Department of Bionano Technology, Gachon University, Sungnam 13120, Korea.
Department of Medicine, Mahidol University, Bangkok 10700, Thailand.
Int J Mol Sci. 2019 Mar 26;20(6):1514. doi: 10.3390/ijms20061514.
Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and prion diseases have a certain degree of clinical, pathological, and molecular overlapping. Previous studies revealed that many causative mutations in AD, PD, and FTD/ALS genes could be found in clinical familial and sporadic AD. To further elucidate the missing heritability in early-onset Alzheimer's disease (EOAD), we genetically characterized a Thai EOAD cohort by Next-Generation Sequencing (NGS) with a high depth of coverage, capturing variants in 50 previously recognized AD and other related disorders' genes. A novel mutation, p.V604M, and the known causative variant, p.E184G, were found in two of the familiar cases. Remarkably, among 61 missense variants were additionally discovered from 21 genes out of 50 genes, six potential mutations including P513A, p.R1628P, p.L211P, and (p.P54Q and pL536V) may be considered to be probably/possibly pathogenic and risk factors for other dementia leading to neuronal degeneration. All allele frequencies of the identified missense mutations were compared to 622 control individuals. Our study provides initial evidence that AD and other neurodegenerative diseases may represent shades of the same disease spectrum, and consideration should be given to offer exactly embracing genetic testing to patients diagnosed with EOAD. Our results need to be further confirmed with a larger cohort from this area.
阿尔茨海默病（AD）、帕金森病（PD）、额颞叶痴呆（FTD）、肌萎缩侧索硬化症（ALS）、亨廷顿病（HD）和朊病毒病具有一定程度的临床、病理和分子重叠。先前的研究表明，AD、PD 和 FTD/ALS 基因中的许多致病突变可在临床家族性和散发性 AD 中发现。为了进一步阐明早发性阿尔茨海默病（EOAD）中的遗传缺失，我们通过下一代测序（NGS）对泰国 EOAD 队列进行了基因特征分析，深度覆盖范围广，可捕获 50 个先前公认的 AD 和其他相关疾病基因中的变异。在两个熟悉的病例中发现了一种新的突变，p.V604M 和已知的致病突变，p.E184G。值得注意的是，在 50 个基因中的 21 个基因中还发现了另外 61 个错义变异，其中 6 个潜在的突变，包括 p.P513A、p.R1628P、p.L211P 和（p.P54Q 和 p.L536V）可能被认为是可能/可能具有致病性和导致神经元变性的其他痴呆的风险因素。鉴定出的错义突变的所有等位基因频率与 622 名对照个体进行了比较。我们的研究提供了初步证据，表明 AD 和其他神经退行性疾病可能代表同一疾病谱的不同表现，应考虑为诊断为 EOAD 的患者提供全面的基因检测。我们的结果需要在该地区的更大队列中进一步确认。
