{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T13:58:42Z","timestamp":1787752722654,"version":"build-2784847793"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T00:00:00Z","timestamp":1720396800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Warts, Hypogammaglobulinemia, Infections, Myelokathexis (WHIM) syndrome is a rare, combined immunodeficiency disease predominantly caused by gain-of-function variants in the <jats:italic>CXCR4<\/jats:italic> gene that typically results in truncation of the carboxyl terminus of C-X-C chemokine receptor type 4 (CXCR4) leading to impaired leukocyte egress from bone marrow to peripheral blood. Diagnosis of WHIM syndrome continues to be challenging and is often made through clinical observations and\/or genetic testing. Detection of a pathogenic <jats:italic>CXCR4<\/jats:italic> variant in an affected individual supports the diagnosis of WHIM syndrome but relies on an appropriate annotation of disease-causing variants. Understanding the genotypic-phenotypic associations in WHIM syndrome has the potential to improve time to diagnosis and guide appropriate clinical management, resulting in a true example of precision medicine. This article provides an overview of the spectrum of <jats:italic>CXCR4<\/jats:italic> variants in WHIM syndrome and summarizes the various lines of clinical and functional evidence that can support interpretation of newly identified variants.<\/jats:p>","DOI":"10.3389\/fimmu.2024.1411141","type":"journal-article","created":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T04:35:07Z","timestamp":1720413307000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Expanding CXCR4 variant landscape in WHIM syndrome: integrating clinical and functional data for variant interpretation"],"prefix":"10.3389","volume":"15","author":[{"given":"Katarina","family":"Zmajkovicova","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Nykamp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Blair","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melis","family":"Yilmaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jolan E.","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,7,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2019.01.045","article-title":"Long-term outcome of Whim syndrome in 18 patients: high risk of lung disease and Hpv-related Malignancies","volume":"7","author":"Dotta","year":"2019","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s10875\u2013022-01312\u20137","article-title":"Disease progression of whim syndrome in an international cohort of 66 pediatric and adult patients","volume":"42","author":"Geier","year":"2022","journal-title":"J Clin Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-019-00665-w","article-title":"Whim syndrome: from pathogenesis towards personalized medicine and cure","volume":"39","author":"Heusinkveld","year":"2019","journal-title":"J Clin Immunol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"699","DOI":"10.1056\/nejm196404022701402","article-title":"\"Myelokathexis\"\u2013a new form of chronic granulocytopenia","volume":"270","author":"Zuelzer","year":"1964","journal-title":"Rep Case. N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/ng1149","article-title":"Mutations in the chemokine receptor gene Cxcr4 are associated with whim syndrome, a combined immunodeficiency disease","volume":"34","author":"Hernandez","year":"2003","journal-title":"Nat Genet"},{"key":"B6","unstructured":"Esid-Pagid Diagnostic Criteria for Whim (Warts-Hypogammaglobulinemia-Infections-Myelokathexis)"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s10875\u2013018-0489\u20138","article-title":"Use of genetic testing for primary immunodeficiency patients","volume":"38","author":"Heimall","year":"2018","journal-title":"J Clin Immunol"},{"key":"B8","article-title":"Expanding C-X-C chemokine receptor 4 variant landscape in warts, hypogammaglobulinemia, infections, myelokathexis (Whim) syndrome: integrating clinical and functional data for variant interpretation","author":"Zmajkovicova","year":""},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2019000929","article-title":"Current genetic landscape in common variable immune deficiency","volume":"135","author":"Abolhassani","year":"2020","journal-title":"Blood"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1186\/1750\u20131172-7\u201371","article-title":"Description and outcome of a cohort of 8 patients with whim syndrome from the French severe chronic neutropenia registry","volume":"7","author":"Beaussant Cohen","year":"2012","journal-title":"Orphanet J Rar"},{"key":"B11","doi-asserted-by":"publisher","first-page":"2994","DOI":"10.1182\/blood.2020007197","article-title":"Results of a phase 2 trial of an oral Cxcr4 antagonist, mavorixafor, for treatment of whim syndrome","volume":"136","author":"Dale","year":"2020","journal-title":"Blood"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2003\u201310-3532","article-title":"Altered leukocyte response to Cxcl12 in patients with warts hypogammaglobulinemia, infections, myelokathexis (Whim) syndrome","volume":"104","author":"Gulino","year":"2004","journal-title":"Blood"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.145688","article-title":"Reduced G protein signaling despite impaired internalization and B-arrestin recruitment in patients carrying a Cxcr4leu317fsx3 mutation causing whim syndrome","volume":"8","author":"Kumar","year":"2023","journal-title":"JCI Insight"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011\u201312-395608","article-title":"Whim syndrome caused by a single amino acid substitution in the carboxy-tail of chemokine receptor Cxcr4","volume":"120","author":"Liu","year":"2012","journal-title":"Blood"},{"key":"B15","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1007\/s10875\u2013016-0276\u20133","article-title":"Whim syndrome caused by Waldenstr\u00f6m\u2019s macroglobulinemia-associated mutation Cxcr4 L329fs","volume":"36","author":"Liu","year":"2016","journal-title":"J Clin Immunol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1485","DOI":"10.1016\/j.jaci.2016.04.057","article-title":"Successful hematopoietic stem cell transplantation for myelofibrosis in an adult with warts-hypogammaglobulinemia-immunodeficiency-myelokathexis syndrome","volume":"138","author":"Moens","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.08.032","article-title":"Targeted next-generation sequencing: A novel diagnostic tool for primary immunodeficiencies","volume":"133","author":"Nijman","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3343\/alm.2017.37.5.446","article-title":"Whim syndrome with a novel Cxcr4 variant in a Korean child","volume":"37","author":"Shin","year":"2017","journal-title":"Ann Lab Med"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2008.12.1133","article-title":"Clinical and genetic diagnosis of warts, hypogammaglobulinemia, infections, and Myelokathexis syndrome in 10 patients","volume":"123","author":"Tassone","year":"2009","journal-title":"J Allergy Clin Immunol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2013020-2265\u20131","article-title":"Whole-genome sequencing of a sporadic primary immunodeficiency cohort","volume":"583","author":"Thaventhiran","year":"2020","journal-title":"Nature"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2004\u201306-2289","article-title":"Whim syndromes with different genetic anomalies are accounted for by impaired Cxcr4 desensitization to Cxcl12","volume":"105","author":"Balabanian","year":"2005","journal-title":"Blood"},{"key":"B22","doi-asserted-by":"publisher","first-page":"101551","DOI":"10.1016\/j.jbc.2021.101551","article-title":"Characterization of a new whim syndrome mutant reveals mechanistic differences in regulation of the chemokine receptor Cxcr4","volume":"298","author":"Luo","year":"2021","journal-title":"J Biol Chem"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.857527","article-title":"Case report: A novel Cxcr4 mutation in a Chinese child with Kawasaki disease causing whim syndrome","volume":"13","author":"Ma","year":"2022","journal-title":"Front Immunol"},{"key":"B24","unstructured":"Cxcr4 (Cxcr4_Human)Gpcrdb"},{"key":"B25","doi-asserted-by":"publisher","first-page":"49","DOI":"10.2147\/blctt.S84157","article-title":"Waldenstr\u00f6m macroglobulinemia: biology, genetics, and therapy","volume":"6","author":"Paludo","year":"2016","journal-title":"Blood Lymphat Cancer"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014\u201301-550905","article-title":"Somatic mutations in myd88 and cxcr4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia","volume":"123","author":"Treon","year":"2014","journal-title":"Blood"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.clml.2019.03.009","article-title":"Characteristics of Waldenstr\u00f6m macroglobulinemia in Korean patients according to mutational status of myd88 and Cxcr4: analysis using ultra-deep sequencing","volume":"19","author":"Shin","year":"2019","journal-title":"Clin Lymphoma Myeloma Leuk"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2017.37","article-title":"Sherloc: A comprehensive refinement of the Acmg-Amp variant classification criteria","volume":"19","author":"Nykamp","year":"2017","journal-title":"Genet Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"B30","unstructured":"What Is Clinvar? National Library of Medicine"},{"key":"B31","unstructured":"Clinvar. Cxcr4[Gene]. National Library of Medicine"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.16.9448","article-title":"Impaired B-lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in Cxcr4- and Sdf-1-deficient mice","volume":"95","author":"Ma","year":"1998","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2013020-2308\u20137","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"B34","unstructured":"C-X-C Motif Chemokine Receptor 4. Gnomad"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fcvm.2022.900431","article-title":"How functional genomics can keep pace with Vus identification","volume":"9","author":"Anderson","year":"2022","journal-title":"Front Cardiovasc Med"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1093\/jlb\/lsx038","article-title":"The known unknown: the challenges of genetic variants of uncertain significance in clinical practice","volume":"4","author":"Hoffman-Andrews","year":"2017","journal-title":"J Law Biosci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1186\/s13073\u2013019-0690\u20132","article-title":"Recommendations for application of the functional evidence Ps3\/Bs3 criterion using the Acmg\/Amp sequence variant interpretation framework","volume":"12","author":"Brnich","year":"2019","journal-title":"Genome Med"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/npjgenmed.2016.1","article-title":"Functional assays provide a robust tool for the clinical annotation of genetic variants of uncertain significance","volume":"1","author":"Woods","year":"2016","journal-title":"NPJ Genom Med"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)42339-8","article-title":"Cloning of a human seven-transmembrane domain receptor, Lestr, that is highly expressed in leukocytes","volume":"269","author":"Loetscher","year":"1994","journal-title":"J Biol Chem"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/382833a0","article-title":"The Cxc chemokine Sdf-1 is the ligand for lestr\/fusin and prevents infection by T-cell-line-adapted Hiv-1","volume":"382","author":"Oberlin","year":"1996","journal-title":"Nature"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012\u201301-403378","article-title":"Proper desensitization of cxcr4 is required for lymphocyte development and peripheral compartmentalization in mice","volume":"119","author":"Balabanian","year":"2012","journal-title":"Blood"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/eci.12949","article-title":"Cxcr4, the master regulator of neutrophil trafficking in homeostasis and disease","author":"De Filippo","year":"2018","journal-title":"Eur J Clin Invest"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01262","article-title":"Enhanced bone marrow homing of natural killer cells following Mrna transfection with gain-of-function variant Cxcr4(R334x)","volume":"10","author":"Levy","year":"2019","journal-title":"Front Immunol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2006.11.002","article-title":"Regulation of Cxcr4 signaling","volume":"1768","author":"Busillo","year":"2007","journal-title":"Biochim Biophys Acta (BBA) - Biomembranes"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0064975","article-title":"Hierarchical organization of multi-site phosphorylation at the Cxcr4 C terminus","volume":"8","author":"Mueller","year":"2013","journal-title":"PloS One"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1111\/j.1582-4934.2010.01210.x","article-title":"Amd3100 is a potent antagonist at Cxcr4 R334x, a hyperfunctional mutant chemokine receptor and cause of whim syndrome","volume":"15","author":"McDermott","year":"2011","journal-title":"J Cell Mol Med"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20010003","article-title":"Adaptive immunodeficiency in whim syndrome","volume":"20","author":"Majumdar","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1172\/jci33187","article-title":"Leukocyte analysis from whim syndrome patients reveals a pivotal role for Grk3 in Cxcr4 signaling","volume":"118","author":"Balabanian","year":"2008","journal-title":"J Clin Invest"},{"key":"B49","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1038\/s41435\u2013022-00181\u20139","article-title":"Genotype-phenotype correlations in whim syndrome: A systematic characterization of Cxcr4(Whim) variants","volume":"23","author":"Zmajkovicova","year":"2022","journal-title":"Genes Immun"},{"key":"B50","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.cyto.2017.12.022","article-title":"Multisystem multitasking by Cxcl12 and its receptors Cxcr4 and Ackr3","volume":"109","author":"Murphy","year":"2018","journal-title":"Cytokine"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2119483119","article-title":"Altered Cxcr4 dynamics at the cell membrane impairs directed cell migration in whim syndrome patients","volume":"119","author":"Garc\u00eda-Cuesta","year":"2022","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B52","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1182\/blood-2007\u201307-102103","article-title":"Cxcr4 dimerization and beta-arrestin-mediated signaling account for the enhanced chemotaxis to Cxcl12 in whim syndrome","volume":"112","author":"Lagane","year":"2008","journal-title":"Blood"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2962","article-title":"Rare and low-frequency coding variants in Cxcr2 and other genes are associated with hematological traits","volume":"46","author":"Auer","year":"2014","journal-title":"Nat Genet"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.3324\/haematol.2021.279254","article-title":"Biallelic Cxcr2 loss-of-function mutations define a distinct congenital neutropenia entity","volume":"107","author":"Marin-Esteban","year":"2022","journal-title":"Haematologica"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1172\/jci41649","article-title":"Cxcr2 and Cxcr4 antagonistically regulate neutrophil trafficking from murine bone marrow","volume":"120","author":"Eash","year":"2010","journal-title":"J Clin Invest"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.0213097","article-title":"G protein-coupled receptor kinase-3-deficient mice exhibit whim syndrome features and attenuated inflammatory responses","volume":"94","author":"Tarrant","year":"2013","journal-title":"J Leukoc Biol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2017\u201302-708552","article-title":"How I treat warts, hypogammaglobulinemia, infections, and Myelokathexis syndrome","volume":"130","author":"Badolato","year":"2017","journal-title":"Blood"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2023022658","article-title":"Phase 3 randomized trial of mavorixafor, Cxcr4 antagonist, in whim syndrome","author":"Badolato","year":"2024","journal-title":"Blood"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1411141\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,8]],"date-time":"2024-07-08T04:35:10Z","timestamp":1720413310000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1411141\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,7,8]]},"references-count":58,"alternative-id":["10.3389\/fimmu.2024.1411141"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1411141","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,7,8]]},"article-number":"1411141"}}