Blauwendraat Cornelis, Wilke Carlo, Jansen Iris E, Schulte Claudia, Simón-Sánchez Javier, Metzger Florian G, Bender Benjamin, Gasser Thomas, Maetzler Walter, Rizzu Patrizia, Heutink Peter, Synofzik Matthis
Applied Genomics for Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany.
Neurobiol Aging. 2016 Jan;37:208.e11-208.e17. doi: 10.1016/j.neurobiolaging.2015.09.016. Epub 2015 Sep 30.
Early-onset Alzheimer's disease (EOAD) accounts for 1%-2% of all Alzheimer's disease (AD) subjects, with large variation in the reported genetic contribution of known dementia genes. In this pilot study, we genetically characterized a German EOAD cohort (23 subjects) by whole-exome sequencing, capturing variants in all recognized AD and frontotemporal dementia genes. After variant filtering, we identified 7 events of altogether 6 different rare variants in 6 subjects, including 4 novel variants. Four of the 6 variants, observed in 5 different index subjects (5/23 = 22%), were considered to be possibly pathogenic. These included 2 presenilin 2 (PSEN2) variants (p.N141I-previously denoted as a Volga German variant, observed in 2 index subjects; and p.L238P), 1 amyloid precursor protein (p.I716M), and 1 presenilin 1 (ΔE9). Using a control exome data set of 96 ethnically matched neurodegenerative disease controls (Parkinson's disease), we identified only 1 variant (PSEN2 p.T18M) (1%), demonstrating a significantly higher mutational burden in the EOAD group (p > 0.0001). Our findings demonstrate a substantial frequency of variants in dementia genes in EOAD, including several seemingly "sporadic" subjects. This indicates that heritability in EOAD might be higher than assumed. The finding of 3 subjects carrying potential pathogenic PSEN2 variants suggests that, in specific populations PSEN2 variants might be as frequent as (or more frequent than) presenilin 1, for example, in German populations which are influenced by Volga German heritage. Variants in AD genes were also associated with rare phenotypes such as frontal AD or primary progressive aphasia, demonstrating the need to screen AD genes in frontotemporal dementia-like phenotypes.
早发型阿尔茨海默病（EOAD）占所有阿尔茨海默病（AD）患者的1%-2%，已知痴呆基因的遗传贡献报道差异很大。在这项初步研究中，我们通过全外显子测序对一个德国EOAD队列（23名受试者）进行了基因特征分析，捕获了所有已确认的AD和额颞叶痴呆基因中的变异。经过变异筛选，我们在6名受试者中鉴定出总共6种不同的罕见变异的7个事件，包括4种新变异。6种变异中的4种，在5名不同的索引受试者中观察到（5/23 = 22%），被认为可能具有致病性。这些包括2种早老素2（PSEN2）变异（p.N141I - 以前称为伏尔加德意志变异，在2名索引受试者中观察到；以及p.L238P）、1种淀粉样前体蛋白（p.I716M）和1种早老素1（ΔE9）。使用96名种族匹配的神经退行性疾病对照（帕金森病）的对照外显子数据集，我们仅鉴定出1种变异（PSEN2 p.T18M）（1%），表明EOAD组的突变负担显著更高（p > 0.0001）。我们的研究结果表明，EOAD中痴呆基因变异的频率相当高，包括一些看似“散发”的受试者。这表明EOAD的遗传度可能比假设的更高。发现3名受试者携带潜在致病性PSEN2变异表明，在特定人群中，PSEN2变异可能与早老素1一样频繁（或更频繁），例如，在受伏尔加德意志血统影响的德国人群中。AD基因变异也与罕见表型相关，如额叶AD或原发性进行性失语，这表明有必要在额颞叶痴呆样表型中筛查AD基因。
