{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T16:43:22Z","timestamp":1771260202389,"version":"3.50.1"},"reference-count":16,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T00:00:00Z","timestamp":1755648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001245","name":"Jeffrey Modell Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>WHIM syndrome is typically caused by C-terminal gain-of-function variants in <jats:italic>CXCR4<\/jats:italic>, yet clinical heterogeneity suggests additional genetic modifiers. We investigated a family in which the 22-year-old proband harbored two heterozygous variants: a novel <jats:italic>CXCR4<\/jats:italic> missense variant, c.1022C&amp;gt;A (p.S341Y), and a frameshift variant in <jats:italic>NFKB1<\/jats:italic>, 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 <jats:italic>CXCR4<\/jats:italic> gain-of-function. The <jats:italic>CXCR4<\/jats:italic> variant co-segregated with mild neutropenia, recurrent respiratory infections, and cutaneous warts in the paternal lineage. In contrast, the maternal <jats:italic>NFKB1<\/jats:italic> 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 <jats:italic>CXCR4<\/jats:italic> variants and highlights how multilocus inheritance can obscure classical diagnostic boundaries and guide individualized therapy.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1641122","type":"journal-article","created":{"date-parts":[[2025,8,20]],"date-time":"2025-08-20T05:33:19Z","timestamp":1755667999000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Case Report: A novel CXCR4 variant (p.S341Y) in a family with a pathogenic NFKB1 variant and variable clinical manifestations"],"prefix":"10.3389","volume":"16","author":[{"given":"Melis","family":"Yilmaz","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katarina","family":"Zmajkovicova","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rahim 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