Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily affecting dopaminergic neurons in the mesencephalon. With rising global incidence, especially in individuals over 60, PD presents with motor and non-motor symptoms. While monogenic forms account for a subset of cases, genetic heterogeneity and variable expressivity complicate diagnosis and management. This study aimed to evaluate the genetic profile of a Turkish PD cohort through clinical exome sequencing (CES), assess genotype-phenotype correlations, and identify structural rearrangements. A retrospective analysis was conducted on 137 patients diagnosed with Parkinson's disease according to the Movement Disorder Society (MDS) clinical diagnostic criteria. Targeted next-generation sequencing (NGS) analysis was performed, and identified genetic variants were strictly classified in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines and current gene-disease validity consensus. Copy number variations (CNVs) were assessed utilizing NGS read-depth algorithms. Following rigorous evaluation according to ACMG criteria and current gene-disease validity consensus, definitive disease-causing variants explaining the PD phenotype were identified in 10 patients (7.30%). This definitive diagnostic yield was driven entirely by established PD loci: GBA1 (9 patients) and a homozygous deletion in PRKN (1 patient). Beyond this definitive group, several notable variants in OMIM-associated PD genes (including LRRK2, FBXO7, PARK7, and EIF4G1) were characterized as VUS or susceptibility findings, displaying strong clinical correlations with progressive motor and complex phenotypes. A monoallelic PINK1 variant and findings in GIGYF2 and UCHL1 were strictly excluded from the causal diagnostic yield. A novel heterozygous duplication involving LRRK2 exons 6-20 was also identified; however, as it likely results in a loss of function, its pathogenicity remains uncertain under dominant gain-of-function models. Clinical exome sequencing effectively delineates the complex genetic landscape of PD in the Turkish population. While the definitive diagnostic rate is 7.30% under strict causal criteria, the characterization of prominent VUS in OMIM-associated genes and a novel LRRK2 structural variant undetected by routine MLPA highlights the evolving complexity of PD genetics and the critical need for integrating comprehensive, read-depth-based CNV analysis into standard pipelines.