Department of Immunology, Ministry of Education Key Laboratory of Major Diseases in Children, Beijing Children's Hospital, National Center for Children's Health, Capital Medical University, No. 56 Nanlishi Road, Beijing, 100045, China.
Beijing Key Laboratory for Genetics of Birth Defects, No. 56 Nanlishi Road, Beijing, 100045, China.
J Clin Immunol. 2024 Aug 22;44(8):183. doi: 10.1007/s10875-024-01783-w.
Severe congenital neutropenia (SCN) comprises a diverse range of rare hematological disorders characterized by recurrent, often life-threatening infections that manifest within the first months of life. Mutations in the ELANE gene are the most prevalent cause of SCN. While over 230 mutations in ELANE have been documented, including substitutions, frameshifts, nonsense mutations, and splice site alterations, the occurrence of deep intronic mutations has not been previously reported. Herein, we present the case of a young girl who exhibited recurrent fever, respiratory infections, skin abscesses, and gingivitis shortly after birth. Laboratory analysis revealed markedly diminished neutrophil levels alongside elevated monocyte and eosinophil counts. Bone marrow examination disclosed a halt in myelopoiesis maturation. ELANE gene full-length sequencing identified a novel de novo deep intron mutation in ELANE (c.598 + 79G > T), subsequently confirmed by Sanger sequencing. cDNA sequencing of the patient demonstrated aberrant gene splicing. Utilizing a mini-gene splicing assay for ELANE intronic variants, we identified a mutant ELANE allele (c.597 + 1_597 + 83ins) leading to the creation of a premature termination codon (p.Gly200ValfsTer40). Confocal microscopy revealed heightened expression of myeloperoxidase and neutrophil elastase in the patient, suggesting a potential role for the unfolded protein response in the pathogenesis of the deep intron ELANE mutation. In summary, our findings illustrate the first reported instance of de novo deep intron ELANE mutations associated with SCN, underscoring the importance of exploring deep intronic regions in SCN patients lacking identifiable disease-causing gene mutations.
严重先天性中性粒细胞减少症（SCN）是一组不同的罕见血液学疾病，其特征是在生命的头几个月内反复出现、常常危及生命的感染。ELANE 基因突变是 SCN 的最常见原因。虽然已经记录了超过 230 种 ELANE 突变，包括取代、移码、无义突变和剪接位点改变，但以前没有报道过深内含子突变的发生。在此，我们报告了一例年轻女孩的病例，她在出生后不久即出现反复发热、呼吸道感染、皮肤脓肿和牙龈炎。实验室分析显示中性粒细胞水平明显降低，同时单核细胞和嗜酸性粒细胞计数升高。骨髓检查显示骨髓造血成熟停滞。ELANE 基因全长测序在 ELANE 基因中发现了一个新的从头深内含子突变（c.598 + 79G > T），随后通过 Sanger 测序得到证实。患者的 cDNA 测序显示基因剪接异常。利用 ELANE 内含子变异的迷你基因剪接测定，我们鉴定了一个突变的 ELANE 等位基因（c.597 + 1_597 + 83ins），导致提前终止密码子（p.Gly200ValfsTer40）的产生。共聚焦显微镜显示患者的髓过氧化物酶和中性粒细胞弹性蛋白酶表达增高，提示未折叠蛋白反应可能在深内含子 ELANE 突变的发病机制中起作用。总之，我们的研究结果首次报道了与 SCN 相关的从头深内含子 ELANE 突变，强调了在缺乏可识别的致病基因突变的 SCN 患者中探索深内含子区域的重要性。
