January 1, 2021
Hospital: Hadassah Medical Center, Jerusalem
Medical condition: Young Onset Parkinson’s disease
The Case: Prof. Orly Elpeleg, Hagar Mor-Shaked, Ph.D. and their team have been analyzing thousands of rare genetic disorders during the last decade and strive to provide accurate diagnosis to patients and their families. With their current platform, they achieve a diagnostic yield of approximately 50%, and for the remaining undiagnosed cases, they choose to implement Geneyx Analysis. One complex case they encountered was a large family presenting with early onset Parkinson’s disease (Juvenile Parkinson), which affected several siblings born to closely related parents. The team had sent 10 samples for exome sequencing, which was the standard and most comprehensive genetic test available for clinical diagnostics. However, the results from exome sequencing were inconclusive, so they implemented whole genome sequencing on a subset of the family and analyzed the data with Geneyx.
Geneyx solution: Geneyx was adopted by this organization due to the automation of raw data processing and ability to quickly annotate whole genome sequencing data. The whole genome sequencing for this analysis was available within a few hours of uploading to the system.
Findings: Linkage analysis identified a ROH event in chromosome 6 among affected siblings, which contained the PRKN gene, that has been observed to be in association with Parkinson. Structural mutations in chromosome 6 were then analyzed with Geneyx, which identified a copy-neutral intragenic inversion of the PRKN gene. This event was not observed in the healthy sibling and was later confirmed using Sanger Sequencing to be specific to an inversion containing exon 5 of PRKN. Because it was a copy-neutral inversion event, it was missed by both exome and CNV analysis. But through implementing whole genome sequencing and Geneyx Analysis, this event was accurately detected.
Prospective value: Geneyx Analysis is an end-to-end platform that can lead to novel findings for challenging undiagnosed cases. As a result, a publication has been created, cited below, and gives insight to others in the field of Parkinson’s disease.
Hagar Mor-Shaked, et al. “Levodopa-responsive dystonia caused by biallelic PRKN exon inversion invisible to exome sequencing”. BRAIN COMMUNICATIONS: 2020;1-8.