Use of Long Read Genome Sequencing in Patients Suffering From Neurodevelopmental Troubles

Completed

• Conditions: Genetic Disease; Neurologic Disorder; Growth Disorders; Developmental Delay Disorder

• Registration Number: NCT05643274
• Lead Sponsor: Nantes University Hospital

Brief Summary

Patients with neurodevelopmental diseases and their families need to identify the genetic cause of the disease to allow for recognition of the disability, genetic counseling, and possible hope for participation in therapeutic research studies. Access to high-throughput genomic exome or genome analysis allows the identification of a genetic cause for approximately half of the patients. However, families with no result or with a variant of unknown significance after these tests may find themselves in a new diagnostic impasse.

The high-throughput sequencing used today generates sequences of the order of 100 base pairs (so-called "short read" sequencing). This allows an analysis of about 90% of the genome. However, many regions are not accessible in regions of interest for the genetic diagnosis of rare diseases. Long fragment sequencing generates sequences that are about 20 times larger and its use has recently made it possible to sequence the human genome almost completely (https://www.science.org/doi/10.1126/science.abj6987). The main contribution lies in the analysis of complex regions of the genome such as segmental duplications or centromeric regions. It is likely that this technology increases the sensitivity of detection of genetic variants in patients with genetic diseases. Its contribution should be studied in patients for whom no genetic cause has been identified by classical techniques.

This study aim to investigate the contribution of long fragment genome sequencing.

Detailed Description

Ten families with a child suffering from a neurodevelopmental disease will be recruited by geneticists being part of the CLAD-Ouest. An EDTA blood sample will be taken from the patient and their parents (trio analysis). The blood samples will then be used to extract nucleic acids (DNA).

The blood samples will be sent and centralized to the genetics laboratory of the Nantes University Hospital. The DNA will be extracted and anonymized.

The files generated after DNA sequencing will have as an identification key the anonymization number provided at the time of inclusion of the individual in the study. The raw data and VCF files will be uploaded to the BIRD computing cluster in Nantes, where they will be stored for the duration of the study (2 years). The different university hospitals will then be able to retrieve the data and analyze the variants identified in the patients recruited by their center. A centralized analysis to annotate, filter and interpret the variants will be performed by a group of bioinformaticians and biologists from HUGO (University Hospital from the Grand Ouest). Long-term archiving of the data will be performed at the Nantes University Hospital.

Study Timeline

• Study First Submitted: 2022-11-22
• Study First Submitted QC: 2022-12-01
• Study First Posted: 2022-12-08
• Study Start: 2022-12-19
• Primary Completion: 2023-03-08
• Study Completion: 2024-03-08
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-23
• Last Update Posted: 2024-04-24

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Use of long read sequencing in patients suffering from a neurodevelopmental disease without pathogenic or probably pathogenic variation identified by short read sequencing	through study completion, an average of 2 years	Identification of a genetic diagnosis : detection of one or several variant(s) - nucleotidic, change in copy number, structural variants- of class 4 or 5 (probably pathogenic or pathogenic), explaining the genetic origin of the neurodevelopmental pathology

Secondary Outcome Measures

Name	Time	Method
Analysis of the implementation of the long read sequencing of trios (patients and parents)	through study completion, an average of 2 years	Measurement of the failing rate of long read sequencing, turn around time between sequencing and results available to clinical team

Trial Locations

Locations (5)

Rennes University Hospital; 🇫🇷 Rennes, Ille-et-Vilaine, France

Brest University Hospital; 🇫🇷 Brest, Finistère, France

Nantes University Hospital; 🇫🇷 Nantes, Loire-Atlantique, France

Angers University Hospital; 🇫🇷 Angers, Maine-et-Loire, France

Tours University Hospital; 🇫🇷 Tours, Indre-et-Loire, France