Genotype-phenotype correlation in PRKN-associated Parkinson's disease.

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Bi-allelic pathogenic variants in the Parkinson disease gene (PRKN) are the most frequent cause of autosomal recessive Parkinson's disease (PD).
• Understanding the spectrum of PRKN variants and their phenotypic consequences is crucial for diagnosing and managing PD patients.

Purpose of the Study:

• To characterize pathogenic variants in PRKN and investigate their association with the phenotype and progression of autosomal recessive Parkinson's disease.
• To identify mutational hotspots within the PRKN gene and their correlation with disease onset and clinical features.

Main Methods:

• International study including 647 patients with PRKN-PD.
• Characterization of pathogenic variants (structural, missense, frameshift, splice site, nonsense, indels) in PRKN.
• Assessment of clinical features, disease progression, and correlation between variant type and phenotype.

Main Results:

• Identified 133 unique pathogenic variants in 582 index cases, with structural variants and exon 3 deletions being most frequent.
• Exon3, RING0, and ubiquitin-like domains were identified as mutational hotspots.
• Frameshift or structural variants were associated with significantly earlier age at onset (3.4-4.7 years earlier).
• PRKN-PD phenotype includes slow motor progression, preserved cognition, good levodopa response, and later motor complications, with common non-motor symptoms.

Conclusions:

• The type of PRKN variant significantly influences the age at onset and clinical phenotype of autosomal recessive Parkinson's disease.
• Findings provide valuable insights for genetic counseling and the development of precision medicine approaches for PRKN-PD.