Integrated sequencing and array comparative genomic hybridization in familial Parkinson disease

Area of Science:

• Genetics
• Neurodegenerative Diseases
• Molecular Biology

Background:

• Familial Parkinson disease (PD) presents complex genetic heterogeneity.
• Distinguishing the roles of single nucleotide variants (SNVs) and copy number variants (CNVs) is crucial for molecular diagnosis.
• Integrated genomic approaches are needed to fully characterize genetic contributions to PD.

Purpose of the Study:

• To determine the contribution of SNVs and CNVs to molecular diagnosis in familial Parkinson disease (PD).
• To integrate exome sequencing (ES) and array-based comparative genomic hybridization (aCGH) for comprehensive genetic analysis.
• To investigate CNV structure and elucidate mutational mechanisms in PD.

Main Methods:

• Performed exome sequencing (ES) on 110 subjects with familial PD.
• Utilized genome-wide array-based comparative genomic hybridization (aCGH) in 99 subjects.
• Interrogated ES and aCGH data for pathogenic SNVs and CNVs at known PD gene loci, confirmed with Sanger sequencing, droplet digital PCR, and breakpoint sequencing.

Main Results:

• Identified known pathogenic SNVs in GBA and LRRK2 genes.
• Discovered SNCA duplication and GBA deletion via aCGH.
• Found compound heterozygosity for SNVs and CNVs at the PRKN locus in five subjects, with microhomology indicating replication error-driven CNV formation.

Conclusions:

• Integrated ES and aCGH achieved a genetic diagnosis in 19.3% of the familial PD cohort.
• Highlighted potential mechanisms for SNCA and PRKN CNV formation.
• Uncovered multilocus pathogenic variation and identified novel SNVs and CNVs for future PD risk allele investigation.