Complementarity of Long-Reads and Optical Mapping in Parkinson's Disease for Structural Variants.
Complementarity of Long-Reads and Optical Mapping in Parkinson's Disease for Structural Variants.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Lübeck, DE · Author affiliation
Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.Location evidence
Seattle, US · Author affiliation
Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, Washington, USA.Location evidence
Bethesda, US · Author affiliation
Molecular Genetics Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.Location evidence
Tokyo, JP · Author affiliation
Department of Neurology, Faculty of Medicine, Juntendo University, Tokyo, Japan.Location evidence
Wako, JP · Author affiliation
Neurodegenerative Disorders Collaborative Laboratory, RIKEN Center for Brain Science, Wako, Japan.Location evidence
Tunis, TN · Author affiliation
Department of Neurology, National Institute of Neurology Mongi Ben Hmida, Tunis, Tunisia.Location evidence
US · Author affiliation · country only
McKnight Brain Institute, Department of Neurology, College of Medicine, University of Florida, Gainesville, Florida, USA.Location evidence
DE · Author affiliation · country only
Division Scientific IT Group, Max Planck Institute for Evolutionary Biology, Plön, Germany.Location evidence
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Original abstract
OBJECTIVE: Long-read sequencing and optical genome mapping technologies have the ability to detect large and complex structural variants. This has led to the discovery of novel pathogenic variants in neurodegenerative movement disorders. Thus, we aimed to systematically compare the SV detection capabilities of OGM and ONT in Parkinson's disease. METHODS: Ultra-high molecular weight DNA was derived from blood and fibroblast cultures of 19 patients with mostly early-onset Parkinson's disease, and used for Nanopore sequencing and optical genome mapping. The size distributions of deletions and insertions were compared, and variants were filtered for rare or potentially pathogenic variants in 134 known movement disorder genes. RESULTS: Both methods identified SVs > 50 kb; however, optical mapping identified fewer structural variants (49,677) compared to Nanopore sequencing (94,400), but detected six times more in the range 50-80 kb. In general, it detected significantly larger deletions and insertions (p < 2.2 × 10-16). Both methods detected a benign intergenic deletion (195 kb) near ITPR1, and optical mapping validated a previously published 7-Mb PRKN inversion. Small heterozygous deletions in ATXN2, SUCLA2, and PNKD detected by optical mapping were identified to be intronic by Nanopore sequencing. No causal variants were identified in movement disorder genes. INTERPRETATION: Optical mapping can be a powerful first-line method for detecting large structural variants, but it requires a high-resolution method to refine breakpoint positions. Despite certain limitations, Nanopore sequencing was highly capable of detecting large variants independently and allows for a highly complementary assessment and validation of structural variation in combination with optical mapping.