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While some CN cases present only with neutropenia, others present with additional extra\u2010hematological manifestations. The most common cause of CN is variants in\n                    <jats:italic>ELANE<\/jats:italic>\n                    ; however, approximately 30 other genes have been implicated. Despite this, the genetic basis remains unknown in roughly 30% of cases. The clinical and genetic heterogeneity of CN makes diagnosis particularly challenging. To address this, we conducted exome or genome sequencing of 60 patients with a suspected diagnosis of CN that remained unresolved following targeted sequencing. A genetic diagnosis was established in 25 patients (42%). Variants were identified in 15 different genes. Half of these cases involved genes traditionally associated with hereditary immunodeficiencies (\n                    <jats:italic>GINS4<\/jats:italic>\n                    ,\n                    <jats:italic>CARD11<\/jats:italic>\n                    ,\n                    <jats:italic>ADA2<\/jats:italic>\n                    ,\n                    <jats:italic>GINS1<\/jats:italic>\n                    ,\n                    <jats:italic>LCP1<\/jats:italic>\n                    ,\n                    <jats:italic>SASH3<\/jats:italic>\n                    , and\n                    <jats:italic>WAS<\/jats:italic>\n                    ). One\u2010third of the cases carried variants in genes linked to syndromic disorders (\n                    <jats:italic>VPS13B<\/jats:italic>\n                    ,\n                    <jats:italic>TAFAZZIN<\/jats:italic>\n                    ,\n                    <jats:italic>CLPB<\/jats:italic>\n                    , and\n                    <jats:italic>TONSL<\/jats:italic>\n                    ), demonstrating variable penetrance of extra\u2010hematological phenotypes. A smaller subset (15%) harbored variants in genes associated with inherited bone marrow failure syndromes (\n                    <jats:italic>BLM<\/jats:italic>\n                    ,\n                    <jats:italic>RPL18<\/jats:italic>\n                    ,\n                    <jats:italic>SAMD9<\/jats:italic>\n                    , and\n                    <jats:italic>SRP72<\/jats:italic>\n                    ), identified incidentally due to atypical presentations. Compared to patients with ELANE\u2010CN, these individuals were diagnosed later, had fewer severe bacterial infections and gingivitis, exhibited less profound neutropenia, lacked monocytosis, and had a granulocytic maturation arrest, often beyond the promyelocytic stage. A shared feature among these cases was a tendency toward reduced lymphocyte subsets, particularly NK cells. This study highlights the significant contribution of exome and genome sequencing in diagnosing CN, given the phenotypic overlap, genetic heterogeneity, and variable penetrance of immunological and extra\u2010hematological features.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70150","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T02:00:24Z","timestamp":1749693624000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Expanding the phenotypic and genetic landscape of congenital neutropenia through whole\u2010exome and genome sequencing"],"prefix":"10.1002","volume":"9","author":[{"given":"S\u00e9verine","family":"Marti","sequence":"first","affiliation":[{"name":"Department of Medical Genetics, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital, Assistance Publique\u2010H\u00f4pitaux de Paris (AP\u2010HP) Sorbonne University Paris France"},{"name":"INSERM UMR1287, Gustave Roussy Paris\u2010Saclay University Villejuif France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Pellet","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital, Assistance Publique\u2010H\u00f4pitaux de Paris (AP\u2010HP) Sorbonne University Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blandine","family":"Beaupain","sequence":"additional","affiliation":[{"name":"French Registry of Chronic Neutropenia Trousseau Hospital Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9a","family":"Durix","sequence":"additional","affiliation":[{"name":"INSERM UMR1287, Gustave Roussy Paris\u2010Saclay University Villejuif France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Buratti","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Piti\u00e9\u2010Salp\u00eatri\u00e8re Hospital, Assistance Publique\u2010H\u00f4pitaux de Paris (AP\u2010HP) Sorbonne University Paris France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Re\u0301guerre","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology and Hematology Centre Hospitalo\u2010Universitaire (CHU) de Saint Denis La Re\u0301union France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Aladjidi","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology and Hematology CHU Bordeaux Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saba","family":"Azarnoush","sequence":"additional","affiliation":[{"name":"Department of Pediatric Hematology and Immunology Robert Debr\u00e9 Hospital, AP\u2010HP Paris 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