Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM U1291, CNRS U5051, University Toulouse III, Toulouse, France; Université Paris Cité, INSERM UMR1163, Imagine Institute, Paris, France; Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital - Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Internal Medicine and Multi-Organic Diseases Department, Hôpital Saint Éloi, CHU Montpellier, Montpellier, France.
Clin Immunol. 2024 Apr;261:110165. doi: 10.1016/j.clim.2024.110165. Epub 2024 Feb 27.
Mutations in NFkB pathway genes can cause inborn errors of immunity (IEI), with NFKB1 haploinsufficiency being a significant etiology for common variable immunodeficiency (CVID). Indeed, mutations in NFKB1 are found in 4 to 5% of in European and United States CVID cohorts, respectively; CVID representing almost ¼ of IEI patients in European countries registries. This case study presents a 49-year-old patient with respiratory infections, chronic diarrhea, immune thrombocytopenia, hypogammaglobulinemia, and secondary lymphoma. Comprehensive genetic analysis, including high-throughput sequencing of 300 IEI-related genes and copy number variation analysis, identified a critical 2.6-kb deletion spanning the first untranslated exon and its upstream region. The region's importance was confirmed through genetic markers indicative of enhancers and promoters. The deletion was also found in the patient's brother, who displayed similar but milder symptoms. Functional analysis supported haploinsufficiency with reduced mRNA and protein expression in both patients. This case underscores the significance of copy number variation (CNV) analysis and targeting noncoding exons within custom gene panels, emphasizing the broader genomic approaches needed in medical genetics.
NFkB 通路基因的突变可导致先天性免疫缺陷（IEI），其中 NFKB1 部分功能不足是常见可变免疫缺陷（CVID）的重要病因。事实上，在欧洲和美国的 CVID 队列中，分别有 4%至 5%的患者存在 NFKB1 突变；在欧洲国家的免疫缺陷登记处，CVID 几乎占 IEI 患者的四分之一。本病例研究介绍了一位 49 岁的患者，其存在呼吸道感染、慢性腹泻、免疫性血小板减少症、低丙种球蛋白血症和继发性淋巴瘤。综合基因分析，包括对 300 个 IEI 相关基因的高通量测序和拷贝数变异分析，确定了一个跨越第一个非翻译外显子及其上游区域的关键 2.6kb 缺失。该区域的重要性通过指示增强子和启动子的遗传标记得到了确认。该缺失也在患者的兄弟中发现，其表现出相似但较轻的症状。功能分析支持单倍体不足，两名患者的 mRNA 和蛋白表达均减少。本病例强调了拷贝数变异（CNV）分析和针对定制基因面板中非编码外显子的重要性，突出了医学遗传学中更广泛的基因组方法的必要性。
