Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing
Mutation screening in Chinese patients with familial Alzheimer's disease by whole-exome sequencing
复制标题
通过全外显子组测序对中国家族性阿尔茨海默病患者进行突变筛查
DOI：
10.1016/j.neurobiolaging.2018.11.024
复制
发表时间：
2019-04-01
影响因子：
4.2
通讯作者：
Wu, Zhi-Ying
中科院分区：
文献类型：
--
作者：
Jiang, Bin;Zhou, Jiong;Wu, Zhi-Ying
家族性阿尔茨海默病（FAD）的特点是具有积极的痴呆症家族史，通常发生在早期，具有常染色体显性遗传模式。淀粉样蛋白前体蛋白（APP）、早老素1 （PSEN1）和早老素2 （PSEN2）是FAD的主要致病基因。FAD患者的突变谱已在高加索人群中广泛研究，但在中国人群中很少研究。在这里，我们对总共15名无关的中国FAD患者进行了全外显子组测序。其中12例在APP、PSEN1、PSEN2中携带错义变异。2个新变异（APP: p.D244G, p.K687Q）， 3个先前未与FAD相关的变异（APP: p.T297M, p.D332G; PSEN1: p.R157S），以及7个先前报道的致病变异（APP: p.V717I; PSEN1: p.M139I, p.T147I, p.L173W, p.F177S, p.R269H; PSEN2: p.V139M）。新变异APP p.K687Q被归类为可能致病，其他4个变异（APP: p.D244G、p.T297M、p.D332G; PSEN1: p.R157S）被归类为不确定意义。因此，APP、PSEN1和PSEN2突变分别占基因型突变阳性病例的2例（25.0%）、5例（62.5%）和1例（12.5%）。此外，还描述了基因型与表型的相关性。我们的发现拓宽了FAD的遗传谱，包括APP、PSEN1和PSEN2变体。(C) 2018爱思唯尔公司版权所有。
Familial Alzheimer's disease (FAD) is characterized by a positive family history of dementia and typically occurs at an early age with an autosomal dominant pattern of inheritance. Amyloid precursor protein (APP), presenilin1 (PSEN1), and presenilin2 (PSEN2) are the major causative genes of FAD. The spectrum of mutations in patients with FAD has been investigated extensively in the Caucasian population but rarely in the Chinese population. Here, we performed whole-exome sequencing in a total of 15 unrelated Chinese patients with FAD. Among them, 12 were found to carry missense variants in APP, PSEN1, and PSEN2. Two novel variants (APP: p.D244G, p.K687Q), 3 variants not previously associated with FAD (APP: p.T297M, p.D332G; PSEN1: p.R157S), and 7 previously reported pathogenic variants (APP: p.V717I; PSEN1: p.M139I, p.T147I, p.L173W, p.F177S, p.R269H; PSEN2: p.V139M) were identified. The novel variant APP p.K687Q was classified as likely pathogenic, and the other 4 variants (APP: p.D244G, p.T297M, p.D332G; PSEN1: p.R157S) were classified as uncertain significance. Therefore, APP, PSEN1, and PSEN2 mutations account for 2 (25.0%), 5 (62.5%), and 1 (12.5%) of the genotyped cases positive for mutations, respectively. Furthermore, the genotype-phenotype correlations were described. Our findings broaden the genetic spectrum of FAD with APP, PSEN1, and PSEN2 variants. (C) 2018 Elsevier Inc. All rights reserved.