Abstract：
Pathogenic variants in LRBA, encoding the LPS Responsive Beige-Like Anchor (LRBA) protein, are responsible for recessive, early-onset hypogammaglobulinemia, severe multi-organ autoimmunity, and lymphoproliferation, with increased risk for malignancy. LRBA deficiency has a wide clinical spectrum with variable age of onset and disease severity. Three apparently unrelated patients with LRBA deficiency, of Georgian Jewish descent, were homozygous for LRBA c.6640C > T, p.R2214*, leading to a stop upstream of the LRBA BEACH domain. Despite carrying the same LRBA genotype, the three patients differed in clinical course: the first patient was asymptomatic until age 25 years; the second presented with failure to thrive at age 3 months; and the third presented at age 7 years with immune cytopenias and severe infections. Two of the patients developed malignancies: the first patient was diagnosed with recurrent Hodgkin\'s disease at age 36 years, and the second patient developed aggressive gastric cancer at age 15 years. Among Georgian Jews, the carrier frequency of the LRBA p.R2214* allele was 1.6% (4 of 236 Georgian Jewish controls). The allele was absent from other populations. Haplotype analysis showed a shared origin of the mutation. These three patients revealed a pathogenic LRBA founder allele in the Georgian Jewish population, support the diverse and complex clinical spectrum of LRBA deficiency, and support the possibility that LRBA deficiency predisposes to malignancy.
摘要：
LRBA的致病变异，编码LPS响应米色样锚定蛋白（LRBA），负责隐性，早发性低丙种球蛋白血症,严重的多器官自身免疫,和淋巴增生，恶性肿瘤的风险增加。LRBA缺乏症具有广泛的临床范围，具有不同的发病年龄和疾病严重程度。三名明显无关的LRBA缺乏症患者，格鲁吉亚犹太血统，对于LRBAc.6640C>T是纯合的，p.R2214*,导致LRBABEACH域的上游停止。尽管携带相同的LRBA基因型，3例患者的临床病程不同:第1例患者在25岁之前无症状;第2例患者在3个月时出现无法茁壮成长;第3例患者在7岁时出现免疫性血细胞减少症和严重感染.其中两名患者发展为恶性肿瘤：第一名患者在36岁时被诊断患有复发性霍奇金病，第二名患者在15岁时发展为侵袭性胃癌。在格鲁吉亚犹太人中，LRBAp.R2214*等位基因的携带频率为1.6%(236名格鲁吉亚犹太人对照中的4名).其他人群中不存在等位基因。单倍型分析显示突变的共同起源。这三名患者在格鲁吉亚犹太人口中发现了致病性LRBA创始人等位基因，支持LRBA缺乏症的多样化和复杂的临床谱，并支持LRBA缺乏易患恶性肿瘤的可能性。
