Bi-allelic pathogenic variants in PRKN are the most common cause of autosomal recessive Parkinson’s disease (PD). 647 patients with PRKN-PD were included in this international study. The pathogenic variants present were characterised and investigated for their effect on phenotype. Clinical features and progression of PRKN-PD was also assessed. Among 133 variants in index cases (n = 582), there were 58 (43.6%) structural variants, 34 (25.6%) missense, 20 (15%) frameshift, 10 splice site (7.5%%), 9 (6.8%) nonsense and 2 (1.5%) indels. The most frequent variant overall was an exon 3 deletion (n = 145, 12.3%), followed by the p.R275W substitution (n = 117, 10%). Exon3, RING0 protein domain and the ubiquitin-like protein domain were mutational hotspots with 31%, 35.4% and 31.7% of index cases presenting mutations in these regions respectively. The presence of a frameshift or structural variant was associated with a 3.4 ± 1.6 years or a 4.7 ± 1.6 years earlier age at onset of PRKN-PD respectively (p < 0.05). Furthermore, variants located in the N-terminus of the protein, a region enriched with frameshift variants, were associated with an earlier age at onset. The phenotype of PRKN-PD was characterised by slow motor progression, preserved cognition, an excellent motor response to levodopa therapy and later development of motor complications compared to early-onset PD. Non-motor symptoms were however common in PRKN-PD. Our findings on the relationship between the type of variant in PRKN and the phenotype of the disease may have implications for both genetic counselling and the design of precision clinical trials.

PRKN的双等位基因致病变异是常染色体隐性遗传帕金森病 (PD) 的最常见原因。这项国际研究纳入了 647 名PRKN -PD 患者。对存在的致病变异进行了表征并研究了它们对表型的影响。还评估了PRKN -PD 的临床特征和进展。在索引病例的 133 个变异中（ n = 582），有 58 个（43.6%）结构变异，34 个（25.6%）错义，20 个（15%）移码，10 个剪接位点（7.5%%），9 个（6.8%）废话和 2 (1.5%) 个插入缺失。总体而言，最常见的变异是外显子 3 缺失（ n = 145，12.3%），其次是 p.R275W 替换（ n = 117，10%）。 Exon3、RING0蛋白结构域和泛素样蛋白结构域是突变热点，分别有31%、35.4%和31.7%的病例在这些区域出现突变。移码或结构变异的存在分别与PRKN -PD 发病年龄提前 3.4 ± 1.6 岁或 4.7 ± 1.6 岁相关（ p < 0.05）。此外，位于蛋白质 N 末端的变异（富含移码变异的区域）与发病年龄较早有关。与早发性 PD 相比， PRKN -PD 的表型特点是运动进展缓慢、认知能力保留、对左旋多巴治疗的良好运动反应以及较晚发生运动并发症。然而，非运动症状在PRKN -PD 中很常见。我们关于PRKN变异类型与疾病表型之间关系的发现可能对遗传咨询和精准临床试验的设计具有影响。