Abstract:
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.
摘要:
对常见可变免疫缺陷性疾病(CVID)的理解还在进化中。CVID以前是排除的诊断。新的诊断标准允许以更高的精度识别疾病。随着下一代测序(NGS)的出现,很明显,越来越多的CVID表型患者具有致病的遗传变异.如果发现了致病变异,这些患者被排除在CVID的总体诊断之外,并被认为患有CVID样疾病.在血缘关系更普遍的人群中,大多数患有严重原发性低丙种球蛋白血症的患者会有潜在的先天免疫错误,通常是早发性常染色体隐性遗传疾病。在非近亲社会,在大约20%~30%的患者中发现了致病变异.这些通常是常染色体显性突变,具有可变的外显率和表达能力。为了增加CVID和CVID样疾病的复杂性,一些遗传变异,如TNFSF13B(跨膜激活钙调节剂亲环蛋白配体相互作用剂)易感,或增强,疾病严重程度。这些变体不是致病的,但可以具有与更有害的突变的上位性(协同性)相互作用以恶化疾病严重程度。这篇综述描述了当前对与CVID和CVID样疾病相关的基因的理解。这些信息将帮助临床医生在调查具有CVID表型的患者的疾病的遗传基础时解释NGS报告。