Complementarity of Long-Reads and Optical Mapping in Parkinson's Disease for Structural Variants

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.

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.

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.

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.