Abstract：
LRBA is a cytoplasmic protein that is ubiquitously distributed. Almost all LRBA domains have a scaffolding function. In 2012, it was reported that homozygous variants in LRBA are associated with early-onset hypogammaglobulinemia. Since its discovery, more than 100 pathogenic variants have been reported. This review focuses on the variants reported in LRBA and their possible associations with clinical phenotypes. In this work LRBA deficiency cases reported more than 11 years ago have been revised. A database was constructed to analyze the type of variants, age at onset, clinical diagnosis, infections, autoimmune diseases, and cellular and immunoglobulin levels. The review of cases from 2012 to 2023 showed that LRBA deficiency was commonly diagnosed in patients with a clinical diagnosis of Common Variable Immunodeficiency, followed by enteropathy, neonatal diabetes mellitus, ALPS, and X-linked-like syndrome. Most cases show early onset of presentation at <6 years of age. Most cases lack protein expression, whereas hypogammaglobulinemia is observed in half of the cases, and IgG and IgA levels are isotypes reported at low levels. Patients with elevated IgG levels exhibited more than one autoimmune manifestation. Patients carrying pathogenic variants leading to a premature stop codon show a severe phenotype as they have an earlier onset of disease presentation, severe autoimmune manifestations, premature death, and low B cells and regulatory T cell levels. Missense variants were more common in patients with low IgG levels and cytopenia. This work lead to the conclusion that the type of variant in LRBA has association with disease severity, which leads to a premature stop codon being the ones that correlates with severe disease.
摘要：
LRBA是广泛分布的细胞质蛋白。几乎所有LRBA结构域都具有支架功能。2012年，据报道，LRBA中的纯合变体与早发性低丙种球蛋白血症有关。自从它被发现,已经报道了100多种致病变异。这篇综述集中在LRBA中报道的变异及其与临床表型的可能关联。在这项工作中，对11年前报告的LRBA缺乏症病例进行了修订。建立了一个数据库来分析变异的类型，发病年龄,临床诊断,感染,自身免疫性疾病，细胞和免疫球蛋白水平。对2012年至2023年病例的回顾显示，LRBA缺乏症通常在临床诊断为常见可变免疫缺陷的患者中诊断。其次是肠病，新生儿糖尿病，阿尔卑斯,和X连锁综合征.大多数病例在小于6岁时表现出早期发作。大多数病例缺乏蛋白质表达，而在一半的病例中观察到低丙种球蛋白血症，IgG和IgA水平是低水平的同种型。IgG水平升高的患者表现出一种以上的自身免疫表现。携带致病变异导致过早终止密码子的患者表现出严重的表型，因为他们有较早的疾病发作。严重的自身免疫表现，过早死亡,和低B细胞和调节性T细胞水平。错义变异在低IgG水平和血细胞减少症患者中更为常见。这项工作得出的结论是，LRBA中变异的类型与疾病的严重程度有关，这导致过早的终止密码子与严重疾病有关。
