Compound Heterozygous Structural Variants in Cases with Unsolved PRKN-Associated Parkinson's Disease

Biallelic mutations in the PRKN gene are a common cause of early-onset Parkinson's disease (EOPD). In addition to single nucleotide variants, structural variants contribute substantially to the mutational profile of PRKN. A significant portion of patients with EOPD remains genetically unsolved.

By using short-read whole genome sequencing (sr-WGS), we aimed to uncover complex genetic alterations at the PRKN locus in EOPD cases which tested negative for mutations in Mendelian PD genes with clinical exome sequencing (CES) and multiplex ligation-dependent probe amplification (MLPA).

We evaluated 498 unrelated EOPD patients, who tested negative using gold-standard diagnostic methods, using sr-WGS. In selected cases, long-read whole genome sequencing (lr-WGS) with Oxford Nanopore technology was employed for an in-depth analysis and validation. The Parkinson's Progression Markers Initiative (PPMI) dataset was interrogated to assess the prevalence of any newly identified elusive pathogenic genetic configurations.

sr-WGS revealed elusive compound heterozygous structural variations, consisting of partially overlapping deletions and duplications within the PRKN gene in three unrelated EOPD cases (two familial, one sporadic). In familial cases, biallelic PRKN structural variants co-segregated with the disease. The exact structure of each variant was resolved using lr-WGS. Similar variants were absent in the large PPMI database, suggesting that they are a rare occurrence.

In this article we describe a rare configuration of compound heterozygous structural variations involving partially overlapping chromosomal regions at the PRKN locus, which are difficult to detect through standard diagnostic genetic technologies. This study highlights the importance of integrating WGS into clinical practice. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.