Early-onset Alzheimer's disease (EOAD) and frontotemporal dementia (FTD) have a high proportion of genetically determined cases. Next-generation sequencing technologies have triggered the discovery of new mutations and genetic variants in dementia-causal genes. We performed whole-exome sequencing and selective analysis of known genes causative of EOAD and FTD in a well-characterized Spanish cohort of 103 patients (60 EOAD, 43 FTD) to find genetic variants associated to patients' phenotype. In EOAD patients, a new likely pathogenic variant in PSEN1 gene (p.G378R) was found. In FTD patients, 2 likely pathogenic variants were found, one in MAPT gene (p.P397S) and one in VCP gene (p.R159H). In our series, 2% of early-onset dementia without criteria for clinical genetic testing according to current guidelines presented a likely pathogenic mutation. We have also detected 13 additional variants of uncertain significance in causal genes, as well as rare variants in risk genes for dementia (ABCA7, SORL1, SQSTM1, and TREM2). Next-generation technologies in neurodegenerative diseases constitute a powerful tool that significantly contributes to patients' diagnosis.

中文翻译：

---

在西班牙早发性痴呆患者中通过全外显子组测序筛选痴呆基因：可能的致病性、不确定性和风险变异。

早发性阿尔茨海默病 (EOAD) 和额颞叶痴呆 (FTD) 有很大比例的基因决定病例。新一代测序技术引发了痴呆症致病基因中新突变和遗传变异的发现。我们在一个由 103 名患者（60 名 EOAD，43 名 FTD）组成的充分表征的西班牙队列中对已知的 EOAD 和 FTD 致病基因进行了全外显子组测序和选择性分析，以寻找与患者表型相关的遗传变异。在 EOAD 患者中，发现了 PSEN1 基因（p.G378R）中一种新的可能致病变异。在 FTD 患者中，发现了 2 个可能的致病变异，一个在 MAPT 基因（p.P397S）中，另一个在 VCP 基因（p.R159H）中。在我们的系列中，根据目前的指南，没有临床基因检测标准的早发性痴呆中有 2% 出现了可能的致病突变。我们还在因果基因中检测到另外 13 个意义不明的变异，以及痴呆风险基因中的罕见变异（ABCA7、SORL1、SQSTM1 和 TREM2）。神经退行性疾病的下一代技术构成了一个强大的工具，对患者的诊断做出了重大贡献。