Objective: The aim of this study was to investigate genetic variants associated with Parkinson’s disease (PD) in a cohort of PD patients from southern Spain and to assess their impact on disease phenotype by genotype-phenotype correlations.

Background: PD is a complex, heterogeneous neurodegenerative disorder with a broad spectrum of clinical manifestations. It is determined by a complex interplay of both environmental and genetic risk factors.

Method: A targeted resequencing panel approach was employed to analyze 27 genes linked to PD (ATP13A2, CHCHD2, DCTN1, DJ1, DNAJC6, DNAJC13, EIF4G1, FBXO7, GIGYF2, HTRA2, LRP10, LRRK2, PINK1, PLA2G6, POLG, PRKN, RAB39B, SMPD1, SNCA, SPR, TMEM230, SYNJ1, UCHL1, VPS13A, VPS13C, VPS35, and GBA) in a cohort of 1185 PD patients. Variants were categorized based on the international guidelines of American College of Medical Genetics and Genomics pathogenicity criteria, and demographic and clinical data were collected. Only variants conformed to the inheritance pattern of the gene were the variants considered to be potential disease-causing variants and the genetic diagnosis was considered positive.

Results: Among the analyzed patients, 13.5% carried potential disease-causing pathogenic or likely pathogenic variants in 12 different genes, indicating a significant genetic heterogeneity. LRRK2, PRKN, and GBA were the most frequently affected genes (72.1% of the positive cases). Gender-specific differences were observed, with a higher proportion of females among LRRK2-patients. Differences in age at onset and clinical features among several mutated genes were observed. Notably, variants in genes associated with atypical parkinsonism presented distinct clinical presentations, highlighting the importance of genetic factors in differential diagnosis.

Conclusion: Our study provides important information into the genetic landscape of PD and its clinical manifestations. The observed genotype-phenotype correlations and gender-specific differences emphasize the complexity of PD pathogenesis, underlining the importance of personalized approaches for diagnosis and treatment of PD. Further investigations into genetic interactions and population-specific effects are warranted to enhance our understanding of PD etiology and improve patient care.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/understanding-parkinsons-disease-in-spain-genetic-and-clinical-insights/