Long-read Genome Sequencing for the Molecular Diagnosis of Dystonia

Sponsor
University Hospital, Strasbourg, France
Study ID
NCT06999096
Status
Recruiting
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Conditions

  • Combined Dystonia
  • Complex Dystonia
  • Dystonia
  • Movement Disorders

Eligibility Criteria

Sex
ALL
Age
N/A - N/A
Healthy Volunteers
Not accepted

Interventions

  • Long-read whole genome sequencing — DIAGNOSTIC_TEST
    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.

Study Details

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.

Key Dates

First listed
May 31, 2025
Start date
Apr 22, 2026
Status verified
May 2026
Primary completion
Aug 31, 2030
Completion
Aug 31, 2030

Study Design

Enrollment
150 participants (estimated)
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC

Arms

  • Experimental: Dystonia patients without molecular diagnosis
    Long-read genome sequencing for identification of genetic causes in dystonia patients without molecular diagnosis

Primary Outcome Measure

Long-read genome sequencing diagnostic rate [ Time Frame: 18 months ]

Central Contacts

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