2025 Movement Disorders Review Article of the Year
Exploration of neurodegenerative diseases using long-read sequencing and optical genome mapping technologies 

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We are delighted to have been awarded the “2025 Review Article of the Year” by the Movement Disorders journal. After submitting to Movement Disorders an article describing two siblings with a phenotype compatible with PRKN-associated Parkinson’s disease (PD) solved by long-read sequencing (LRS), the Editor-in-Chief kindly invited us to write a review focusing on emerging technologies for a non-geneticist audience.

We believed this review came at the right time for two reasons. First, more people were using LRS in the context of neurodegenerative diseases, and a growing amount of evidence from the literature proved its ability to solve cases unexplained by whole exome or whole genome short-read sequencing. Second, the most recent review had been published in 2021 by Su et al. in Neurology, therefore an update appeared to be necessary. We were pleased to accept the writing, and aimed to offer a broad perspective of the recent achievements of both LRS and optical genome mapping (OGM), as well as their limitations, challenges, and opportunities for the future. 

There are three main types of genetic variations influencing human traits: small variants (variants including less than 50 base pairs, also called single nucleotide variants and insertions/deletions), short tandem repeats (also known as repeat expansions REs), and structural variants (SVs, deletions, insertions, duplications, inversions, translocations). Many likely monogenic disorders still lack accurate molecular diagnosis, primarily because conventional sequencing methods are not effective at detecting SVs and REs, both of which are causal in many neurogenetic diseases. Therefore, several initiatives aim at using LRS and/or OGM to decipher the genetic underpinnings of neurodegenerative diseases. We provided several comprehensive examples in the review to offer the reader an understanding of the achievements of LRS and OGM. We discuss how LRS allowed us to unveil variants not called by short-read sequencing in known neurodegenerative disease (e.g. PRKN, SPG4) and discover new causal genes (e.g. Neuronal Intranuclear inclusion disease and NOTCH2NLC 5’UTR expansion, Spinocerebellar ataxia type 4 and ZFHX3). We also illustrate the ability of LRS to characterize the size and motif of repeats, which influence age of onset, penetrance, inheritance, and clinical phenotypes (CANVAS and RFC1, FXTAS and FMR1, SCA27B and FGF14). We also describe the possibility to phase variants using LRS and distinguish variants in genes from those in their pseudogene (GBA1, SORD2), as well as the possibility to identify new transcripts. We also emphasize the pros and cons of optical genome mapping in the identification of SVs and REs. Although these technologies are mostly used in a research setting for now, we anticipate broader implementation in clinical laboratories in the future. We hope this review is helpful for professionals in understanding their utility and limitations and in using them wisely, either in the context of diagnosis or research!  

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