Department of Pediatric Hematology, Immunology and Infectious Diseases, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands; Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
Department of Haematology, University of Cambridge, Cambridge, United Kingdom; NHS Blood and Transplant Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom.
J Allergy Clin Immunol. 2018 Oct;142(4):1285-1296. doi: 10.1016/j.jaci.2018.01.039. Epub 2018 Mar 2.
The genetic cause of primary immunodeficiency disease (PID) carries prognostic information.
We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort.
In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses.
Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21 B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases.
We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.
原发性免疫缺陷病（PID）的遗传病因具有预后意义。
我们进行了一项全基因组测序研究，评估了英国国家健康研究所生物资源-罕见病队列中的很大一部分患者。
在主要为欧洲血统、以散发性、无亲缘关系的 PID 病例为主的研究人群（n=846）中，一种新的贝叶斯方法确定了核因子κB 亚基 1（NFKB1）是与 PID 关联最强的基因之一，这种关联可由 16 种新的杂合性截断、错义和基因缺失变异来解释。这占队列中普通可变免疫缺陷（CVID）病例（n=390）的 4%。通过分析结构蛋白数据评估预测为致病性的氨基酸取代。通过对淋巴细胞进行免疫表型分析、免疫印迹和体外刺激来确定这些变体的功能影响。为了进行基因型-表型共分离分析，收集了详细的临床和家系信息。
无论是散发性还是家族性病例，均有 CVID 非传染性并发症的证据，包括巨大淋巴结病（24%）、原因不明的脾肿大（48%）和自身免疫性疾病（48%），这些特征与先前的研究中与更差的临床预后相关。尽管在某些家系中观察到了临床症状的部分外显率，但所有携带者均存在 B 淋巴细胞分化缺陷。对 B 淋巴细胞数量、表型和功能的详细评估可识别出存在增加的 CD21+B 细胞群。结合致病变异的鉴定，这可将健康个体、无症状携带者和临床受累者区分开来。
我们表明，NFKB1 中的杂合性失功能变异是最常见的已知单基因 CVID 病因，导致产生免疫球蛋白的 B 细胞形成的暂时性进行性缺陷。
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