BACKGROUND Alzheimer's disease, frontotemporal lobar degeneration, dementia with Lewy bodies, and Parkinson's disease (PD) overlap in clinical characteristics, neuropathology, and genetics. OBJECTIVE The aim of this study was to evaluate the role of pathogenic mutations and rare variants in genes associated with PD among early-onset dementia (EOD) patients. METHODS Rare non-synonymous variants (MAF < 0.01) in ten genes (SNCA, PARK2, PARK7, LRRK2, PINK1, ATP13A2, UCHL1, HTRA2, GBA, and SNCAIP) and low-frequency (MAF < 0.05) GBA variants were screened using a targeted next-generation sequencing panel in a strictly defined cohort of 37 early-onset (age at onset (AAO) <65 years) dementia patients presenting with atypical features (e.g., myoclonia or spasticity), rapidly progressive course of the disease or with a family history of dementia. The identified variations were further screened in a larger cohort of EOD (n = 279, mean AAO 57, range 36-65) patients. RESULTS No pathogenic mutations were found, but we identified seven possible risk variants for neurodegeneration (LRRK2 p.Arg793Met, PARK2 p.Ala82Glu, SNCAIP p.Arg240Gln, SNCAIP p.Phe369Leu, GBA p.Asn409Ser, GBA p.Glu365Lys, GBA p.Thr408Met). DISCUSSION Altogether, the frequency of these variants was two times higher in the first selected cohort compared to the whole cohort. This suggests that specific rare variants in the genes associated with PD might play a role also especially in familial EOD.

中文翻译：

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芬兰早期痴呆患者队列中与帕金森氏病相关基因的突变分析。

背景技术阿尔茨海默氏病，额颞叶变性，路易体痴呆和帕金森氏病（PD）在临床特征，神经病理学和遗传学方面重叠。目的本研究旨在评估早发性痴呆（EOD）患者中与PD相关的基因中的致病性突变和稀有变异的作用。方法使用10个基因（SNCA，PARK2，PARK7，LRRK2，PINK1，ATP13A2，UCHL1，HTRA2，GBA和SNCAIP）和低频（MAF <0.05）GBA变体筛选罕见的非同义变体（MAF <0.01）严格定义的一组具有非典型特征（例如，肌阵挛或痉挛）的37例早发性痴呆患者（发病年龄（AAO）<65岁）中的靶向下一代测序专家组，该病进展迅速或患有痴呆症家族史。在较大规模的EOD（n = 279，平均AAO 57，范围36-65）患者中进一步筛选了鉴定出的变异。结果未发现致病突变，但我们确定了7种可能的神经退行性变体（LRRK2 p.Arg793Met，PARK2 p.Ala82Glu，SNCAIP p.Arg240Gln，SNCAIP p.Phe369Leu，GBA p.Asn409Ser，GBA p.Glu365Lys，GBA p。 Thr408Met）。讨论总的来说，与整个队列相比，在第一个所选队列中这些变体的频率高出两倍。这表明与PD相关的基因中的特定稀有变异体也可能起着作用，尤其是在家族性EOD中。结果未发现致病突变，但我们确定了7种可能的神经退行性变体（LRRK2 p.Arg793Met，PARK2 p.Ala82Glu，SNCAIP p.Arg240Gln，SNCAIP p.Phe369Leu，GBA p.Asn409Ser，GBA p.Glu365Lys，GBA p。 Thr408Met）。讨论总的来说，与整个队列相比，在第一个所选队列中这些变体的频率高出两倍。这表明与PD相关的基因中的特定稀有变异体也可能起着作用，尤其是在家族性EOD中。结果未发现致病突变，但我们确定了7种可能的神经退行性变体（LRRK2 p.Arg793Met，PARK2 p.Ala82Glu，SNCAIP p.Arg240Gln，SNCAIP p.Phe369Leu，GBA p.Asn409Ser，GBA p.Glu365Lys，GBA p。 Thr408Met）。讨论总的来说，在第一个入选人群中，这些变异的频率是整个人群的两倍。这表明与PD相关的基因中的特定稀有变异体也可能起着作用，尤其是在家族性EOD中。