Jiao Bin, Liu Hui, Guo Lina, Xiao Xuewen, Liao Xinxin, Zhou Yafang, Weng Ling, Zhou Lu, Wang Xin, Jiang Yaling, Yang Qijie, Zhu Yuan, Zhou Lin, Zhang Weiwei, Wang Junling, Yan Xinxiang, Li Jinchen, Tang Beisha, Shen Lu
Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
National Clinical Research Center for Geriatric Disorders, Central South University, Changsha, China.
NPJ Genom Med. 2021 Aug 13;6(1):69. doi: 10.1038/s41525-021-00235-3.
Neurodegenerative dementias are a group of diseases with highly heterogeneous pathology and complicated etiology. There exist potential genetic component overlaps between different neurodegenerative dementias. Here, 1795 patients with neurodegenerative dementias from South China were enrolled, including 1592 with Alzheimer's disease (AD), 110 with frontotemporal dementia (FTD), and 93 with dementia with Lewy bodies (DLB). Genes targeted sequencing analysis were performed. According to the American College of Medical Genetics (ACMG) guidelines, 39 pathogenic/likely pathogenic (P/LP) variants were identified in 47 unrelated patients in 14 different genes, including PSEN1, PSEN2, APP, MAPT, GRN, CHCHD10, TBK1, VCP, HTRA1, OPTN, SQSTM1, SIGMAR1, and abnormal repeat expansions in C9orf72 and HTT. Overall, 33.3% (13/39) of the variants were novel, the identified P/LP variants were seen in 2.2% (35/1592) and 10.9% (12/110) of AD and FTD cases, respectively. The overall molecular diagnostic rate was 2.6%. Among them, PSEN1 was the most frequently mutated gene (46.8%, 22/47), followed by PSEN2 and APP. Additionally, the age at onset of patients with P/LP variants (51.4 years), ranging from 30 to 83 years, was ~10 years earlier than those without P/LP variants (p < 0.05). This study sheds insight into the genetic spectrum and clinical manifestations of neurodegenerative dementias in South China, further expands the existing repertoire of P/LP variants involved in known dementia-associated genes. It provides a new perspective for basic research on genetic pathogenesis and novel guiding for clinical practice of neurodegenerative dementia.
神经退行性痴呆是一组病理高度异质性且病因复杂的疾病。不同神经退行性痴呆之间存在潜在的遗传成分重叠。在此，纳入了来自中国南方的1795例神经退行性痴呆患者，其中包括1592例阿尔茨海默病（AD）患者、110例额颞叶痴呆（FTD）患者和93例路易体痴呆（DLB）患者。进行了基因靶向测序分析。根据美国医学遗传学学会（ACMG）指南，在47例无亲缘关系的患者中，于14个不同基因中鉴定出39个致病/可能致病（P/LP）变异，包括PSEN1、PSEN2、APP、MAPT、GRN、CHCHD10、TBK1、VCP、HTRA1、OPTN、SQSTM1、SIGMAR1，以及C9orf72和HTT中的异常重复扩增。总体而言，33.3%（13/39）的变异是新发现的，鉴定出的P/LP变异分别见于2.2%（35/1592）的AD病例和10.9%（12/110）的FTD病例。总体分子诊断率为2.6%。其中，PSEN1是最常发生突变的基因（46.8%，22/47），其次是PSEN2和APP。此外，具有P/LP变异的患者发病年龄（51.4岁，范围为30至83岁）比无P/LP变异的患者早约10岁（p < 0.05）。本研究深入了解了中国南方神经退行性痴呆的遗传谱和临床表现，进一步扩展了已知痴呆相关基因中涉及的P/LP变异的现有清单。它为遗传发病机制的基础研究提供了新视角，并为神经退行性痴呆临床实践提供了新指导。
