Advancing Neurogenetic Diagnoses Through Long-Read Sequencing (NRGEN-NGS3)

NRGEN-NGS3 : Advancing Neurogenetic Diagnoses Through Long-Read Sequencing

Nucleotide repeats emerge as one of the most prolific classes of genetic variations. They have the propensity to in-crease in length across generations, and have been implicated in at least 65 known neurological/ neurodevelop-mental and neuromuscular conditions. Simultaneous analysis of all these nucleotide repeats is now possible through the cutting-edge methodologies recently developed that are the long-read sequencing and the optical genome mapping. Investigator propose to test these methodologies in patients carrying expansions in those repeats and to determine the capacity of these technics to detect novel repeats in patients with no genetic diagnosis yet.

Study Overview

• Status: Not yet recruiting
• Conditions: Neurogenetic Diseases
• Intervention / Treatment: Procedure: Skin biopsy; Procedure: blood sampling

Detailed Description

Hereditary neurological diseases caused by nucleotide repeat expansions present significant clinical challenges due to overlapping clinical symptoms and extensive genetic diversity, often resulting in complex diagnostic journeys for patients. In addition, current diagnostic approaches rely on sequential genetic analyses of targeted loci across multiple consultations and dispatching samples to various molecular genetic laboratories. The recent advancement of long-read sequencing technology from Oxford Nanopore and of the optical Genome Mapping from Bionano offer promising and innovative avenues for investigating nucleotide repeat expansions.

This project has then 2 main objectives, to enhance the genetic diagnosis of such mutational events and to identify novel candidate genes or repetitive sequences in neurogenetic conditions.

These methodologies will be applied to 120 carriers of established repeat expansions to help better define the threshold and composition of large repeats leveraging the main advantage offered by each technics to allow full analysis of these repeat sequences. In the case of long read sequencing, an enrichment methodology will be used (adaptive sampling). In order to be sure to analyze 120 patients, investigators will recruit 180 patients (90 in each group).

The second objective relies on the fact that a substantial portion of patients still lack a molecular diagnosis in neuro-genetics. Investigator aim to uncover new abnormal repeat expansions using the same technologies in a separate cohort of patients affected by candidate neurological conditions for these repeats, where genomic data have not revealed mutations or expansions in known genes. The consortium will analyze samples from 30 families affected by a candidate neurogenetic condition

• Study Type: Interventional
• Enrollment (Estimated): 304
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Cyril GOIZET, PROF; Phone Number: +335 56 79 59 52; Email: cyril.goizet@chu-bordeaux.fr

Study Locations

• France
  • France
    • Bordeaux, France, France, 33076
      • CHU Bordeaux - Hopital Pellegrin
      • Contact: Cyril GOIZET, PROF; Phone Number: +335 56 79 59 52; Email: cyril.goizet@chu-bordeaux.fr
    • Paris, France, France, 75013
      • AP-HP Hopital Pitie-Salpetriere
      • Contact: Eric LEGUERN, PROF; Phone Number: +331 42 16 13 46; Email: eric.leguern@aphp.fr
      • Principal Investigator: Eric LEGUERN, PROF

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• All participants :

  • Participants affiliated with or beneficiaries of a social security scheme
  • Participants who speak French
  • Participants aged ≥ 6 and ≤ 60 years

• For patients requiring a new sample:

  • Free and informed consent, signed by the parents or the holder of parental authority for patients under the age of 18
  • Free and informed consent, signed by the patient's representative for adults under guardianship
  • Free and informed consent, signed by the adult patient

• For diagnosed patients :

  • DeoxyriboNucleic Acid (DNA) sample from a subject carrying a nucleotide repeat expansion in one of the selected genes.

  • DNA available in sufficient quantity (5-10 µg) or patient agreeing to a blood draw from which DNA will be extracted.
  • DNA extraction methods known and validated by the steering committee (see paragraph 7).

• For participants from undiagnosed families :

  o Index cases:

  • Patient affected by a neurological disease candidate for these repeats, for which genomic data did not reveal mutations or expansions in known genes.

  • Patient whose DNA is already available and whose extraction method is known and validated by the steering committee or patient whose DNA is not available but who agrees to a blood draw.
  • Patient willing to undergo a skin biopsy if not previously obtained.
  • Patient with no family members affected by any of the neurological diseases candidate for these repeats, i.e., genomic data do not reveal mutations or expansions in known genes.

  • Patient from a family in which at least one affected and one unaffected member agree to partici-pate in the study by providing a sample, or whose DNA is already available and extracted using a method known and validated by the steering committee.

    • For all related members of undiagnosed families who have agreed to participate:
  • Have at least two other family members who have agreed to participate in the study.
  • Agree to provide a blood sample or have DNA already available in sufficient quantity and extracted using a method known and validated by the steering committee.
  • Patient willing to undergo a skin biopsy if not previously obtained.
  • Be affected by a neurological disease candidate for these repeats, for which genomic data did not reveal mutations or expansions in known genes, or be unaffected and have had a neurological examination showing no signs related to any of the neurological diseases candidate for these repeats.
• For controls :

Participant for whom:

• a consultation is scheduled at CHU Bordeaux for a reason other than a neurological disorder, has agreed to a neurological examination showing no signs of neurological disease, and has agreed to a blood draw and skin biopsy, or
• the samples required for the study are already available in sufficient quantity in the CHU Bordeaux biobank and extracted using a method known and validated by the steering committee, or
• accompanying a patient attending a consultation at CHU Bordeaux, showing no signs of neurologi-cal disease, and agreeing to a blood draw and skin biopsy, or whose samples are already available in sufficient quantity and extracted using a method known and validated by the steering committee.

Exclusion Criteria:

For all participants:

• Refusal to participate in research: Refusal to provide informed consent or opposition to the use of these samples.

• By the parents or the holder of parental authority for patients under the age of 18
• By the patient's representative for adults under guardianship

• By the adult patient This opposition from the patient must be communicated to the site investigator within a maximum of one month after the information note has been sent. If the letter confirming consent is returned due to an incorrect address, the patient will not be included.

  • Degraded DNA or average size < 30 kb

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Control	Procedure: Skin biopsy; Skin biopsy is a minimally invasive procedure. It will be performed during a follow-up visit. The skin biopsy is a technically simple procedure performed using a 5-mm diameter punch under local anesthesia. The procedure can be carried out in a consultation room under strict aseptic conditions and takes a total of approximately 15 minutes.The biopsy may be performed at several anatomical sites but is generally carried out on the inner aspect of the arm. It will be performed by a resident or a senior registrar. The skin biopsy sample is placed in a vial containing physiological saline and sent at room temperature.; Procedure: blood sampling; Blood sampling is a routine biological procedure performed under the same conditions as during a follow-up consultation. Pain, redness, or bleeding may occur at the puncture site. If the required samples are not already available, they will be collected. The maximum volumes collected will be as follows and will represent a total volume of less than two tablespoons (for participants weighing less than 30 kg, only one tube of each type will be collected)
Other: Diagnosed family	Procedure: blood sampling; Blood sampling is a routine biological procedure performed under the same conditions as during a follow-up consultation. Pain, redness, or bleeding may occur at the puncture site. If the required samples are not already available, they will be collected. The maximum volumes collected will be as follows and will represent a total volume of less than two tablespoons (for participants weighing less than 30 kg, only one tube of each type will be collected)
Other: Undiagnosed family	Procedure: Skin biopsy; Skin biopsy is a minimally invasive procedure. It will be performed during a follow-up visit. The skin biopsy is a technically simple procedure performed using a 5-mm diameter punch under local anesthesia. The procedure can be carried out in a consultation room under strict aseptic conditions and takes a total of approximately 15 minutes.The biopsy may be performed at several anatomical sites but is generally carried out on the inner aspect of the arm. It will be performed by a resident or a senior registrar. The skin biopsy sample is placed in a vial containing physiological saline and sent at room temperature.; Procedure: blood sampling; Blood sampling is a routine biological procedure performed under the same conditions as during a follow-up consultation. Pain, redness, or bleeding may occur at the puncture site. If the required samples are not already available, they will be collected. The maximum volumes collected will be as follows and will represent a total volume of less than two tablespoons (for participants weighing less than 30 kg, only one tube of each type will be collected)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Diagnosis by NGS technology	The first primary endpoint is the ability of the proposed Next-Generation Sequencing (NGS) technology to establish the diagnosis of each neurogenetic disease studied, defined as the presence or absence of the disease, in comparison with the currently used reference method (gene-specific Polymerase Chain reaction (PCR)). NGS analysis will be performed blinded to the results previously obtained on the same samples using the reference technique, taking into account the disease under investigation and the number of repeat amplifications.	Inclusion visit
Molecular diagnosis	Identification a molecular diagnosis in families undergoing a diagnostic odyssey, by demonstrating both the presence of repeat expansions in affected family members and the absence of such expansions in unaffected individuals within the same family.	Inclusion visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
New complex haplotypes	Identification of new complex haplotypes	Inclusion visit
Deleterious biological effect	Identification of a deleterious biological effect of one or more newly identified variants in the new gene(s) of inter-est.	Inclusion visit

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Principal Investigator: Cyril GOIZET, PROF, University Hospital, Bordeaux

Study record dates

Study Major Dates

• Study Start (Estimated): September 1, 2026
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028

Study Registration Dates

• First Submitted: June 11, 2026
• First Submitted That Met QC Criteria: June 18, 2026
• First Posted (Actual): June 24, 2026

Study Record Updates

• Last Update Posted (Actual): June 24, 2026
• Last Update Submitted That Met QC Criteria: June 18, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: genetic diagnosis; long read sequencing; cytogenetics; nucletotide repeat expansion; neurogenetic disease
• Additional Relevant MeSH Terms: Investigative Techniques; Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Blood Specimen Collection
• Other Study ID Numbers: CHUBX 2025/017

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No