Objective: To explore the diagnostic yield of a large PD-targeted panel that contains 85 genes in a Taiwanese cohort of young-onset and familial PD.

Background: Approximately 5-10% of Parkinson’s disease (PD) cases are attributed to genetic causes. Recent advancements in genetic analysis techniques and cost reductions have resulted in the discovery of numerous novel PD-causing genes, some validated and others pending confirmation. Targeted genetic panels offer advantages such as precise and efficient analysis focused on a particular condition and cost-effectiveness. However, they have the limitation of difficulty detecting novel variants or structural variations.

Method: Patients with young-onset (≤ 55 years old) (YOPD) or familial Parkinsonism (FPD) were enrolled from the movement disorders clinic at Taipei Veterans General Hospital. We designed a targeted gene panel that contains 85 genes to include confirmed PD genes, previously reported but unvalidated genes, and genes related to disorders that usually present with other phenotypes but can have prominent Parkinsonism. We utilized Human Mutation Database (HGMD) Professional to identify pathogenic genetic variants and ACMG guidelines to confirm the pathogenicity of the variants.

Results: Genetic analysis was performed on 143 patients (81 YOPD, 78 FPD). Eight heterozygous pathogenic mutations according to the HGMD were found in 10 patients ( DNAJC13(Arg1382His), EIF4G1(Pro1036Ser), GIGYF2(Ile278Val), LRP10(Gln581His), KCND3(Arg431His), POLG(Arg964Cys), POLG (Arg562Gln), and VPS35 (Ala320Val)). However, when applying the ACMG guidelines, six variants were classified as benign or likely benign, and two as variants of unknown significance. On the other hand, 13 patients were found to carry one of the two risk variants in LRRK2 (R1628P or G2385R), and 7 patients with GBA variants (A495P, A448H, A419Y, A316C, L303I, G241A).

Conclusion: Increasing the genetic targets in the targeted panel does not increase diagnostic yield for YOPD and FPD. One possible explanation is that copy number variations are more common in young-onset PD. Conversely, due to the rarity of autosomal dominant PD and the continually expanding list of genes associated with PD, whole exome sequencing might be a more suitable option when seeking both established and new genes for patients with a strong family history.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/diagnosing-young-onset-and-familial-parkinsons-disease-using-an-extensive-targeted-panel/