Objective: Identify unrevealed variants in PRKN and PINK1 genes from young onset Parkinson’s disease (YOPD) patients.

Background: Long-read sequencing has identified pathogenic repeats and structural variants in various diseases. However, it has not been widely applied to Parkinson’s disease (PD). PRKN and PINK1 are the most frequently causative genes for young onset autosomal recessive PD and are known to have structural variants. However, there are large numbers of young onset PD (YOPD) patients who are still genetically unresolved. We recently identified a large inversion in PRKN using long-read sequencing in an early onset PD family. Following this case, we hypothesized that some YOPD patients with heterozygous variants of PRKN or PINK1 gene will likely have complex structural variants in the PRKN or PINK1 gene as an unrevealed second damaging variant which is difficult to identify using short-read sequencing.  Therefore, we applied long-read sequencing to a cohort of YOPD with one PRKN/PINK1 variant.

Method: Patients with YOPD, identified by an onset age younger than 50 years, underwent genetic screening for causative variants in PD-related genes. This screening utilized short-read sequencing, Sanger sequencing, and multiplex ligation-dependent probe amplification techniques. Only YOPD subjects who harbored heterozygous variants in either the PRKN or PINK1 genes, without any other known causative variants in PD-related genes, were subsequently subjected to long-read sequencing.

Results: In this study, we included 23 patients carrying a single variant in the PRKN gene and 12 patients with a single variant in the PINK1 gene. Long-read sequencing revealed a second variant in the PRKN gene in 26% (6/23)  of the YOPD subjects who initially presented with a single heterozygous PRKN variant. However, no pathogenic structural variants were detected in subjects carrying a single heterozygous PINK1 variant.

Conclusion: Long-read sequencing has proven to be a good technique to identify a second causative variant in YOPD patients initially found to carry only one variant in autosomal recessive PD genes. We are currently broadening our analysis to encompass a more diverse and larger population. This technique is expected to become a key tool in the diagnosis of YOPD, offering more comprehensive genetic insights.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/long-read-sequencing-to-identify-unrevealed-second-hit-in-autosomal-recessive-parkinsons-disease/