Institut de Biologia Evolutiva (UPF-CSIC), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Parc de Recerca Biomèdica de Barcelona, Barcelona, Spain.
Allergy and Clinical Immunology Department, Hospital Sant Joan de Déu, Institut de Recerca Pediàtrica Hospital Sant Joan de Déu, Barcelona, Spain.
Front Immunol. 2018 May 14;9:636. doi: 10.3389/fimmu.2018.00636. eCollection 2018.
Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency characterized by recurrent infections, hypogammaglobulinemia and poor response to vaccines. Its diagnosis is made based on clinical and immunological criteria, after exclusion of other diseases that can cause similar phenotypes. Currently, less than 20% of cases of CVID have a known underlying genetic cause. We have analyzed whole-exome sequencing and copy number variants data of 36 children and adolescents diagnosed with CVID and healthy relatives to estimate the proportion of monogenic cases. We have replicated an association of CVID to p.C104R in TNFRSF13B and reported the second case of homozygous patient to date. Our results also identify five causative genetic variants in , and , as well as other very likely causative variants in , or among others. We experimentally validate the effect of the stop-gain mutation which abolishes protein production and downregulates the expression of CTLA4, and of the frameshift indel in producing expression downregulation of the protein. Our results indicate a monogenic origin of at least 15-24% of the CVID cases included in the study. The proportion of monogenic patients seems to be lower in CVID than in other PID that have also been analyzed by whole exome or targeted gene panels sequencing. Regardless of the exact proportion of CVID monogenic cases, other genetic models have to be considered for CVID. We propose that because of its prevalence and other features as intermediate penetrancies and phenotypic variation within families, CVID could fit with other more complex genetic scenarios. In particular, in this work, we explore the possibility of CVID being originated by an oligogenic model with the presence of heterozygous mutations in interacting proteins or by the accumulation of detrimental variants in particular immunological pathways, as well as perform association tests to detect association with rare genetic functional variation in the CVID cohort compared to healthy controls.
普通变异型免疫缺陷病（CVID）是最常见的有症状原发性免疫缺陷病，其特征为反复感染、低丙种球蛋白血症和疫苗反应不良。其诊断基于临床和免疫标准，在排除其他可引起类似表型的疾病后作出。目前，不到 20%的 CVID 病例有明确的潜在遗传原因。我们分析了 36 名被诊断为 CVID 的儿童和青少年及其健康亲属的全外显子测序和拷贝数变异数据，以估计单基因病例的比例。我们复制了 CVID 与 TNFRSF13B 的 p.C104R 的关联，并报告了迄今为止第二例纯合子患者。我们的结果还确定了 、 和 中的五个致病遗传变异，以及 或 中的其他极可能的致病变异。我们通过实验验证了 导致蛋白产生缺失的 终止突变以及 导致蛋白表达下调的移码插入缺失的效应。我们的结果表明，在所研究的 CVID 病例中，至少有 15-24%的病例具有单基因起源。与已通过全外显子或靶向基因panel 测序进行分析的其他 PID 相比，CVID 中单基因患者的比例似乎较低。无论 CVID 单基因病例的确切比例如何，都需要考虑其他遗传模型。我们提出，由于其普遍性和其他特征，如中等外显率和家族内表型变异，CVID 可能符合其他更复杂的遗传情况。特别是，在这项工作中，我们探索了 CVID 由相互作用蛋白中的杂合突变或特定免疫途径中有害变异的积累引起的寡基因模型的可能性，以及进行关联测试以检测与 CVID 队列中罕见遗传功能变异的关联，与健康对照组相比。
