Long-read Genome Sequencing for the Molecular Diagnosis of Dystonia

NCT06999096 | Not Yet Recruiting

• 1 other identifier: 9433
• Study Type: interventional
• Target: 150
• Locations: 0 countries
• Sites: N/A

Brief 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

Dystonia; Movement Disorders; Combined Dystonia; Complex Dystonia

Keywords

Dystonia; Genome Sequencing; Long-read Sequencing; Molecular diagnosis; Neurogenetics

Outcome Measures

Primary Outcomes (1)

• Long-read genome sequencing diagnostic rate

  Proportion (expressed as a percentage) of families in which a causal genetic variant (classified as class 4 or 5 according to the American College of Medical Genetics and Genomics) explaining the patients' symptoms was identified through long-read genome sequencing, after no diagnosis had been reached using prior short-read genome analysis.

  18 months

Secondary Outcomes (5)

• Technical issues rate

  18 months

• Proportion of activable disorders

  24 months

• New molecular causes of dystonia

  18 months

• Resolution following reanalysis of short-read whole genome sequencing data

  18 months

• Medico-economic impact of molecular diagnosis

  24 months

Study Arms (1)

Dystonia patients without molecular diagnosis

EXPERIMENTAL

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

Diagnostic Test: Long-read whole genome sequencing

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.

Dystonia patients without molecular diagnosis

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Index case affected by familial dystonia (≥1 first-degree relative affected) and/or sporadic early-onset dystonia (symptom onset before age 50), meeting the criteria of the PFMG-2025 program.
• Index case who has undergone short-read genome sequencing, which did not lead to a molecular diagnosis.
• Ability to understand and sign informed consent by the index case and/or their parents or legal guardians for patients under 18 years of age.
• Availability of a blood sample from the index case and at least two relatives, either affected or unaffected.
• Symptomatic or asymptomatic relative of an index case, who has also undergone short-read genome sequencing without a conclusive molecular diagnosis.
• Ability to understand and sign informed consent.

You may not qualify if:

• Index case or relatives who are not affiliated with or not beneficiaries of a social security scheme.
• Index case and their parents presenting with a condition that, in the opinion of the investigator, would contraindicate participation in the study.
• Suspected non-genetic etiology (e.g., perinatal hypoxic-ischemic injury, kernicterus, history of severe head trauma or central nervous system infection).

Sponsors & Collaborators

• University Hospital, Strasbourg, France: lead

MeSH Terms

Conditions

Dystonia; Movement Disorders

Condition Hierarchy (Ancestors)

Dyskinesias; Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Central Nervous System Diseases

Central Study Contacts

Thomas WIRTH, Doctor

CONTACT

+33 3 88 12 89 19; thomas.wirth@chru-strasbourg.fr

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 22, 2025
• First Posted: May 31, 2025
• Study Start: August 1, 2025
• Primary Completion (Estimated): August 1, 2030
• Study Completion (Estimated): August 1, 2030
• Last Updated: May 31, 2025

Record last verified: 2025-05