■布鲁顿酪氨酸激酶(BTK)是参与B细胞发育的细胞质蛋白。X连锁无丙种球蛋白血症(XLA)是由BTK基因突变引起的,这导致非常低或缺乏B细胞。受影响的男性免疫球蛋白水平显着降低,这使得他们容易反复和严重的细菌感染。方法:2010-2018年期间,纳入疑似X连锁无丙种球蛋白血症的患者。临床总结,并记录这些患者的免疫学特征。收集外周血样本进行单核细胞BTK蛋白表达检测和BTK基因分析。对2020年1月至2023年6月的医疗记录进行了审查,以调查XLA的COVID-19。
■22例患者(来自16个无关家庭)被分子诊断为XLA。基因检测发现了15种不同的突变,包括四个剪接突变,四个错义突变,三个无意义的突变,三个短删除,和一个大的indel突变。这些突变散布在整个BTK基因中,并且主要影响激酶结构域。通过计算机模拟预测工具预测包括五个新突变的所有突变是致病性的或有害的。基因检测证实,11位母亲和7位姐妹是这种疾病的携带者,而三个突变是从头的。流式细胞术分析显示13名患者具有最低BTK表达(0-15%),而8名患者具有降低的BTK表达(16-64%)。由于样品不足,一名患者未进行单核细胞BTK表达测试。肺炎(n=13)是最常见的表现,而铜绿假单胞菌是患者中最常见的病原体(n=4)。4例患者报告轻度或无症状COVID-19。
■本报告首次概述了人口统计,临床,马来西亚XLA的免疫学和遗传数据。流式细胞术评估和BTK基因分析的结合为XLA患者提供了明确的诊断,尤其是不典型的临床表现。此外,它还可以检测携带者,并协助遗传咨询和产前诊断。
Bruton\'s tyrosine kinase (BTK) is a cytoplasmic protein involved in the B cell development. X-linked agammaglobulinemia (
XLA) is caused by mutation in the BTK gene, which results in very low or absent B cells. Affected males have markedly reduced immunoglobulin levels, which render them susceptible to recurrent and severe bacterial infections. Methods: Patients suspected with X-linked agammaglobulinemia were enrolled during the period of 2010-2018. Clinical summary, and immunological profiles of these patients were recorded. Peripheral blood samples were collected for monocyte BTK protein expression detection and BTK genetic analysis. The medical records between January 2020 and June 2023 were reviewed to investigate COVID-19 in
XLA.
Twenty-two patients (from 16 unrelated families) were molecularly diagnosed as
XLA. Genetic testing revealed fifteen distinct mutations, including four splicing mutations, four missense mutations, three nonsense mutations, three short deletions, and one large indel mutation. These mutations scattered throughout the BTK gene and mostly affected the kinase domain. All mutations including five novel mutations were predicted to be pathogenic or deleterious by in silico prediction tools. Genetic testing confirmed that eleven mothers and seven sisters were carriers for the disease, while three mutations were de novo. Flow cytometric analysis showed that thirteen patients had minimal BTK expression (0-15%) while eight patients had reduced BTK expression (16-64%). One patient was not tested for monocyte BTK expression due to insufficient sample. Pneumonia (n=13) was the most common manifestation, while Pseudomonas aeruginosa was the most frequently isolated pathogen from the patients (n=4). Mild or asymptomatic COVID-19 was reported in four patients.
This report provides the first overview of demographic, clinical, immunological and genetic data of
XLA in Malaysia. The combination of flow cytometric assessment and BTK genetic analysis provides a definitive diagnosis for
XLA patients, especially with atypical clinical presentation. In addition, it may also allow carrier detection and assist in genetic counselling and prenatal diagnosis.