PDF(Pubmed)
Abstract：
At present, the knowledge about disease-causing mutations in IRF2BP2 is very limited because only a few patients affected by this condition have been reported. As previous studies have described, the haploinsufficiency of this interferon transcriptional corepressors leads to the development of CVID. Very recently, a more accurate phenotype produced by truncating variants in this gene has been defined, manifesting CVID with gastrointestinal inflammatory symptoms and autoimmune manifestations.
We analyzed 5 index cases with suspected primary immunodeficiency by high throughput sequencing. They were submitted for a genetic test with a panel of genes associated with immune system diseases, including IRF2BP2. The screening of SNVs, indels and CNVs fulfilling the criteria with very low allelic frequency and high protein impact, revealed five novel variants in IRF2BP2. In addition, we isolated both wild-type and mutated allele of the cDNA from one of the families.
In this study, we report five novel loss-of-function (LoF) mutations in IRF2BP2 that likely cause primary immunodeficiency, with CVID as more frequent phenotype, variable expression of inflammatory gastrointestinal features, and one patient with predisposition of viral infection. All identified variants were frameshift changes, and one of them was a large deletion located on chromosome 1q42, which includes the whole sequence of IRF2BP2, among other genes. Both de novo and dominant modes of inheritance were observed in the families here presented, as well as incomplete penetrance.
We describe novel variants in a delimited low-complex region, which may be considered a hotspot in IRF2BP2. Moreover, this is the first time that a large CNV in IRF2BP2 has been reported to cause CVID. The distinct mechanisms than LoF in IRF2BP2 could cause different phenotype compared with the mainly described. Further investigations are necessary to comprehend the regulatory mechanisms of IRF2BP2, which could be under variable expression of the disease.
We analyzed 5 index cases with suspected primary immunodeficiency by high throughput sequencing. They were submitted for a genetic test with a panel of genes associated with immune system diseases, including IRF2BP2. The screening of SNVs, indels and CNVs fulfilling the criteria with very low allelic frequency and high protein impact, revealed five novel variants in IRF2BP2. In addition, we isolated both wild-type and mutated allele of the cDNA from one of the families.
In this study, we report five novel loss-of-function (LoF) mutations in IRF2BP2 that likely cause primary immunodeficiency, with CVID as more frequent phenotype, variable expression of inflammatory gastrointestinal features, and one patient with predisposition of viral infection. All identified variants were frameshift changes, and one of them was a large deletion located on chromosome 1q42, which includes the whole sequence of IRF2BP2, among other genes. Both de novo and dominant modes of inheritance were observed in the families here presented, as well as incomplete penetrance.
We describe novel variants in a delimited low-complex region, which may be considered a hotspot in IRF2BP2. Moreover, this is the first time that a large CNV in IRF2BP2 has been reported to cause CVID. The distinct mechanisms than LoF in IRF2BP2 could cause different phenotype compared with the mainly described. Further investigations are necessary to comprehend the regulatory mechanisms of IRF2BP2, which could be under variable expression of the disease.
摘要：
■目前，关于IRF2BP2致病突变的知识非常有限,因为仅报道了少数受该疾病影响的患者.正如以前的研究所描述的，这种干扰素转录辅抑制因子的单倍体不足导致CVID的发展。最近,已经定义了通过截断该基因中的变体产生的更准确的表型，表现为具有胃肠道炎症症状和自身免疫表现的CVID。
■我们通过高通量测序分析了5例疑似原发性免疫缺陷的指标病例。他们接受了一组与免疫系统疾病相关的基因的基因测试，包括IRF2BP2。SNV的筛选，indels和CNVs以非常低的等位基因频率和高蛋白影响满足标准，揭示了IRF2BP2中的五个新变体。此外,我们从一个家族中分离出cDNA的野生型和突变等位基因。
■在这项研究中，我们报告了IRF2BP2中可能导致原发性免疫缺陷的五个新的功能丧失（LoF）突变，CVID作为更常见的表型，炎性胃肠道特征的可变表达，还有一名有病毒感染倾向的病人.所有确定的变体都是移码变化，其中之一是位于1q42号染色体上的大缺失，其中包括IRF2BP2的整个序列以及其他基因。在这里介绍的家庭中观察到从头和显性遗传模式，以及不完整的外显率。
■我们描述了一个界定的低复杂区域中的新变体，这可能被认为是IRF2BP2中的热点。此外，这是首次报道IRF2BP2中的大量CNV引起CVID.与主要描述的相比，IRF2BP2中与LoF不同的机制可能导致不同的表型。需要进一步的研究来理解IRF2BP2的调节机制，该机制可能在疾病的可变表达下。
■我们通过高通量测序分析了5例疑似原发性免疫缺陷的指标病例。他们接受了一组与免疫系统疾病相关的基因的基因测试，包括IRF2BP2。SNV的筛选，indels和CNVs以非常低的等位基因频率和高蛋白影响满足标准，揭示了IRF2BP2中的五个新变体。此外,我们从一个家族中分离出cDNA的野生型和突变等位基因。
■在这项研究中，我们报告了IRF2BP2中可能导致原发性免疫缺陷的五个新的功能丧失（LoF）突变，CVID作为更常见的表型，炎性胃肠道特征的可变表达，还有一名有病毒感染倾向的病人.所有确定的变体都是移码变化，其中之一是位于1q42号染色体上的大缺失，其中包括IRF2BP2的整个序列以及其他基因。在这里介绍的家庭中观察到从头和显性遗传模式，以及不完整的外显率。
■我们描述了一个界定的低复杂区域中的新变体，这可能被认为是IRF2BP2中的热点。此外，这是首次报道IRF2BP2中的大量CNV引起CVID.与主要描述的相比，IRF2BP2中与LoF不同的机制可能导致不同的表型。需要进一步的研究来理解IRF2BP2的调节机制，该机制可能在疾病的可变表达下。
