Keller Michael D, Pandey Rahul, Li Dong, Glessner Joseph, Tian Lifeng, Henrickson Sarah E, Chinn Ivan K, Monaco-Shawver Linda, Heimall Jennifer, Hou Cuiping, Otieno Frederick G, Jyonouchi Soma, Calabrese Leonard, van Montfrans Joris, Orange Jordan S, Hakonarson Hakon
Division of Allergy and Immunology, Children's National Medical Center, Washington, DC.
Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, Pa.
J Allergy Clin Immunol. 2016 Aug;138(2):544-550.e4. doi: 10.1016/j.jaci.2016.01.018. Epub 2016 Mar 23.
Genome-wide association studies have shown a pattern of rare copy number variations and single nucleotide polymorphisms in patients with common variable immunodeficiency disorder (CVID), which was recognizable by a support vector machine (SVM) algorithm. However, rare monogenic causes of CVID might lack such a genetic fingerprint.
We sought to identify a unique monogenic cause of familial immunodeficiency and evaluate the use of SVM to identify patients with possible monogenic disorders.
A family with multiple members with a diagnosis of CVID was screened by using whole-exome sequencing. The proband and other subjects with mutations associated with CVID-like phenotypes were screened through the SVM algorithm from our recent CVID genome-wide association study. RT-PCR, protein immunoblots, and in vitro plasmablast differentiation assays were performed on patient and control EBV lymphoblastoids cell lines.
Exome sequencing identified a novel heterozygous mutation in IRF2BP2 (c.1652G>A:p.[S551N]) in affected family members. Transduction of the mutant gene into control human B cells decreased production of plasmablasts in vitro, and IRF2BP2 transcripts and protein expression were increased in proband versus control EBV-immortalized lymphoblastoid cell lines. The SVM algorithm categorized the proband and subjects with other immunodeficiency-associated gene variants in TACI, BAFFR, ICOS, CD21, LRBA, and CD27 as genetically dissimilar from polygenic CVID.
A novel IRFBP2 mutation was identified in a family with autosomal dominant CVID. Transduction experiments suggest that the mutant protein has an effect on B-cell differentiation and is likely a monogenic cause of the family's CVID phenotype. Successful grouping by the SVM algorithm suggests that our family and other subjects with rare immunodeficiency disorders cluster separately and lack the genetic pattern present in polygenic CVID cases.
全基因组关联研究显示，常见可变免疫缺陷病（CVID）患者存在罕见拷贝数变异和单核苷酸多态性模式，这可通过支持向量机（SVM）算法识别。然而，CVID的罕见单基因病因可能缺乏这种遗传特征。
我们试图确定家族性免疫缺陷的独特单基因病因，并评估使用SVM识别可能患有单基因疾病患者的情况。
对一个有多名成员被诊断为CVID的家族进行全外显子组测序筛查。先证者和其他具有与CVID样表型相关突变的受试者通过我们最近的CVID全基因组关联研究中的SVM算法进行筛查。对患者和对照EBV淋巴母细胞系进行逆转录聚合酶链反应（RT-PCR）、蛋白质免疫印迹和体外浆母细胞分化试验。
外显子组测序在受影响的家族成员中发现了IRF2BP2基因的一个新的杂合突变（c.1652G>A:p.[S551N]）。将突变基因转导至对照人B细胞中可降低体外浆母细胞的产生，并且与对照EBV永生化淋巴母细胞系相比，先证者的IRF2BP2转录本和蛋白质表达增加。SVM算法将先证者和其他在肿瘤坏死因子受体超家族成员13B（TACI）、B细胞活化因子受体（BAFFR）、诱导共刺激分子（ICOS）、补体受体2（CD21）、富含亮氨酸重复序列的BAFF结合蛋白（LRBA）和CD27中具有其他免疫缺陷相关基因变异的受试者分类为与多基因CVID在遗传上不同。
在一个常染色体显性CVID家族中发现了一个新的IRFBP2突变。转导实验表明，突变蛋白对B细胞分化有影响，可能是该家族CVID表型的单基因病因。SVM算法成功分组表明，我们的这个家族和其他患有罕见免疫缺陷疾病的受试者是分开聚类的，并且缺乏多基因CVID病例中存在的遗传模式。
