{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,2]],"date-time":"2025-08-02T18:28:18Z","timestamp":1754159298388,"version":"3.41.2"},"reference-count":18,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T00:00:00Z","timestamp":1753401600000},"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>Mutations in the <jats:italic>ELANE<\/jats:italic> gene, which encodes neutrophil elastase, are known to cause cyclic neutropenia (CyN) and severe congenital neutropenia (SCN). Currently, targeting <jats:italic>ELANE<\/jats:italic> for insertion-deletion to trigger nonsense-mediated mRNA decay (NMD) may be a simple and universal method to treat SCN caused by <jats:italic>ELANE<\/jats:italic> mutations. Here, we present a patient with a heterozygous out-of-frame frameshift variant (-2 frame indel) in exon 4 of the <jats:italic>ELANE<\/jats:italic> gene. The patient underwent whole exome sequencing during hospitalization for acute parotitis and bronchitis, and found a variant in <jats:italic>ELANE<\/jats:italic>, c.581_588del AGGCCGGC (p.Q194Rfs*93), inherited from the father. The father of the patient, without neutropenia, did not present any clinically significant symptoms and showed no evidence of somatic mosaicism. During the subsequent three-year follow-up period, the patient did not experience any other major infections, and neutrophil counts remained consistently within the normal range. More importantly, bone marrow cytology indicated mild granulocytic hypoplasia without evidence of maturation arrest. This case provides clinical evidence supporting the notion that late exon frameshift -2 frame indel insertions can inhibit mRNA translation efficiency and prevent the production of mutant proteins, thereby promoting neutrophil maturation. It also bolsters the ongoing development of gene therapy for <jats:italic>ELANE<\/jats:italic>-related diseases.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1617868","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T06:17:24Z","timestamp":1753424244000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: Heterozygous out-of-frame frameshift variant in ELANE without evidence of neutropenia"],"prefix":"10.3389","volume":"16","author":[{"given":"Yulin","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lang","family":"Yu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yishi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuemei","family":"Tang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaodong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/70544","article-title":"Mutations in ELA2, encoding neutrophil elastase, define a 21-day biological clock in cyclic hematopoiesis","volume":"23","author":"Horwitz","year":"1999","journal-title":"Nat Genet"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V96.7.2317","article-title":"Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia","volume":"96","author":"Dale","year":"2000","journal-title":"Blood."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1097\/MOH.0b013e3282f13cd2","article-title":"Severe congenital neutropenia and the unfolded protein response","volume":"15","author":"Xia","year":"2008","journal-title":"Curr Opin Hematol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1182\/blood-2005-11-4689","article-title":"Mutations in neutrophil elastase causing congenital neutropenia lead to cytoplasmic protein accumulation and induction of the unfolded protein response","volume":"108","author":"K\u00f6llner","year":"2006","journal-title":"Blood"},{"key":"B5","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.hoc.2012.10.004","article-title":"ELANE mutations in cyclic and severe congenital neutropenia","volume":"27","author":"Horwitz","year":"2013","journal-title":"Hematology\/Oncology Clinics North America"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2021.04.007","article-title":"Neutrophil elastase: Nonsense lost in translation","volume":"28","author":"Horwitz","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B7","doi-asserted-by":"publisher","first-page":"798","DOI":"10.1007\/s10875-022-01243-3","article-title":"Loss of function mutation in ELF4 causes autoinflammatory and immunodeficiency disease in human","volume":"42","author":"Sun","year":"2022","journal-title":"J ClinImmunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-015-0165-1","article-title":"Mosaicism of an ELANE mutation in an asymptomatic mother in a familial case of cyclic neutropenia","volume":"35","author":"Hirata","year":"2015","journal-title":"J Clin Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1097\/GIM.0b013e31816b5cae","article-title":"Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee. ACMG recommendations for standards for interpretation and reporting of sequence variations: revisions 2007","volume":"10","author":"Richards","year":"2008","journal-title":"Genet Med: Off J Am Coll Med Genet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22308","article-title":"The spectrum of ELANE mutations and their implications in severe congenital and cyclic neutropenia","volume":"34","author":"Germeshausen","year":"2013","journal-title":"Hum Mutat"},{"key":"B11","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1016\/j.stem.2020.12.015","article-title":"Dissecting ELANE neutropenia pathogenicity by human HSC gene editing","volume":"28","author":"Rao","year":"2021","journal-title":"Cell Stem Cell"},{"key":"B12","doi-asserted-by":"publisher","first-page":"598","DOI":"10.3324\/haematol.2019.221804","article-title":"CRISPR\/Cas9-mediated ELANE knockout enables neutrophilic maturation of primary hematopoietic stem and progenitor cells and induced pluripotent stem cells of severe congenital neutropenia patients","volume":"105","author":"Nasri","year":"2020","journal-title":"Hematologica"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0517-5","article-title":"The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy","volume":"51","author":"Lindeboom","year":"2019","journal-title":"Nat Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2023012171","article-title":"Impact of different genetic mutations on granulocyte development and G-CSF responsiveness in congenital neutropenia","volume":"8","author":"Meng","year":"2024","journal-title":"Blood Adv"},{"key":"B15","doi-asserted-by":"publisher","first-page":"592","DOI":"10.1186\/s12887-023-04428-w","article-title":"Screening for ELANE, HAX1 and GFI1 gene mutations in children with neutropenia and clinical characterization of two novel mutations in ELANE gene","volume":"23","author":"Komvilaisak","year":"2023","journal-title":"BMC Pediatr"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1002\/pbc.25654","article-title":"Paternal somatic mosaicism of a novel frameshift mutation in ELANE causing severe congenital neutropenia: somatic mosaicism of ELANE mutation","volume":"62","author":"Kim","year":"2015","journal-title":"Pediatr Blood Cancer"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2019000498","article-title":"Normal peripheral blood neutrophil numbers accompanying ELANE whole gene deletion mutation","volume":"3","author":"Horwitz","year":"2019","journal-title":"Blood Adv"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2023-190110","article-title":"Absence of neutropenia in patient with an exon 2 nonsense mutation in ELANE : clinical evidence to support gene therapy efforts for severe congenital neutropenia","volume":"142","author":"Joos","year":"2023","journal-title":"Blood"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1617868\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T06:17:29Z","timestamp":1753424249000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1617868\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,25]]},"references-count":18,"alternative-id":["10.3389\/fimmu.2025.1617868"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1617868","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,25]]},"article-number":"1617868"}}