Transcriptomic Approach for the Identification and Prioritization of Genome Variants in Neurodevelopmental Disorders With Malformation

Not Applicable

Not yet recruiting

• Conditions: Neurodevelopmental Disorders and Developmental Abnormalities

• Registration Number: NCT06762678
• Lead Sponsor: University Hospital, Angers

Brief Summary

Three million persons in France are impacted by rare diseases. Amid the 7000 different diseases which are identified today, neurodevelopmental disorders are the main symptoms found interesting 35 000 birth every years, according to the French Health Authority. In half of these cases, patients are under 5 years old and a molecular diagnosis is only available in 50% of them, associated with a diagnostic wandering exceeding 5 years for 25% of every patients.

High throughput DNA sequencing technologies are powerful tools to elucidate new causative variants. Although the diagnostic yield was refined by DNA-seq, data interpretation and technology limits remain the two major obstacles which still need be overcame. Missing a molecular diagnosis through a genomic approach alone highlight the need to integrate multi-omic approaches such as Ribonucleic Acid sequencing. This sequencing level allows new insight such like the evidence of aberrant gene expression, mono allelic allele expression, or abnormal alternative splicing. It makes possible too, to detect variants which are unable to be found via genome sequencing only.

Recently, a diagnostic performance improvement has been described trough the association of the two technics, i.e. Ribonucleic Acid-seq and genome sequencing, in a context of neuromuscular diseases. However, only few studies were carry out on neurodevelopmental disorders in addition with malformative features. We demonstrated by the end of 2022, a diagnostic results enhancement by carrying genome sequencing plus Ribonucleic Acid-seq at the same time on patient with previously exome negative analysis. Moreover in 2023, Dekker et al. work shed light on a diagnostic yield improvement via the same analytic schema.

In face of those first observations, our study aims to evaluate the diagnostic contribution of Ribonucleic Acid-seq paired with genome sequencing in a trio way versus the genome sequencing in a solo way, to identify the find a final diagnosis for patient presenting neurodevelopmental disorders with developmental abnormalities and without an evident diagnosis after chromosome microarray and/or exome sequencing analysis.

To successfully carry out our study, we plan to recruit patient in a protocol considered with minimal risk and minimal constraints, to compare Ribonucleic Acid-seq performed on fibroblasts, in addition to genome sequencing in a solo or a trio manner, to trio genome sequencing alone, with the final objective in mind to obtain an etiology diagnostic for a patient presenting with neurodevelopmental disorders and development abnormalities.

Detailed Description

Not available

Study Timeline

• Status Verified: 2024-12
• Study First Submitted: 2024-12-31
• Study First Submitted QC: 2024-12-31
• Last Update Submitted: 2024-12-31
• Study First Posted: 2025-01-07
• Last Update Posted: 2025-01-07
• Study Start: 2025-02-01
• Primary Completion: 2026-08-01
• Study Completion: 2027-08-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 58

Inclusion Criteria

Not provided

Exclusion Criteria

• Neurodevelopmental disorders with developmental anomaly from non genetic causes or highly evident diagnosis for which a molecular test is available in routine practices and whose the cost is inferior than the cost of the genome and the RNA sequencing
• unwillingness to participate, from the patient or from the legal representatives
• Pregnant or lactating women

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Compare the interest of RNA sequencing in addition to a genome sequencing in trio, versus a genome sequencing trio analyse carried out alone, to identify the etiologic diagnosis of patient with neurodevelopmental disorders and developmental abnormalities	12 months	To compare the interest of RNA sequencing, carried out into fibroblasts in addition to a genome sequencing in trio, versus a genome sequencing-trio analyse carried out alone, to identify the etiologic diagnosis of patient with neurodevelopmental disorders and developmental abnormalities, without any obvious clinical diagnosis a priori, and without no identified result after Chromosomal Microarray and/or solo or trio exome sequencing Number of class 4 or class 5 (according the American College of Medical Genetics classification) variants newly identified and allowing a diagnosis to explain patient' symptoms, following RNA sequencing + genome sequencing-trio, vs genome sequencing trio alone.