Department of Clinical immunology, Auckland Hospital, Auckland, New Zealand; Department of Virology and Immunology, Auckland Hospital, Auckland, New Zealand; Department of Molecular Medicine and Pathology, School of Medicine, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, and Allergy and Clinical Immunology Laboratory, Department of Immunology, Monash University, Melbourne, VIC, Australia.
J Allergy Clin Immunol Pract. 2023 Jun;11(6):1646-1664. doi: 10.1016/j.jaip.2023.01.048. Epub 2023 Feb 14.
The understanding of common variable immunodeficiency disorders (CVID) is in evolution. CVID was previously a diagnosis of exclusion. New diagnostic criteria have allowed the disorder to be identified with greater precision. With the advent of next-generation sequencing (NGS), it has become apparent that an increasing number of patients with a CVID phenotype have a causative genetic variant. If a pathogenic variant is identified, these patients are removed from the overarching diagnosis of CVID and are deemed to have a CVID-like disorder. In populations where consanguinity is more prevalent, the majority of patients with severe primary hypogammaglobulinemia will have an underlying inborn error of immunity, usually an early-onset autosomal recessive disorder. In nonconsanguineous societies, pathogenic variants are identified in approximately 20% to 30% of patients. These are often autosomal dominant mutations with variable penetrance and expressivity. To add to the complexity of CVID and CVID-like disorders, some genetic variants such as those in TNFSF13B (transmembrane activator calcium modulator cyclophilin ligand interactor) predispose to, or enhance, disease severity. These variants are not causative but can have epistatic (synergistic) interactions with more deleterious mutations to worsen disease severity. This review is a description of the current understanding of genes associated with CVID and CVID-like disorders. This information will assist clinicians in interpreting NGS reports when investigating the genetic basis of disease in patients with a CVID phenotype.
对普通变异型免疫缺陷病（CVID）的认识在不断发展。CVID 以前是一种排除性诊断。新的诊断标准使得该疾病的诊断更加精确。随着下一代测序（NGS）的出现，越来越多具有 CVID 表型的患者具有致病的遗传变异变得显而易见。如果确定了致病变异，这些患者将不再被归入 CVID 的总体诊断中，而被认为患有 CVID 样疾病。在血缘关系更为普遍的人群中，大多数患有严重原发性低丙种球蛋白血症的患者将患有潜在的先天性免疫缺陷，通常是早发性常染色体隐性疾病。在非血缘关系的社会中，大约 20%至 30%的患者会发现致病性变异。这些通常是具有可变外显率和表现度的常染色体显性突变。为了增加 CVID 和 CVID 样疾病的复杂性，一些遗传变异，如 TNFSF13B（跨膜激活剂钙调节剂环孢素配体相互作用蛋白）中的变异，会导致或加重疾病的严重程度。这些变异不是致病的，但可以与更具破坏性的突变产生上位性（协同）相互作用，从而使疾病严重程度恶化。这篇综述描述了与 CVID 和 CVID 样疾病相关的基因的最新认识。这些信息将有助于临床医生在调查具有 CVID 表型的患者疾病遗传基础时，解释 NGS 报告。
