The Parkinson’s Families Project is a UK-wide study aimed at identifying genetic variation associated with familial and early-onset Parkinson’s disease (PD). We recruited individuals with a clinical diagnosis of PD and age at motor symptom onset ≤45 years and/or a family history of PD in up to third-degree relatives. Where possible, we also recruited affected and unaffected relatives. We analysed DNA samples with a combination of single nucleotide polymorphism (SNP) array genotyping, multiplex ligation-dependent probe amplification (MLPA), and whole-genome sequencing (WGS). We investigated the association between identified pathogenic mutations and demographic and clinical factors such as age at motor symptom onset, family history, motor symptoms (MDS-UPDRS) and cognitive performance (MoCA). We performed baseline genetic analysis in 718 families, of which 205 had sporadic early-onset PD (sEOPD), 113 had familial early-onset PD (fEOPD), and 400 had late-onset familial PD (fLOPD). 69 (9.6%) of these families carried pathogenic variants in known monogenic PD-related genes. The rate of a molecular diagnosis increased to 28.1% in PD with motor onset ≤35 years. We identified pathogenic variants in LRRK2 in 4.2% of families, and biallelic pathogenic variants in PRKN in 3.6% of families. We also identified two families with SNCA duplications and three families with a pathogenic repeat expansion in ATXN2, as well as single families with pathogenic variants in VCP, PINK1, PNPLA6, PLA2G6, SPG7, GCH1, and RAB32. An additional 73 (10.2%) families were carriers of at least one pathogenic or risk GBA1 variant. Most early-onset and familial PD cases do not have a known genetic cause, indicating that there are likely to be further monogenic causes for PD.

帕金森病家庭项目是一项英国范围的研究，旨在确定与家族性和早发性帕金森病 （PD） 相关的遗传变异。我们招募了临床诊断为 PD 且运动症状发作年龄为 ≤45 岁和/或最高三级亲属有 PD 家族史的个体。在可能的情况下，我们还招募了受影响和未受影响的亲属。我们结合单核苷酸多态性 （SNP） 阵列基因分型、多重连接依赖性探针扩增 （MLPA） 和全基因组测序 （WGS） 分析了 DNA 样本。我们调查了已识别的致病突变与人口统计学和临床因素之间的关联，例如运动症状发作的年龄、家族史、运动症状 （MDS-UPDRS） 和认知表现 （MoCA）。我们对 718 个家系进行了基线遗传学分析，其中 205 个家系为散发性早发性 PD （sEOPD），113 个为家族性早发性 PD （fEOPD），400 个为晚发性家族性 PD （fLOPD）。这些家族中有 69 个 （9.6%） 在已知的单基因 PD 相关基因中携带致病性变异。运动发作 ≤ 35 岁的 PD 分子诊断率增加到 28.1%。我们在 4.2% 的家系中发现了 LRRK2 中的致病性变异，在 3.6% 的家系中发现了 PRKN 中的双等位基因致病性变异。我们还鉴定了 2 个具有 SNCA 重复的家族和 3 个在 ATXN2 中具有致病性重复扩增的家族，以及在 VCP 、 PINK1 、 PNPLA6 、 PLA2G6 、 SPG7 、 GCH1 和 RAB32 中具有致病性变异的单个家族。另有 73 个 （10.2%） 家庭是至少一种致病性或风险 GBA1 变异的携带者。 大多数早发性和家族性 PD 病例没有已知的遗传原因，这表明 PD 可能还有更多的单基因原因。