The Role of Genetic Testing in the Clinical Practice and Research of Early-Onset Parkinsonian Disorders in a Hungarian Cohort: Increasing Challenge in Genetic Counselling, Improving Chances in Stratification for Clinical Trials

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.

Over-Mutated Mitochondrial, Lysosomal and TFEB-Regulated Genes in Parkinson’s Disease

“…It is also interesting to highlight that two out of the three heterozygous carriers of PRKN mutations and three out of the six carriers of ATP7B variants had an early onset presentation of the disease, being diagnosed before 50 years of age ( Supplementary Table S1 ). These data are in agreement with previous observations [ 38 , 39 , 40 ].…”

Look Alike, Sound Alike: Phenocopies in Steroid-Resistant Nephrotic Syndrome

“…Parkinson’s disease shows a clear Mendelian inheritance pattern and familial aggregation in about 3–10% of cases [ 52 ]. More than 20 disease-segregating genes or loci causing Parkinson’s disease have been identified so far, with SNCA , LRRK2 , Parkin and PINK1 representing the most frequently involved [ 53 , 54 ]. However, inheritance patterns do not always follow classic Mendelian genetics and incomplete penetrance and variable disease expressivity are common among affected family members of a pedigree.…”

Age Cutoff for Early‐Onset Parkinson's Disease: Recommendations from the International Parkinson and Movement Disorder Society Task Force on Early Onset Parkinson's Disease

“…Czech Republic 40-45 [32][33][34] Finland 55 21 Germany 50 35 Greece 50 Hungary 50 36 Iceland 50 37 Ireland 50 38 Italy 40-50 22,39 Kazakhstan 50 40 Luxembourg 50 41 Netherlands 40-50 18 Norway 45 42 Poland 40 43 Portugal 50 44 Russia 40 45,46 Serbia 50 47 Slovakia 40 48,49 Spain 50 50 Sweden 50 51 United Kingdom 40-50 11 Americas Argentina 40 52 Brazil 20-45 53,54 Canada 40 55 Colombia 50 56 Ecuador 50 56 Mexico 45 57 United States 40-55 14,15,17,25 Asia-Pacific Middle East, North Africa, and South Asia: consensus from the MDS Task Force for the Middle East 50 58 Australia 50 59 China 40 60 (Continues) Guam 51 61 India 40-50 [62][63][64] New Zealand 60 65 South Korea 40-50 66 Vietnam 50 67 Japan 40-50 28 Africa Morocco 45 68 Nigeria 50…”