Objective: This study aims to better investigating the pathogenetic of PD and improving the diagnostic approach in the molecular genetics, using the NGS.

Background: Parkinson’s disease (PD) is the second most common neurodegenerative disease, with an incidence of 1% at the age 65 and 5% at the age 85, and with a ratio that is 1.5 higher among men than women. It is an age related complex disease with interplay between environmental and genetics factors. Mendelian inheritance pattern represent 5 -10% of PD cases (familial PD) while the remaining 90-95% cases are considered sporadic PD. Today, thanks to the molecular genetics advancess, we account 28 distinct chromosomal regions related to the disorder with 6 genes who conclusively cause monogenic PD. The identification of the shared genetic defects between the familial and the sporadic PD was a breakthrough to elucidating the molecular pathogenesis of the disorder, improving its differential diagnosis and discussing new therapeutic approaches.

Method: 15 PD patients from the Neuromed-IRCCS clinic were selected, they had different PD phenotypes and different age-onset. During this study we performed a direct diagnosis using novel technologies for genetic testing for PD. MLPA was performed for copy number variations detection in 10 genes. Then, targeted NGS was performed to screening 13 genes for the patients who had negative MLPA test. Finally, automated sequencing using Sanger method was perfored to confirm suspicious variants detected by NGS.

Results: The molecular diagnosis is confirmed for 9 patients and excluded for 6. We detected different mutations in 5 different PD-related genes (LRRK2, PARKN, PINK1, VPS35 and GBA). NGS identified 1 risk factor variant in GBA, 2 potentially pathogenic variants in LRRK2, 2 variants in PINK1 reported to be pathogenic in an Italian patient in a different study, and 1 potentially pathogenic variant in VPS35). Our results show the complexity and diversity of the PD phenotypes and the contribution of the genetic tests (MLPA and NGS) used in our study as they helped provide accurate information in a short time; Thus, helping better taking care of the patients by providing an earlier and more specific diagnosis.

Conclusion: The substantial progress made by investigating the Mendelian inheritance pattern among PD patients provided us with key discoveries to better understand PD, improve its diagnosis and patients management.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/the-application-of-next-generation-sequencing-in-the-parkinson-disease/