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.

中文翻译：

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非编码调控区的大量缺失导致两个成年兄弟姐妹的 NFKB1 单倍体不足

NFkB 通路基因突变可导致先天性免疫缺陷 (IEI)，其中 NFKB1 单倍体不足是常见变异型免疫缺陷 (CVID) 的重要病因。事实上，在欧洲和美国 CVID 队列中，分别有 4% 至 5% 的人发现了 NFKB1 突变；CVID 代表欧洲国家登记处近 1/4 的 IEI 患者。本病例研究介绍了一名 49 岁患者，患有呼吸道感染、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。综合遗传分析，包括 300 个 IEI 相关基因的高通量测序和拷贝数变异分析，确定了跨越第一个非翻译外显子及其上游区域的关键 2.6 kb 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证实。患者的兄弟也发现了这种缺失，他表现出类似但较轻微的症状。功能分析支持两名患者的单倍体不足，mRNA 和蛋白质表达减少。该案例强调了拷贝数变异（CNV）分析和针对定制基因组中的非编码外显子的重要性，强调了医学遗传学所需的更广泛的基因组方法。