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Long-read Genome Sequencing for the Molecular Diagnosis of Dystonia

NCT06999096 · Status: RECRUITING · Phase: NA · Type: INTERVENTIONAL · Enrollment: 150

Last updated 2026-05-20

No results posted yet for this study

Summary

Dystonia is a motor disorder caused by involuntary, intermittent, or sustained muscle contractions, leading to abnormal movements or postures. It can affect any body region and often results in significant functional disability and healthcare burden. Although its familial nature was recognized early on, the advent of high-throughput DNA sequencing has dramatically increased the identification of dystonia-associated genes. Dystonia now encompasses all modes of inheritance-autosomal dominant (e.g., TOR1A, KMT2B), autosomal recessive, X-linked, and mitochondrial-and over 100 genes have been implicated. Many forms involve structural variants (SVs) or copy number variations (CNVs), which are challenging to detect using standard short-read sequencing (srWGS).

Molecular diagnosis is essential, ending the diagnostic odyssey and enabling genetic counseling, prognosis, reproductive planning, and-in some cases-targeted therapies. For instance, GNAO1-related dystonia may respond to deep brain stimulation, while dopa-responsive dystonia benefits from levodopa.

Despite advances, srWGS has key limitations, especially for detecting repeat expansions, SVs, and phasing alleles. This likely explains the low diagnostic yield in dystonia compared to other neurological disorders, with over 70% of cases remaining unsolved.

Long-read sequencing (lrWGS), such as Oxford Nanopore technology, overcomes many of these challenges by reading native DNA fragments thousands of bases long. It enables comprehensive detection of SNVs, indels, SVs, CNVs, methylation changes, and repeat expansions-including known and newly discovered pathogenic expansions (e.g., in NOTCH2NLC). It also allows phasing without parental samples, which is crucial in recessive cases.

The investigators propose that lrWGS could significantly increase the diagnostic yield in dystonia, improving patient care, enabling appropriate genetic counseling, and paving the way for personalized treatment strategies.

Conditions

Interventions

DIAGNOSTIC_TEST

Long-read whole genome sequencing

Pseudonymized blood samples will undergo high-molecular-weight DNA extraction, followed by long-read whole-genome sequencing (lrWGS) using Oxford Nanopore technology. Index cases will be sequenced at high depth (\>30X), while relatives will be multiplexed (\>15X). Sequencing data will be analyzed through a dedicated bioinformatics pipeline to detect SNVs, indels, structural variants, and repeat expansions. Results will be interpreted by expert teams and discussed in monthly clinical-genetic meetings. Variants of interest will be validated by appropriate molecular techniques, and family segregation will be assessed when relevant.

Sponsors & Collaborators

  • University Hospital, Strasbourg, France

    lead OTHER

Study Design

Allocation
NA
Purpose
DIAGNOSTIC
Masking
NONE
Model
SINGLE_GROUP

Eligibility

Sex
ALL
Healthy Volunteers
No

Timeline & Regulatory

Start
2026-04-22
Primary Completion
2030-08-31
Completion
2030-08-31

Countries

  • France

Study Locations

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Entities

Diseases

Read the full study record

This page highlights key information. For complete eligibility criteria, study locations, investigator contacts, and the full protocol, visit the original record on ClinicalTrials.gov.

View NCT06999096 on ClinicalTrials.gov