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. 2020 Sep 1;15(9):e0238098.
doi: 10.1371/journal.pone.0238098. eCollection 2020.

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

Tejera-Parrado Cristina  1 , Mir Pablo  1   2 , Periñán María Teresa  1   2 , Vela-Desojo Lydia  3 , Abreu-Rodríguez Irene  1 , Alonso-Cánovas Araceli  4 , Bernal-Bernal Inmaculada  1 , Bonilla-Toribio Marta  1 , Buiza-Rueda Dolores  1   2 , Catalán-Alonso María José  5 , García-Ramos Rocío  5 , García-Ruiz Pedro José  6 , Huertas-Fernández Ismael  1 , Jesús Silvia  1   2 , Miguel A-Espinosa Labrador  1   2 , López-Manzanares Lydia  7 , Martínez-Castrillo Juan Carlos  4 , Ignacio J Posada  8 , Rojo-Sebastián Ana  9 , Ruiz-Huete Cristina  10 , Del Val Javier  6 , Pilar Gómez-Garre  1   2
Affiliations

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

Tejera-Parrado Cristina et al. PLoS One. .

Erratum in

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.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Flowchart of sequencing data analysis.
Horizontal boxes represent steps in the workflow. In silico analysis were carried out in 224 SNVs. SIFT: Sorting Intolerant From Tolerant. Polyphen-2: Polymorphism Phenotyping 2. GERP: Genomic Evolutionary Rate Profiling. CADD: Combined Annotation Dependent Depletion. RadialSVM: Radial Support Vector Machine. LR: Logistic Regresion. LRT: Likelihood Ratio Test. FATHMM: Functional Analysis Through Hidden Markov Models. GWAVA: Genome Wide Annotation of Variants. ReMM: Regulatory Mendelian Mutation. IW-score: Integrative Weighted score (with an associated p-value<0.5).
Fig 2
Fig 2. Number and distribution of detected variants in our population using a 17-gene sequencing panel.
Variants in all 17 genes were evaluated and only those described a priori as a variant of unknown significance, likely pathogenic or pathogenic, according to ACMG, are shown. Genes with variants and the variant distribution are displayed (A), and the proportions of coding and non-coding variants are shown for all genes (B).
Fig 3
Fig 3. Pie plot showing the distribution and frequencies of likely pathogenic variants found.
In our population, we identified 32 patients carrying likely pathogenic variants (A), of which more than a half presented variations in PARK2 (50%) or LRRK2 (21.88%) (B). UG: Unconfirmed genes. RF: Risk factor. SF: Susceptibility factor. N: number of subjects. n: number of carriers subjects with pathogenic variations in each gene.
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