Dataset Information

A genetic analysis of a Spanish population with early onset Parkinson's disease.

ABSTRACT:

Introduction

Both recessive and dominant genetic forms of Parkinson's disease have been described. The aim of this study was to assess the contribution of several genes to the pathophysiology of early onset Parkinson's disease in a cohort from central Spain.

Methods/patients

We analyzed a cohort of 117 unrelated patients with early onset Parkinson's disease using a pipeline, based on a combination of a next-generation sequencing panel of 17 genes previously related with Parkinson's disease and other Parkinsonisms and CNV screening.

Results

Twenty-six patients (22.22%) carried likely pathogenic variants in PARK2, LRRK2, PINK1, or GBA. The gene most frequently mutated was PARK2, and p.Asn52Metfs*29 was the most common variation in this gene. Pathogenic variants were not observed in genes SNCA, FBXO7, PARK7, HTRA2, DNAJC6, PLA2G6, and UCHL1. Co-occurrence of pathogenic variants involving two genes was observed in ATP13A2 and PARK2 genes, as well as LRRK2 and GIGYF2 genes.

Conclusions

Our results contribute to the understanding of the genetic architecture associated with early onset Parkinson's disease, showing both PARK2 and LRRK2 play an important role in Spanish Parkinson's disease patients. Rare variants in ATP13A2 and GIGYF2 may contribute to PD risk. However, a large proportion of genetic components remains unknown. This study might contribute to genetic diagnosis and counseling for families with early onset Parkinson's disease.

SUBMITTER: Cristina TP

PROVIDER: S-EPMC7462269 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundGenetic factors play an important role in the pathogenesis of early-onset Parkinson's disease (EOPD). To date, more than 20 pathogenic genes associated with Parkinson's disease (PD) have been identified. This study aims to explore the mutation spectrum of EOPD and the clinical characteristics of mutation carriers in eastern China.MethodsWe recruited 155 unrelated EOPD patients, including 8 familial and 147 sporadic EOPD (age at onset ≤ 50 years). Overall, 24 known PD-associated genes were detected by whole exome sequencing and multiplex ligation-dependent probe amplification (MLPA) from patient samples. The genetic and clinical characteristics of pathogenic/likely pathogenic (P/LP) loci in this cohort were analyzed.ResultsOverall, 14 (9.03%) patients were detected with P/LP variants distributed in seven genes. The most frequent mutation occurred in PRKN (7/155, 4.52%), followed by LRRK2 (2/155, 1.29%), SNCA, CHCHD2, TMEM230, DNAJC13 and PLA2G6 (1/155, 0.64%, respectively). Exon rearrangement mutations accounted for 57.9% (11/19) of all mutations in PRKN. Four novel variants were detected: c.14T > C (p.M5T) in SNCA, c.297C > A (p.Y99X) in CHCHD2, c.2578C > T (p.R860C) in DNAJC13 and c.4C > T (p.Q2X) in TMEM230. We found the first case of LRRK2 c.6055G > A (p.G2019S) mutation in Chinese population. The median onset age of patients with P/LP mutations in autosomal recessive genes (PRKN and PLA2G6) was about 18.0 years earlier than patients without mutation. The proportion of patients with mutations were 63.64%, 27.03% and 9.68% when patients were stratified according to the age of onset at ≤ 30, ≤ 40 and ≤ 50 years, respectively.ConclusionEarly-onset Parkinson's disease patients from eastern China present a regional specific mutation spectrum. Analysis of larger patient cohorts is required to support these findings, and mechanistic studies of the four novel missense/non-sense mutations will clarify their role in the pathogenicity of EOPD.