A Novel CXCR4 Variant (p.S341Y) in a Family with a Pathogenic NFKB1 Variant and Variable Clinical Manifestations

Melis Yilmaz¹Katarina Zmajkovicova²Rahim Miller^3,4*Grace Blair³Maryssa Ellison³Boglarka Ujhazi³Maria Chitty Lopez³Joseph F Dasso³Jacob Bledsoe⁵Krisztian Csomos³Barbara Maierhofer²Adriana Badarau²Joao P. Pereira⁶Henry Kanarek⁷Christoph B Geier⁸Jolan Eszter Walter^3,9*

• ¹University of South Florida, Tampa, United States
• ²X4 Pharmaceuticals (Austria) GmbH, Vienna, Austria
• ³Department of Pediatrics, University of South Florida, Tampa, United States
• ⁴Department of Pediatrics, Johns Hopkins All Children’s Hospital, St. Petersburg, United States
• ⁵Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, United States
• ⁶Department of Immunobiology, Yale School of Medicine, New Haven, United States
• ⁷Kanarek Allergy, Asthma & Immunology, Overland Park, United States
• ⁸Institute of Medical Genetics, Carl von Ossietzky Universitat Oldenburg, Oldenburg, Germany
• ⁹Johns Hopkins All Children's Hospital, St. Petersburg, United States

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 - enhanced 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-inherence 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.