Yiying Wang, Runqing Ju, Jingsi Jiang, Le Mao, Xiaogang Li, Min Deng
{"title":"Concomitant presence of a novel ARPP21 variant and CNVs in Chinese familial amyotrophic lateral sclerosis-frontotemporal dementia patients","authors":"Yiying Wang, Runqing Ju, Jingsi Jiang, Le Mao, Xiaogang Li, Min Deng","doi":"10.1007/s10072-024-07759-3","DOIUrl":null,"url":null,"abstract":"<p>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the degeneration of motor neurons and progressive muscle weakness. Heredity plays an important part in the pathogenesis of ALS. Recently, with the emergence of the oligogenic pathogenic mechanism in ALS and the ongoing discovery of new mutated genes and genomic variants, there is an emerging need for larger-scale and more comprehensive genetic screenings in higher resolution. In this study, we performed whole-genome sequencing (WGS) on 34 familial ALS probands lacking the most common disease-causing mutations to explore the genetic landscape of Chinese ALS patients further. Among them, we identified a novel <i>ARPP21</i> c.1231G > A (p.Glu411Lys) variant and two copy number variations (CNVs) affecting the <i>PFN1</i> and <i>RBCK1</i> genes in a patient with ALS-frontotemporal dementia (FTD). This marks the first report of an <i>ARPP21</i> variant in Chinese ALS-FTD patients, providing fresh evidence for the association between <i>ARPP21</i> and ALS. Our findings also underscore the potential role of CNVs in ALS-FTD, suggesting that the cumulative effect of multiple rare variants may contribute to disease onset. Furthermore, compared to the averages in our cohort and the reported Chinese ALS population, this patient displayed a shorter survival time and more rapid disease progression, suggesting the possibility of an oligogenic mechanism in disease pathogenesis. Further research will contribute to a deeper understanding of the rare mutations and their interactions, thus advancing our understanding of the genetic mechanisms underlying ALS and ALS-FTD.</p>","PeriodicalId":19191,"journal":{"name":"Neurological Sciences","volume":null,"pages":null},"PeriodicalIF":2.7000,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Neurological Sciences","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s10072-024-07759-3","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder marked by the degeneration of motor neurons and progressive muscle weakness. Heredity plays an important part in the pathogenesis of ALS. Recently, with the emergence of the oligogenic pathogenic mechanism in ALS and the ongoing discovery of new mutated genes and genomic variants, there is an emerging need for larger-scale and more comprehensive genetic screenings in higher resolution. In this study, we performed whole-genome sequencing (WGS) on 34 familial ALS probands lacking the most common disease-causing mutations to explore the genetic landscape of Chinese ALS patients further. Among them, we identified a novel ARPP21 c.1231G > A (p.Glu411Lys) variant and two copy number variations (CNVs) affecting the PFN1 and RBCK1 genes in a patient with ALS-frontotemporal dementia (FTD). This marks the first report of an ARPP21 variant in Chinese ALS-FTD patients, providing fresh evidence for the association between ARPP21 and ALS. Our findings also underscore the potential role of CNVs in ALS-FTD, suggesting that the cumulative effect of multiple rare variants may contribute to disease onset. Furthermore, compared to the averages in our cohort and the reported Chinese ALS population, this patient displayed a shorter survival time and more rapid disease progression, suggesting the possibility of an oligogenic mechanism in disease pathogenesis. Further research will contribute to a deeper understanding of the rare mutations and their interactions, thus advancing our understanding of the genetic mechanisms underlying ALS and ALS-FTD.
肌萎缩侧索硬化症(ALS)是一种以运动神经元变性和进行性肌无力为特征的破坏性神经退行性疾病。遗传在 ALS 的发病机制中起着重要作用。最近,随着 ALS 寡基因致病机制的出现以及新突变基因和基因组变异的不断发现,人们开始需要进行更大规模、更全面、分辨率更高的基因筛查。在本研究中,我们对 34 例缺乏最常见致病基因突变的家族性 ALS 患者进行了全基因组测序(WGS),以进一步探索中国 ALS 患者的基因状况。其中,我们在一名ALS-额颞叶痴呆(FTD)患者中发现了一个新的ARPP21 c.1231G > A (p.Glu411Lys) 变异和两个影响PFN1和RBCK1基因的拷贝数变异(CNVs)。这是中国首次报道ARPP21变异在ALS-FTD患者中的应用,为ARPP21与ALS之间的关联提供了新的证据。我们的研究结果还强调了CNVs在ALS-FTD中的潜在作用,表明多种罕见变异的累积效应可能会导致疾病的发生。此外,与我们队列中的平均值和报道的中国 ALS 群体相比,该患者的生存时间更短,疾病进展更快,这表明疾病发病机制中可能存在寡源性机制。进一步的研究将有助于加深对罕见突变及其相互作用的理解,从而推进我们对 ALS 和 ALS-FTD 遗传机制的认识。
期刊介绍:
Neurological Sciences is intended to provide a medium for the communication of results and ideas in the field of neuroscience. The journal welcomes contributions in both the basic and clinical aspects of the neurosciences. The official language of the journal is English. Reports are published in the form of original articles, short communications, editorials, reviews and letters to the editor. Original articles present the results of experimental or clinical studies in the neurosciences, while short communications are succinct reports permitting the rapid publication of novel results. Original contributions may be submitted for the special sections History of Neurology, Health Care and Neurological Digressions - a forum for cultural topics related to the neurosciences. The journal also publishes correspondence book reviews, meeting reports and announcements.