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

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Biallelic mutations in the PRKN gene are a frequent cause of early-onset Parkinson's disease (EOPD).
• Structural variants, alongside single nucleotide variants, significantly contribute to the PRKN mutational landscape.
• A notable proportion of EOPD cases remain genetically undiagnosed by current methods.

Purpose of the Study:

• To identify complex genetic alterations at the PRKN locus in EOPD patients.
• To investigate cases negative for Mendelian PD genes via clinical exome sequencing (CES) and multiplex ligation-dependent probe amplification (MLPA).
• To utilize short-read whole genome sequencing (sr-WGS) for uncovering elusive genetic variations.

Main Methods:

• Evaluated 498 unrelated EOPD patients negative for mutations by standard genetic tests using sr-WGS.
• Employed long-read whole genome sequencing (lr-WGS) for in-depth analysis and validation of complex variants.
• Interrogated the Parkinson's Progression Markers Initiative (PPMI) dataset to assess variant prevalence.

Main Results:

• sr-WGS identified compound heterozygous structural variations (overlapping deletions/duplications) in the PRKN gene in three EOPD cases.
• In familial cases, these biallelic PRKN structural variants co-segregated with the disease.
• lr-WGS precisely resolved variant structures; similar variants were not found in the PPMI database, indicating rarity.

Conclusions:

• Described a rare configuration of compound heterozygous structural variations at the PRKN locus.
• These complex variants are challenging to detect using standard diagnostic genetic technologies.
• Emphasized the importance of integrating whole genome sequencing (WGS) into clinical diagnostics for EOPD.