Sassi Celeste, Guerreiro Rita, Gibbs Raphael, Ding Jinhui, Lupton Michelle K, Troakes Claire, Lunnon Katie, Al-Sarraj Safa, Brown Kristelle S, Medway Chirstopher, Lord Jenny, Turton James, Mann David, Snowden Julie, Neary David, Harris Jeniffer, Bras Jose, Morgan Kevin, Powell John F, Singleton Andrew, Hardy John
University College London (UCL) Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
University College London (UCL) Institute of Neurology, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
Neurobiol Aging. 2014 Oct;35(10):2422.e13-6. doi: 10.1016/j.neurobiolaging.2014.04.026. Epub 2014 May 2.
Early-onset Alzheimer's disease (EOAD) represents 1%-2% of the Alzheimer's disease (AD) cases, and it is generally characterized by a positive family history and a rapidly progressive symptomatology. Rare coding and fully penetrant variants in amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2) are the only causative mutations reported for autosomal dominant AD. Thus, in this study we used exome sequencing data to rapidly screen rare coding variability in APP, PSEN1, and PSEN2, in a British cohort composed of 47 unrelated EOAD cases and 179 elderly controls, neuropathologically proven. We report 2 novel and likely pathogenic variants in PSEN1 (p.L166V and p.S230R). A comprehensive catalog of rare pathogenic variants in the AD Mendelian genes is pivotal for a premortem diagnosis of autosomal dominant EOAD and for the differential diagnosis with other early onset dementias such as frontotemporal dementia (FTD) and Creutzfeldt-Jakob disease (CJD).
早发性阿尔茨海默病（EOAD）占阿尔茨海默病（AD）病例的1%-2%，其一般特征为家族史阳性和症状快速进展。淀粉样前体蛋白（APP）、早老素1（PSEN1）和早老素2（PSEN2）中罕见的编码且完全显性的变异是常染色体显性AD唯一报道的致病突变。因此，在本研究中，我们使用外显子组测序数据，对一个由47例无亲缘关系的EOAD病例和179例经神经病理学证实的老年对照组成的英国队列中的APP、PSEN1和PSEN2罕见编码变异进行快速筛查。我们报告了PSEN1中的2个新的且可能致病的变异（p.L166V和p.S230R）。AD孟德尔基因中罕见致病变异的综合目录对于常染色体显性EOAD的生前诊断以及与其他早发性痴呆如额颞叶痴呆（FTD）和克雅氏病（CJD）的鉴别诊断至关重要。
