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Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations
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Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations
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Journal Article
Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations
2025
Overview
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.
Publisher
Frontiers Media SA,Frontiers Media S.A
Subject
/ CVID
/ CXCR4
/ Female
/ Heredity
/ Humans
/ Immunologic Deficiency Syndromes - diagnosis
/ Immunologic Deficiency Syndromes - genetics
/ Immunologic Deficiency Syndromes - immunology
/ Kinases
/ Male
/ NF-kappa B p50 Subunit - genetics
/ NFKB1
/ Pedigree
/ Primary Immunodeficiency Diseases - diagnosis
/ Primary Immunodeficiency Diseases - genetics
/ Primary Immunodeficiency Diseases - immunology
/ Warts
/ WHIM
