AUTHOR=Yilmaz Melis , Zmajkovicova Katarina , Miller Rahim Z. , Blair Grace , Ellison Maryssa , Ujhazi Boglarka , Lopez Maria Chitty , Dasso Joseph F. , Bledsoe Jacob R. , Csomos Krisztian , Maierhofer Barbara , Badarau Adriana , Pereira Joao P. , Kanarek Henry , Geier Christoph B. , Walter Jolan E. 

TITLE=Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations

JOURNAL=Frontiers in Immunology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1641122

DOI=10.3389/fimmu.2025.1641122

ISSN=1664-3224

ABSTRACT=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.