PDF(Pubmed)
Abstract：
Inborn errors of immunity (IEI) are a heterogeneous group of disorders characterized by increased risk of infections, autoimmunity, autoinflammatory diseases, malignancy and allergy. Next-generation sequencing has revolutionized the identification of genetic background of these patients and assists in diagnosis and treatment. In this study, we identified a probable unique monogenic cause of IEI, and evaluated the immunological methods and pathogenic detections.
A family with a member with a clinical diagnosis of IEI was screened by whole genomic sequencing (WGS). Demographic data, clinical manifestations, medical history, physical examination, laboratory findings and imaging features of the patient were extracted from medical records. Comprehensive immune monitoring methods include a complete blood count with differential, serum levels of cytokines and autoantibodies, T-cell and B-cell subsets analysis and measurement of serum immunoglobulins. In addition, metagenomic sequencing (mNGS) of blood, cerebrospinal fluid and biopsy from small intestine were used to detect potential pathogens.
The patient manifested with recurrent infections and autoimmune disorders, who was eventually diagnosed with IEI. Repetitive mNGS tests of blood, cerebrospinal fluid and biopsy from small intestine didn\'t detect pathogenic microorganism. Immunological tests showed a slightly decreased level of IgG than normal, elevated levels of tumor necrosis factor and interleukin-6. Lymphocyte flow cytometry showed elevated total B cells and natural killer cells, decreased total T cells and B-cell plasmablasts. WGS of the patient identified a novel heterozygous mutation in IRF2BP2 (c.439_450dup p. Thr147_Pro150dup), which was also confirmed in his father. The mutation was classified as variant of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics guidelines.
We identified a novel IRF2BP2 mutation in a family with a member diagnosed with IEI. Immune monitoring and WGS as auxiliary tests are helpful in identifying genetic defects and assisting diagnosis in patients with clinically highly suspected immune abnormalities and deficiencies in inflammation regulation. In addition, mNGS techniques allow a more comprehensive assessment of the pathogenic characteristics of these patients. This report further validates the association of IRF2BP2 deficiency and IEI, and expands IEI phenotypes.
A family with a member with a clinical diagnosis of IEI was screened by whole genomic sequencing (WGS). Demographic data, clinical manifestations, medical history, physical examination, laboratory findings and imaging features of the patient were extracted from medical records. Comprehensive immune monitoring methods include a complete blood count with differential, serum levels of cytokines and autoantibodies, T-cell and B-cell subsets analysis and measurement of serum immunoglobulins. In addition, metagenomic sequencing (mNGS) of blood, cerebrospinal fluid and biopsy from small intestine were used to detect potential pathogens.
The patient manifested with recurrent infections and autoimmune disorders, who was eventually diagnosed with IEI. Repetitive mNGS tests of blood, cerebrospinal fluid and biopsy from small intestine didn\'t detect pathogenic microorganism. Immunological tests showed a slightly decreased level of IgG than normal, elevated levels of tumor necrosis factor and interleukin-6. Lymphocyte flow cytometry showed elevated total B cells and natural killer cells, decreased total T cells and B-cell plasmablasts. WGS of the patient identified a novel heterozygous mutation in IRF2BP2 (c.439_450dup p. Thr147_Pro150dup), which was also confirmed in his father. The mutation was classified as variant of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics guidelines.
We identified a novel IRF2BP2 mutation in a family with a member diagnosed with IEI. Immune monitoring and WGS as auxiliary tests are helpful in identifying genetic defects and assisting diagnosis in patients with clinically highly suspected immune abnormalities and deficiencies in inflammation regulation. In addition, mNGS techniques allow a more comprehensive assessment of the pathogenic characteristics of these patients. This report further validates the association of IRF2BP2 deficiency and IEI, and expands IEI phenotypes.
摘要：
先天性免疫错误（IEI）是一组异质性疾病，其特征是感染风险增加。自身免疫,自身炎症性疾病,恶性肿瘤和过敏。下一代测序彻底改变了这些患者的遗传背景的识别，并有助于诊断和治疗。在这项研究中,我们确定了IEI的一个可能的独特的单基因原因，并对免疫学方法和病原检测进行了评价。
■通过全基因组测序(WGS)筛选具有IEI临床诊断的成员的家族。人口统计数据,临床表现，病史,体检,我们从病历中提取了患者的实验室检查结果和影像学特征.全面的免疫监测方法包括具有差异的全血细胞计数，细胞因子和自身抗体的血清水平，T细胞和B细胞亚群分析和血清免疫球蛋白的测量。此外,血液的宏基因组测序（mNGS），脑脊液和小肠活检用于检测潜在的病原体。
■患者表现为反复感染和自身免疫性疾病，最终被诊断出患有IEI。血液的重复mNGS测试，脑脊液和小肠活检未检测到病原微生物。免疫化验显示IgG水平较正常轻微下降,肿瘤坏死因子和白细胞介素-6水平升高。淋巴细胞流式细胞术显示总B细胞和自然杀伤细胞升高，减少总T细胞和B细胞浆母细胞。患者的WGS在IRF2BP2中鉴定出一种新的杂合突变（c.439_450dupp.Thr147_Pro150dup），这在他父亲身上也得到了证实。根据美国医学遗传学和基因组学学院指南，该突变被归类为不确定意义的变体（VUS）。
■我们在一个成员被诊断为IEI的家族中鉴定了一个新的IRF2BP2突变。免疫监测和WGS作为辅助测试有助于识别遗传缺陷并协助临床高度怀疑免疫异常和炎症调节缺陷的患者的诊断。此外,mNGS技术可以更全面地评估这些患者的致病特征。本报告进一步验证了IRF2BP2缺乏症与IEI的关联，并扩展IEI表型。
■通过全基因组测序(WGS)筛选具有IEI临床诊断的成员的家族。人口统计数据,临床表现，病史,体检,我们从病历中提取了患者的实验室检查结果和影像学特征.全面的免疫监测方法包括具有差异的全血细胞计数，细胞因子和自身抗体的血清水平，T细胞和B细胞亚群分析和血清免疫球蛋白的测量。此外,血液的宏基因组测序（mNGS），脑脊液和小肠活检用于检测潜在的病原体。
■患者表现为反复感染和自身免疫性疾病，最终被诊断出患有IEI。血液的重复mNGS测试，脑脊液和小肠活检未检测到病原微生物。免疫化验显示IgG水平较正常轻微下降,肿瘤坏死因子和白细胞介素-6水平升高。淋巴细胞流式细胞术显示总B细胞和自然杀伤细胞升高，减少总T细胞和B细胞浆母细胞。患者的WGS在IRF2BP2中鉴定出一种新的杂合突变（c.439_450dupp.Thr147_Pro150dup），这在他父亲身上也得到了证实。根据美国医学遗传学和基因组学学院指南，该突变被归类为不确定意义的变体（VUS）。
■我们在一个成员被诊断为IEI的家族中鉴定了一个新的IRF2BP2突变。免疫监测和WGS作为辅助测试有助于识别遗传缺陷并协助临床高度怀疑免疫异常和炎症调节缺陷的患者的诊断。此外,mNGS技术可以更全面地评估这些患者的致病特征。本报告进一步验证了IRF2BP2缺乏症与IEI的关联，并扩展IEI表型。
