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

Abstract

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 Unified 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. Of the 2262 participants recruited to the Tracking Parkinson’s study, 424 had young-onset Parkinson’s disease (age at onset ≤ 50) and 1799 had late onset Parkinson’s disease. A range of methods were used to genotype 2005 patients: 302 young-onset patients were fully genotyped with multiplex ligation-dependent probe amplification and either Sanger and/or exome sequencing; and 1701 late-onset patients were genotyped with the LRRK2 ‘Kompetitive’ allele-specific polymerase chain reaction assay and/or exome sequencing (two patients had missing age at onset). We identified 29 (1.4%) patients carrying pathogenic mutations. Eighteen 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, and P113Xfs, R275W, G430D and R33X. In PINK1, two patients carried deletions in exon 1 and 5, and the W90Xfs point mutation. Eighteen per cent 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 biallelic mutations in PRKN or PINK1. Across the whole cohort, 18 patients (0.9%) carried pathogenic LRRK2 mutations and one (0.05%) carried an 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 young-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.

Replication‐Based Rearrangements Are a Common Mechanism for SNCA Duplication in Parkinson's Disease

“…However, whole‐gene multiplications had been more frequently detected than the single‐nucleotide variants (SNVs). It has been reported that multiplications of SNCA are observed in around 0.05% of European PD patient populations . Other genes related to hereditary forms of PD have copy number variations (CNVs) demonstrating the role of loss of function .…”

Ansätze zur Etablierung von Präzisionsmedizin bei der Parkinson-Krankheit mit dem Schwerpunkt Genetik

“…Der Anteil der Patienten mit monogenetischen Formen aufgrund bekannter Mutationen wird auf bis zu 10% geschätzt [31], kann aber in Abhängigkeit der Population selbst für eine spezifische Mutation, z.B. G2019 S-Mutation im LRRK2-Gen, bis zu 30% betragen [32].…”

Clinical Phenotype of <b><i>LRRK2</i></b> R1441C in 2 Chinese Sisters

“…Other causative autosomal dominant LRRK2 mutations (e.g., involving substitution of Arginine at position 1,441 with cysteine, glycine, or histidine) appear to be rare worldwide, with the exception of the R1441G mutation underlying a large proportion of familial PD cases in the Spanish Basque population [4,9]. Only 2 Asian cases of R1441C PARK-LRRK2 have been reported previously [10][11][12][13][14], and further study is needed as many under-represented populations have not been tested [6,15,16].…”