Abstract：
BACKGROUND: Parkinson\'s disease (PD) is a progressive neurodegenerative disorder with a multifactorial pathogenesis. Several genetic variants increase the risk of PD and about 5-10% of cases are monogenic. This study aims to define the genetic bases and clinical features of PD in a cohort of patients from Northeastern Italy, a peculiar geographical area previously not included in genetic screenings.
METHODS: Using an NGS multigenic panel, 218 PD patients were tested based on age at onset, family history and development of atypical features.
RESULTS: A total of 133 genetic variants were found in 103 patients. Monogenic PD was diagnosed in 43 patients (20% of the cohort); 28 (12.8%) carried mutations in GBA1, 10 in LRRK2 (4.6%) and 5 in PRKN (2.3%). In 17% of patients the genetic defect remained of uncertain interpretation. The selection criterion \"age of onset < 55 years\" was a significant predictor of a positive genetic test (OR 3.8, p 0.0037). GBA1 patients showed more severe symptoms and a higher burden of motor and non-motor complications compared to negative patients (dyskinesias OR 3, sleep disturbances OR 2.8, cognitive deficits OR 3.6; p < 0.05), with greater autonomic dysfunction (COMPASS-31 score 34.1 vs 20.2, p 0.03).
CONCLUSIONS: Applying simple clinical criteria for genetic testing allows to increase the probability to identify patients with monogenic PD and better allocate resources. This process is critical to widen the understanding of disease mechanisms and to increase the individuation of patients potentially benefitting from future disease-modifying therapies.
METHODS: Using an NGS multigenic panel, 218 PD patients were tested based on age at onset, family history and development of atypical features.
RESULTS: A total of 133 genetic variants were found in 103 patients. Monogenic PD was diagnosed in 43 patients (20% of the cohort); 28 (12.8%) carried mutations in GBA1, 10 in LRRK2 (4.6%) and 5 in PRKN (2.3%). In 17% of patients the genetic defect remained of uncertain interpretation. The selection criterion \"age of onset < 55 years\" was a significant predictor of a positive genetic test (OR 3.8, p 0.0037). GBA1 patients showed more severe symptoms and a higher burden of motor and non-motor complications compared to negative patients (dyskinesias OR 3, sleep disturbances OR 2.8, cognitive deficits OR 3.6; p < 0.05), with greater autonomic dysfunction (COMPASS-31 score 34.1 vs 20.2, p 0.03).
CONCLUSIONS: Applying simple clinical criteria for genetic testing allows to increase the probability to identify patients with monogenic PD and better allocate resources. This process is critical to widen the understanding of disease mechanisms and to increase the individuation of patients potentially benefitting from future disease-modifying therapies.
摘要：
背景：帕金森病（PD）是一种进行性神经退行性疾病，具有多因素的发病机制。几种遗传变异会增加PD的风险，约5-10％的病例是单基因的。这项研究旨在确定来自意大利东北部的一组患者中PD的遗传基础和临床特征。以前不包括在基因筛查中的特殊地理区域。
方法：使用NGS多基因面板，218例PD患者根据发病年龄进行了测试，家族史和发展的非典型特征。
结果：在103例患者中发现了133种遗传变异。在43例患者（占队列的20％）中诊断出单基因PD；28例（12.8％）携带GBA1突变，10例LRRK2（4.6％）和5例PRKN（2.3％）。在17％的患者中，遗传缺陷仍不确定。选择标准“发病年龄<55岁”是遗传测试阳性的重要预测因子（OR3.8，p0.0037）。与阴性患者相比，GBA1患者表现出更严重的症状和更高的运动和非运动并发症负担（运动障碍OR3，睡眠障碍OR2.8，认知障碍OR3.6;p<0.05），自主神经功能障碍更大（COMPASS-31评分34.1vs20.2，p0.03）。
结论：应用简单的临床标准进行基因检测可以提高识别单基因PD患者的概率，并更好地分配资源。这个过程对于扩大对疾病机制的理解并增加可能从未来疾病修饰疗法中受益的患者的个性化至关重要。
方法：使用NGS多基因面板，218例PD患者根据发病年龄进行了测试，家族史和发展的非典型特征。
结果：在103例患者中发现了133种遗传变异。在43例患者（占队列的20％）中诊断出单基因PD；28例（12.8％）携带GBA1突变，10例LRRK2（4.6％）和5例PRKN（2.3％）。在17％的患者中，遗传缺陷仍不确定。选择标准“发病年龄<55岁”是遗传测试阳性的重要预测因子（OR3.8，p0.0037）。与阴性患者相比，GBA1患者表现出更严重的症状和更高的运动和非运动并发症负担（运动障碍OR3，睡眠障碍OR2.8，认知障碍OR3.6;p<0.05），自主神经功能障碍更大（COMPASS-31评分34.1vs20.2，p0.03）。
结论：应用简单的临床标准进行基因检测可以提高识别单基因PD患者的概率，并更好地分配资源。这个过程对于扩大对疾病机制的理解并增加可能从未来疾病修饰疗法中受益的患者的个性化至关重要。
