Parkinson’s Disease Variant Detection and Disclosure: Comprehensive Report

Background

Parkinson’s Disease (PD) is a progressive neurodegenerative disorder primarily characterized by motor dysfunction and non-motor symptoms. Research has shown that at least seven genes (LRRK2, GBA1, PRKN, SNCA, PINK1, PARK7, VPS35) are directly related to the occurrence of Parkinson’s disease. However, due to the lack of corresponding genetic testing in clinical practice, many Parkinson’s disease patients remain unaware of their genetic status. This not only affects the implementation of personalized medicine but also leads to low participation rates in gene mutation-targeted drug research. Therefore, understanding the output of gene panel-based genetic testing in a broad population in North America helps patients, clinicians, researchers, and insurance companies better grasp the importance of genetics in Parkinson’s disease treatment.

Paper Source and Author Introduction

This study was conducted through multi-institutional collaboration, involving multiple medical and genetic research institutions in the United States and Canada. The main authors include Lola Cook, Jennifer Verbrugge, Tae-Hwi Schwantes-An, and others, with research institutions including Indiana University School of Medicine, Parkinson’s Foundation, Columbia University Irving Medical Center, etc. The paper was published in the journal “Brain” and was available online ahead of print on July 30, 2024.

Research Design and Methods

Research Process

This study is a multi-center, observational study aimed at providing genetic testing, result feedback, and genetic counseling services for Parkinson’s disease patients. The research was divided into three phases:

1. Pilot Phase: Verify the feasibility of the study and record participant and provider satisfaction with the testing process.
2. Clinical Phase: Expand to multiple clinical centers and collect detailed clinical data.
3. Registry Phase: Streamline the protocol to further increase geographic, ethnic, and cultural diversity.

Study Subjects and Samples

Participants had to meet the following criteria: meet the clinical diagnostic criteria for Parkinson’s disease, be at least 18 years old, be able to provide informed consent in English or Spanish, and complete study activities. The study included 10,510 participants from over 85 centers in the United States (including Puerto Rico), Canada, and the Dominican Republic. Subjects participated through on-site or remote self-registration. Genetic testing was conducted by the certified laboratory Fulgent Genetics, covering targeted testing of seven major Parkinson’s disease-related genes.

Experimental Methods

Genetic testing used Next-Generation Sequencing (NGS) technology, including genomic DNA preparation, library construction, hybrid capture enrichment, Illumina platform sequencing, data analysis, and variant detection. Sanger sequencing and quantitative PCR (qPCR) were used for validation in specific cases. Data analysis used Fulgent Genetics’ bioinformatics pipeline.

Data Processing and Variant Interpretation

Variant detection and interpretation followed the guidelines of the American College of Medical Genetics and Genomics (ACMG). Reportable variants included pathogenic (P) and likely pathogenic (LP) variants, while variants of uncertain significance (VUS) were not reported to clinicians and participants.

Research Results

Overall Results

Between September 2019 and June 2023, 8,301 participants completed genetic testing and received results. Reportable genetic variants were found in 13% of participants, with this proportion being 18% in high-risk populations and 9.1% in populations without high-risk factors. Among all tested genes, GBA1 variants were the most common (7.7%), followed by LRRK2 (2.4%) and PRKN (2.1%).

Detailed Results

1. GBA1 Gene: Among risk variants, c.1093G>A (p.Glu365Lys) was the most common.
2. LRRK2 Gene: The most common variant was c.6055G>A (p.Gly2019Ser), including two homozygous variants.
3. PRKN Gene: Included multiple unique types of copy number variants (CNVs) and single nucleotide variants (SNVs).

Additionally, 34 participants (0.4%) carried variants in multiple genes simultaneously.

Subgroup Analysis

The study conducted detailed comparative analyses of different genetic backgrounds and clinical characteristics, including high-risk ancestry, early onset age, and family history. Results showed that the rate of reportable variants was significantly higher in participants with these high-risk factors.

Conclusions and Value of the Study

This study reveals the high yield of large-scale genetic testing in Parkinson’s disease patients, especially highlighting the importance of testing in patients without high-risk factors for clinical management and prognosis of Parkinson’s disease. The authors suggest expanding genetic testing to all Parkinson’s disease patients, not just high-risk populations. This strategy helps early identification of potential gene variant carriers and paves the way for personalized treatment and precision medicine.

Research Highlights

1. Broad Geographic and Population Coverage: Covering a wide population across North America and the Caribbean, providing a highly representative study sample.
2. Rich Data Analysis: Detailed discussion of various gene variants and their clinical relevance, including relationships with Parkinson’s disease onset age, disease course, gender ratio, and other factors.
3. Achieving Barrier-Free Genetic Testing: Eliminating concerns and barriers for patients and clinicians by providing free genetic testing and counseling services.

Further Work

Future research will continue to focus on recruiting more underrepresented groups, such as African and Latino populations. At the same time, further exploration and analysis of Parkinson’s disease gene variants in these populations will be conducted to comprehensively understand the genetic background and pathogenesis of Parkinson’s disease.

Conclusion

In summary, this study implemented large-scale genetic testing for Parkinson’s disease, effectively revealing the high incidence of reportable variants, proposing the importance and necessity of generalizing genetic testing, and providing a solid foundation for personalized treatment and precision medicine in Parkinson’s disease.

This paper provides important references for clinical diagnosis, prognosis, and treatment of Parkinson’s disease through the detection and analysis of related gene variants, and also lays the foundation for more gene-related research in the future.