Long-Read Sequencing Resolves a Complex Structural Variant in PRKN Parkinson's Disease

Area of Science:

• Genetics
• Neuroscience
• Genomic Medicine

Background:

• Parkin RBR E3 ubiquitin-protein ligase (PRKN) mutations are the primary cause of young-onset and autosomal recessive Parkinson's disease (PD).
• The PRKN gene is located in a common fragile site (FRA6E), making it susceptible to structural variations.
• Complex structural variants, like inversions within PRKN, are rarely reported, indicating potential underdiagnosis.

Purpose of the Study:

• To identify complex structural variants, specifically inversions, within the PRKN gene using advanced long-read sequencing technology.
• To investigate the genetic underpinnings of young-onset Parkinson's disease in cases with unresolved genetic causes.

Main Methods:

• Employed a combination of targeted sequencing, whole exome sequencing, multiple ligation probe amplification, and long-read sequencing to analyze monozygotic twins with dystonia-parkinsonism.
• Utilized whole-genome sequencing data from large cohorts (UK-Biobank and AMP-PD) to assess the frequency and impact of PRKN inversions.

Main Results:

• A novel heterozygous exon 3 deletion in PRKN was detected, alongside a significant 7 Mb inversion encompassing a substantial portion of the PRKN coding sequence.
• Diagnosed affected individuals as compound heterozygous carriers of PRKN mutations.
• Identified nine potentially damaging inversions in the UK-Biobank and two in the AMP-PD dataset, likely affecting PRKN gene expression.

Conclusions:

• This research presents the first description of a large 7 Mb inversion with breakpoints located outside the PRKN gene.
• Emphasizes the critical role of long-read sequencing in uncovering complex structural variants for diagnosing unresolved young-onset Parkinson's disease cases.