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Genetic analysis of Mendelian mutations in a large UK population-based Parkinson’s disease study

Research output: Contribution to journalArticle

Original languageEnglish
DateAccepted/In press - 28 Apr 2019


Our objective was to define the prevalence and clinical features of genetic Parkinson’s disease in a large UK population-based cohort, the largest multicentre prospective clinico-genetic incident study in the world. We collected demographic data, Movement Disorder Society Parkinson’s Disease Rating Scale scores, and Montreal Cognitive Assessment scores. We analysed mutations in PRKN (parkin), PINK1, LRRK2 and SNCA in relation to age at symptom onset, family history and clinical features.

2,262 participants were recruited to the Tracking Parkinson’s study. 424 had young-onset Parkinson’s disease (age at onset ≤ 50) and 1,799 had late onset Parkinson’s disease. 2005 patients were genotyped with a range of methods. 302 young-onset patients were fully genotyped with Multiplex Ligation-dependent Probe Amplification and either Sanger and/or exome sequencing. 1701 late-onset patients were genotyped with the LRRK2 ‘Kompetitive’ allele-specific polymerase chain reaction assay and/or exome sequencing. We identified 29 (1.4%) patients carrying pathogenic mutations. 18 patients carried the G2019S or R1441C mutations in LRRK2, and one patient carried a heterozygous duplication in SNCA. In PRKN, we identified patients carrying deletions of exons 1, 4 and 5, P113Xfs, R275W, G430D and R33X. In PINK1, 2 patients carried deletions in exon 1 and 5, and the W90Xfs point mutation.

Eighteen percent of patients with age at onset ≤ 30 and 7.4% of patients from large dominant families carried pathogenic Mendelian gene mutations. Of all young-onset patients, 10 (3.3%) carried bi-allelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried a SNCA duplication. There is a significant burden of LRRK2 G2019S in patients with both apparently sporadic and familial disease. In young-onset patients, dominant and recessive mutations were equally common. There were no differences in clinical features between LRRK2 carriers and non-carriers. However, we did find that PRKN and PINK1 mutation carriers have distinctive clinical features compared to early onset non-carriers, with more postural symptoms at diagnosis and less cognitive impairment, after adjusting for age and disease duration. This supports the idea that there is a distinct clinical profile of PRKN and PINK1-related Parkinson’s disease.

We estimate that there are approaching 1000 patients with a known genetic aetiology in the UK Parkinson’s disease population. A small but significant number of patients carry causal variants in LRRK2, SNCA, PRKN and PINK1 that could potentially be targeted by new therapies, such as LRRK2 inhibitors.

    Research areas

  • Parkinson’s disease, genetics, phenotype, heterogeneity, prevalence



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