Mutations in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP) are major genetic causes of early-onset Alzheimer's disease (EOAD). Clinical heterogeneity is frequently observed in patients with PSEN1 and PSEN2 mutations. Using whole exome sequencing, we screened a Dutch cohort of 68 patients with EOAD for rare variants in Mendelian Alzheimer's disease, frontotemporal dementia, and prion disease genes. We identified 3 PSEN1 and 2 PSEN2 variants. Three variants, 1 in PSEN1 (p.H21Profs*2) and both PSEN2 (p.A415S and p.M174I), were novel and absent in control exomes. These novel variants can be classified as probable pathogenic, except for PSEN1 (p.H21Profs*2) in which the pathogenicity is uncertain. The initial clinical symptoms between mutation carriers varied from behavioral problems to memory impairment. Our findings extend the mutation spectrum of EOAD and underline the clinical heterogeneity among PSEN1 and PSEN2 mutation carriers. Screening for Alzheimer's disease-causing genes is indicated in presenile dementia with an overlapping clinical diagnosis.

中文翻译：

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早发性阿尔茨海默病的基因筛查发现了三种新的早老素突变

早老素 1 (PSEN1)、早老素 2 (PSEN2) 和淀粉样前体蛋白 (APP) 的突变是早发性阿尔茨海默病 (EOAD) 的主要遗传原因。在具有 PSEN1 和 PSEN2 突变的患者中经常观察到临床异质性。使用全外显子组测序，我们筛选了 68 名 EOAD 荷兰患者队列，以寻找孟德尔阿尔茨海默病、额颞叶痴呆和朊病毒病基因的罕见变异。我们确定了 3 个 PSEN1 和 2 个 PSEN2 变体。三个变体，1 个在 PSEN1 (p.H21Profs*2) 和 PSEN2 (p.A415S 和 p.M174I)，是新的，并且在对照外显子组中不存在。除了 PSEN1 (p.H21Profs*2) 致病性不确定外，这些新变异可归类为可能的致病性变异。突变携带者之间的初始临床症状从行为问题到记忆障碍不等。我们的研究结果扩展了 EOAD 的突变谱，并强调了 PSEN1 和 PSEN2 突变携带者之间的临床异质性。阿尔茨海默病致病基因的筛查适用于临床诊断重叠的老年痴呆症。