine, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesDivision of Allergy and Immunology, Department of Pediatrics and Medicine, Morsani College of Medicine, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesDivision of Allergy and Immunology, Department of Pediatrics and Medicine, Morsani College of Medicine, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesDivision of Allergy and Immunology, Department of Pediatrics, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesDivision of Allergy and Immunology, Department of Pediatrics and Medicine, Morsani College of Medicine, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesDepartment of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United StatesDivision of Allergy and Immunology, Department of Pediatrics and Medicine, Morsani College of Medicine, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesResearch Department, Formerly X4 Pharmaceuticals (Austria) GmbH, Vienna, AustriaResearch Department, Formerly X4 Pharmaceuticals (Austria) GmbH, Vienna, AustriaDepartment of Immunobiology, Yale School of Medicine, Yale University, New Haven, CT, United StatesKanarek Allergy, Asthma & Immunology, Overland Park, KS, United StatesDivision of Immunology, Faculty of Medicine and Health Sciences, University Medicine Oldenburg, Oldenburg, GermanyInstitute of Medical Genetics, Faculty of Medicine and Health Sciences, University Medicine Oldenburg, Oldenburg, GermanyDivision of Allergy and Immunology, Department of Pediatrics and Medicine, Morsani College of Medicine, University of South Florida at Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesDivision of Allergy and Immunology, Department of Pediatrics, Johns Hopkins All Children’s Hospital, St. Petersburg, FL, United StatesWHIM syndrome is typically caused by C-terminal gain-of-function variants in CXCR4, yet clinical heterogeneity suggests additional genetic modifiers. We investigated a family in which the 22-year-old proband harbored two heterozygous variants: a novel CXCR4 missense variant, c.1022C>A (p.S341Y), and a frameshift variant in NFKB1, c.980dup (p.A328Sfs*12). Functionally, CXCR4 p.S341Y substitution - located two residues upstream of the known pathogenic p.E343K variant - increased CXCL12-induced chemotaxis and ERK/AKT signaling while minimally affecting receptor internalization, supporting a partial CXCR4 gain-of-function. The CXCR4 variant co-segregated with mild neutropenia, recurrent respiratory infections, and cutaneous warts in the paternal lineage. In contrast, the maternal NFKB1 variant was associated with agammaglobulinemia and autoimmunity. Their co-inheritance in the proband resulted in a blended WHIM/CVID phenotype characterized by myelokathexis, B-cell maturation arrest and T-cell dysregulation. This case expands the phenotypic spectrum of CXCR4 variants and highlights how multilocus inheritance can obscure classical diagnostic boundaries and guide individualized therapy.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1641122/fullCXCR4WHIMNFKB1neutropeniaCVID |
| spellingShingle | Melis Yilmaz Katarina Zmajkovicova Rahim Z. Miller Rahim Z. Miller Grace Blair Maryssa Ellison Boglarka Ujhazi Maria Chitty Lopez Maria Chitty Lopez Joseph F. Dasso Jacob R. Bledsoe Krisztian Csomos Barbara Maierhofer Adriana Badarau Joao P. Pereira Henry Kanarek Christoph B. Geier Christoph B. Geier Jolan E. Walter Jolan E. Walter Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations Frontiers in Immunology CXCR4 WHIM NFKB1 neutropenia CVID |
| title | Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations |
| title_full | Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations |
| title_fullStr | Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations |
| title_full_unstemmed | Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations |
| title_short | Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations |
| title_sort | case report a novel cxcr4 variant p s341y in a family with a pathogenic nfkb1 variant and variable clinical manifestations |
| topic | CXCR4 WHIM NFKB1 neutropenia CVID |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1641122/full |
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