Abstract
The genetic analysis of early-onset Parkinsonian disorder (EOPD) is part of the clinical diagnostics. Several genes have been implicated in the genetic background of Parkinsonism, which is clinically indistinguishable from idiopathic Parkinson’s disease. The identification of patient’s genotype could support clinical decision-making process and also track and analyse outcomes in a comprehensive fashion. The aim of our study was to analyse the genetic background of EOPD in a Hungarian cohort and to evaluate the clinical usefulness of different genetic investigations. The age of onset was between 25 and 50 years. To identify genetic alterations, multiplex ligation-dependent probe amplification (n = 142), Sanger sequencing of the most common PD-associated genes (n = 142), and next-generation sequencing (n = 54) of 127 genes which were previously associated to neurodegenerative disorders were carried out. The genetic analysis identified several heterozygous damaging substitutions in PD-associated genes (C19orf12, DNAJC6, DNAJC13, EIF4G1, LRRK2, PRKN, PINK1, PLA2G6, SYNJ1). CNVs in PRKN and SNCA genes were found in five patients. In our cohort, nine previously published genetic risk factors were detected in three genes (GBA, LRRK2, and PINK1). In nine cases, two or three coexisting pathogenic mutations and risk variants were identified. Advances of sequencing technologies make it possible to aid diagnostics of PD by widening the scope of analysis to genes which were previously linked to other neurodegenerative disorders. Our data suggested that rare damaging variants are enriched versus neutral variants, among PD patients in the Hungarian population, which raise the possibility of an oligogenic effect. Heterozygous mutations of multiple recessive genes involved in the same pathway may perturb the molecular process linked to PD pathogenesis. Comprehensive genetic assessment of individual patients can rarely reveal monogenic cause in EOPD, although it may identify the involvement of multiple PD-associated genes in the background of the disease and may facilitate the better understanding of clinically distinct phenocopies. Due to the genetic complexity of the disease, genetic counselling and management is getting more challenging. Clinical geneticist should be prepared for counselling of patients with coexisting disease-causing mutations and susceptibility factors. At the same time, genomic-based stratification has increasing importance in future clinical trials.
Highlights
Parkinsonian disorders are a group of progressive neurodegenerative movement disorders, in which pathogenesis both genetic and environmental factors play a role
Our study involved 142 Hungarian patients, who were diagnosed with early-onset Parkinsonism based on Movement Disorder Society (MDS) criteria (Postuma et al, 2015)
The identified variants were classified into four groups: (1) rare damaging mutations in Parkinsonian disorders (PDs)-associated genes, potentially compatible with a monogenic PDs; (2) previously reported genetic risk variants of PD; (3) multiple-hit mechanism impacting the risk of PD; (4) single heterozygous mutations in autosomal recessive form of PD (AR-PD)-associated genes
Summary
Parkinsonian disorders are a group of progressive neurodegenerative movement disorders, in which pathogenesis both genetic and environmental factors play a role. The differential diagnosis of Parkinsonism from common idiopathic Parkinson's disease generally stands challenges for clinicians, because of heterogeneous phenotypes (motor and nonmotor symptoms), related comorbidities, and the absence of specific biomarkers (Klein and Schlossmacher, 2006). Several genes were linked to different PD phenotypes, which may provide a new possible tool for clinicians to distinguish the specific patterns of symptoms or disease course. It is important to emphasise that, even the similar involvement of these disease-genes, the clinical phenotype can be variable, it differs considerably from that of idiopathic PD (Klein, 2005). Other movement disorders can sometimes mimic PD phenotype, which could make more difficult to set up the proper diagnosis without an effective aid by biomarkers
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