Xu Yangqi, Liu Xiaoli, Shen Junyi, Tian Wotu, Fang Rong, Li Binyin, Ma Jianfang, Cao Li, Chen Shengdi, Li Guanjun, Tang Huidong
1Department of Neurology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
3Department of Neurology, Shanghai Fengxian District Central Hospital, Shanghai Jiao Tong University Affiliated Sixth People's Hospital South Campus, Shanghai, China.
Aging Dis. 2018 Aug 1;9(4):696-705. doi: 10.14336/AD.2018.0208. eCollection 2018 Aug.
Our study aimed to identify the underlying causes in patients with early onset dementia by clinical and genetic exploration. We recruited a group of 38 patients with early-onset dementia. Firstly, hexanucleotide repeat expansions in gene were screened in all subjects to exclude the possibility of copy number variation. Then, the whole exome sequencing (WES) was conducted, and the data were analyzed focusing on 89 dementia-related causing and susceptible genes. The effects of identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) standards and guidelines. There were no pathogenic expansions in detected. According to the ACMG standards and guidelines, we identified five known pathogenic mutations, P284L, c.857-1G>A, I143T, G209E and G389R, and one novel pathogenic mutation K687N. All these mutations caused dementia with the mean onset age of 38.3 (range from 27 to 51) and rapid progression. Eleven variants with uncertain significance were also detected and needed further verification. The clinical phenotypes of dementia are heterogeneous, with both onset ages and clinical features being influenced by mutation position as well as the causative gene. WES can serve as efficient diagnostic tools for different heterogeneous dementia.
我们的研究旨在通过临床和基因探索确定早发性痴呆患者的潜在病因。我们招募了一组38例早发性痴呆患者。首先，对所有受试者筛查基因中的六核苷酸重复扩增，以排除拷贝数变异的可能性。然后，进行全外显子组测序（WES），并重点分析89个与痴呆相关的致病和易感基因的数据。根据美国医学遗传学与基因组学学会（ACMG）的标准和指南对鉴定出的变异的影响进行分类。在检测中未发现致病性扩增。根据ACMG标准和指南，我们鉴定出5个已知的致病突变，即P284L、c.857-1G>A、I143T、G209E和G389R，以及1个新的致病突变K687N。所有这些突变均导致痴呆，平均发病年龄为38.3岁（范围为27至51岁），且病情进展迅速。还检测到11个意义未明的变异，需要进一步验证。痴呆的临床表型具有异质性，发病年龄和临床特征均受突变位置以及致病基因的影响。WES可作为不同异质性痴呆的有效诊断工具。
