在亚洲,阿尔茨海默病(AD)患者的数量正在迅速增加。淀粉样蛋白前体(APP)的突变,早老素-1(PSEN1),和早老素-2(PSEN2)基因可引起常染色体显性形式的早发性AD(EOAD)。尽管这些基因已被广泛研究,变体分类仍然是一个挑战,强调需要在人群中联合突变。在这项研究中,我们对APP中的突变进行了基因筛查,PSEN1和PSEN2基因在四个亚洲国家的200名临床诊断的EOAD患者中,包括泰国,马来西亚,菲律宾,和韩国,2009年至2018年。32例(16%)患者出现致病性APP,PSEN1或PSEN2变体;八个(25%),19(59%),32名患者中有5名(16%)提出了APP,PSEN1和PSEN2变体,分别。在21种新颖和已知的非同义变体中,在韩国患者中发现了5种APP变异,在1例泰国EOAD患者中发现了1种APP变异.九,两个,在一名韩国患者中发现了一个PSEN1突变,马来西亚兄弟姐妹,还有一个泰国病人,分别。与PSEN1突变不同,在EOAD患者中PSEN2突变很少;在韩国EOAD患者中仅发现了三种变体。比较亚洲国家的AD致病点突变;我们的发现仅解释了一小部分患者,留下大约84%(p=0.01)的常染色体显性谱系遗传原因不明。我们建议对EOAD患者使用高通量测序技术可以潜在地提高我们对AD分子机制的理解。
The number of patients with Alzheimer\'s disease (AD) is rapidly increasing in Asia. Mutations in the amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes can cause autosomal dominant forms of early-onset AD (
EOAD). Although these genes have been extensively studied, variant classification remains a challenge, highlighting the need to colligate mutations across populations. In this study, we performed a genetic screening for mutations in the APP, PSEN1, and PSEN2 genes in 200 clinically diagnosed EOAD patients across four Asian countries, including Thailand, Malaysia, the Philippines, and Korea, between 2009 and 2018. Thirty-two (16%) patients presented pathogenic APP, PSEN1, or PSEN2 variants; eight (25%), 19 (59%), and five (16%) of the 32 patients presented APP, PSEN1, and PSEN2 variants, respectively. Among the 21 novel and known non-synonymous variants, five APP variants were found in Korean patients and one APP variant was identified in a Thai patient with
EOAD. Nine, two, and one PSEN1 mutation was found in a Korean patient, Malaysian siblings, and a Thai patient, respectively. Unlike PSEN1 mutations, PSEN2 mutations were rare in patients with
EOAD; only three variants were found in Korean patients with
EOAD. Comparison of AD-causative point mutations in Asian countries; our findings explained only a small fraction of patients, leaving approximately 84% (p = 0.01) of autosomal dominant pedigrees genetically unexplained. We suggest that the use of high-throughput sequencing technologies for
EOAD patients can potentially improve our understanding of the molecular mechanisms of AD.