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Integrating long-read nanopore sequencing for precision resolution of genomic variants in dystonia.
Mov. Disord., DOI: 10.1002/mds.70072 (2025)
BACKGROUND: Although many individuals with dystonia present with features indicative of single-gene etiologies, obtaining definitive genetic diagnoses can be challenging. OBJECTIVE: We assessed the value of nanopore-based long-read sequencing (LRS) in achieving molecular clarification of dystonic syndromes. METHODS: From a large dystonia cohort with short-read sequencing (SRS) data, 14 cases with unclear, difficult-to-evaluate, or missing causative variants were recruited. Long-read whole-genome sequencing was performed according to Oxford Nanopore Technologies (ONT) protocols. RESULTS: ONT sequencing produced long-range haplotypes, variant calls inaccessible to short-read technology, as well as methylation data. Phase inference allowed for changes in variant classification, establishing compound heterozygosity of causative variants in four cases. We illustrate an important advantage of LRS compared with SRS in (re)defining the identity of dystonia-causing structural variants and repeat expansions for seven individuals. One patient was found to harbor a novel exonic LINE-1 insertion in SGCE, expanding the genetic mechanism in myoclonus-dystonia. ONT data also provided unexpected insights into apparent mosaic expanded repeats in FMR1 in a subject with isolated focal dystonia. We further showed that LRS outperformed SRS in avoiding erroneous calls resulting from confounding pseudogene sequences and in discovering pathogenic alterations missed by conventional pipeline utilization (three cases). Moreover, simultaneous methylome analysis aided in directing the interpretation of three variants, including a KMT2B variant of uncertain significance that was reclassified as causal by LRS-based episignature profiling. CONCLUSIONS: ONT-based LRS uniquely improves analysis of dystonia-associated variations that had not previously been resolved by SRS, implying broad utility for future exploration of the molecular origins of the condition. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Complex Structural Variants ; Dystonia ; Long‐range Phasing ; Long‐read Sequencing ; Nanopore Technology ; Repeat Expansions; Joint Consensus Recommendation; Copy-number; Medical Genetics; American-college; Exome; Standards
Language
english
Publication Year
2025
HGF-reported in Year
2025
ISSN (print) / ISBN
0885-3185
e-ISSN
1531-8257
Journal
Movement Disorders
Publisher
Wiley
Publishing Place
111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status
Peer reviewed
Institute(s)
Institute of Neurogenomics (ING)
POF-Topic(s)
30205 - Bioengineering and Digital Health
Research field(s)
Genetics and Epidemiology
PSP Element(s)
G-503200-001
G-503292-001
G-503292-001
Grants
Scientific Advisory Council of the Dystonia Medical Research Foundation
WOS ID
001584458000001
Scopus ID
105017823097
PubMed ID
41028987
Erfassungsdatum
2025-11-06