Submission Details

CXCR4 was first reported in relation to autosomal dominant WHIM syndrome in 2003 (Hernandez PA, et al., 2003, PMID: 12692554). CRCX4 is a G-protein–coupled receptor, specific for CXCL12, which initiates signal transduction to activate downstream effectors such as calcium flux, AKT, and Erk1/2 to trigger cellular responses, including adhesion and cell migration. WHIM syndrome has four key manifestations: warts (due to HPV infection), hypogammaglobulinemia, immunodeficiency, and myelokathexis (reviewed in PMID: 30565238). Mature neutrophils fail to exit the bone marrow and B- and T-cell abundance or function is variably deficient. WHIM patients with significant T cell lymphopenia can by identified by TREC-based newborn screening (PMID: 33415666). There are differences in clinical expressivity and all patients may not have the full tetrad of WHIM features (i.e., PMID: 16275383). The mechanism of disease is proposed as gain-of-function; decreased internalization of mutated CXCR4 leads to prolongation/enhancement of signaling and may provide the biochemical basis for the autosomal dominant abnormalities of cell trafficking and function associated with WHIM syndrome. All reported, genetically defined cases have variants altering the last 10-19 amino acids in the carboxy-tail, with at least ten variants (predominantly nonsense and frameshift) reported. This curation includes ten probands from eight publications (PMIDs: 12692554, 15026312, 17087743, 19321197, 22596258, 23009155, 24139496, 27059040) and 13 additional affected family members. Additional cases are available in the literature (including PMID: 35947323) however the maximum score for genetic evidence has been reached. A role in disease is supported by expression of CXCR4 in bone marrow and lymphoid tissue (PMID: 9570576) where CXCR4 functions as a regulator of neutrophil release (PMID: 19264920), which is altered in patients due to impaired internalization (PMID: 15536153). A partial blockade by a CXCR4 antagonist, rescues the phenotype in patients, including an increase in absolute lymphocyte, monocyte, and neutrophil counts (PMID: 21890643). Additionally, neutropenia and myelokathexis have been recapitulated in mice (PMID: 22438253) and zebrafish (PMID: 20592249) genetically modified to express CXCR4 variant Arg334Ter. In summary CXCR4 is definitively associated with autosomal dominant WHIM syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.