Marti Séverine, Pellet Philippe, Beaupain Blandine, Durix Léa, Buratti Julien, Réguerre Yves, Aladjidi Nathalie, Azarnoush Saba, Clauin Severine, Chahla Wahid Abou, Blaison Gilles, Bertand Jeremy, Bodet Damien, Brethon Benoit, Chane-Teng Jessica, Delafoy Manon, Dupraz Chrystelle, Gandemer Virginie, Denizeau Philippe, Goldenberg Alice, Hirsch Pierre, l'Haridon Anaïs, Marie-Cardine Aude, Vera Gabriella, Nelken Brigitte, Nizery Laure, Nolla Marie, Pasquet Marlène, Rosain Jérémie, Terriou Louis, Plo Isabelle, Donadieu Jean, Bellanné-Chantelot Christine
Department of Medical Genetics, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP) Sorbonne University Paris France.
INSERM UMR1287, Gustave Roussy Paris-Saclay University Villejuif France.
Hemasphere. 2025 Jun 11;9(6):e70150. doi: 10.1002/hem3.70150. eCollection 2025 Jun.
Congenital neutropenia (CN) comprises a heterogeneous group of rare genetic disorders. While some CN cases present only with neutropenia, others present with additional extra-hematological manifestations. The most common cause of CN is variants in ; 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 (, , , , , , and ). One-third of the cases carried variants in genes linked to syndromic disorders (, , , and ), demonstrating variable penetrance of extra-hematological phenotypes. A smaller subset (15%) harbored variants in genes associated with inherited bone marrow failure syndromes (, , , and ), identified incidentally due to atypical presentations. Compared to patients with ELANE-CN, 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-hematological features.
先天性中性粒细胞减少症（CN）是一组由罕见遗传疾病组成的异质性疾病。虽然一些CN病例仅表现为中性粒细胞减少，但其他病例还伴有额外的血液外表现。CN最常见的病因是 基因的变异；然而，大约还有30个其他基因也与之相关。尽管如此，在大约30%的病例中，遗传基础仍然不明。CN的临床和遗传异质性使得诊断极具挑战性。为了解决这一问题，我们对60例疑似CN的患者进行了外显子组或基因组测序，这些患者在靶向测序后诊断仍未明确。25例患者（42%）确诊。在15个不同基因中发现了变异。其中一半病例涉及传统上与遗传性免疫缺陷相关的基因（ 、 、 、 、 、 、 ）。三分之一的病例携带与综合征性疾病相关基因的变异（ 、 、 、 ），表明血液外表型的外显率可变。一小部分（15%）患者在与遗传性骨髓衰竭综合征相关的基因（ 、 、 、 ）中存在变异，这些变异是由于非典型表现而偶然发现的。与ELANE-CN患者相比，这些个体诊断较晚，严重细菌感染和牙龈炎较少，中性粒细胞减少程度较轻，无单核细胞增多，且存在粒细胞成熟停滞，通常超过早幼粒细胞阶段。这些病例的一个共同特征是淋巴细胞亚群，特别是自然杀伤细胞有减少的趋势。鉴于表型重叠、遗传异质性以及免疫和血液外特征的可变外显率，本研究强调了外显子组和基因组测序在CN诊断中的重要作用。
