Background: Somatic mutations occur in neurons but their role in synucleinopathies is unknown. Aim: We aimed to identify disease-relevant low-level somatic single nucleotide variants (SNVs) in brains from sporadic patients with synucleinopathies and a monozygotic twin carrying LRRK2 G2019S, whose penetrance could be explained by somatic variation. Methods and Results: We included different brain regions from 26 Parkinsons disease (PD), 1 Incidental Lewy body, 3 multiple system atrophy cases and 12 controls. The whole SNCA locus and exons of other genes associated with PD and neurodegeneration were deeply sequenced using molecular barcodes to improve accuracy. We selected 21 variants at 0.33-5% allele frequencies for validation using accurate methods for somatic variant detection. Conclusions: We could not detect disease-relevant somatic SNVs, however we cannot exclude their presence at earlier stages of degeneration. Our results support that coding somatic SNVs in neurodegeneration are rare, but other types of somatic variants may hold pathological consequences in synucleinopathies.

中文翻译：

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研究人脑中针对与帕金森氏病相关基因的体细胞突变

背景：体细胞突变发生在神经元中，但其在突触核病中的作用尚不清楚。目的：我们旨在从散发性突触核蛋白病患者和携带LRRK2 G2019S的单卵双胞胎的大脑中鉴定与疾病相关的低水平体细胞单核苷酸变异体（SNV），其外显率可以通过体细胞变异来解释。方法和结果：我们包括26个帕金森病（PD），1个顺时针路易体，3个多系统萎缩病例和12个对照组的不同大脑区域。使用分子条形码对整个SNCA基因座和与PD和神经变性相关的其他基因的外显子进行了深度测序，以提高准确性。我们选择了0.33-5％等位基因频率的21个变体，以使用准确的体细胞变体检测方法进行验证。结论：我们无法检测到与疾病相关的体型SNV，但是，我们不能排除它们在变性的早期阶段的存在。我们的结果支持在神经退行性疾病中编码体细胞SNV的情况很少，但是其他类型的体细胞变异体可能在突触核蛋白病中具有病理后果。