Integration of New Generation Multi-omics Analyses for the Diagnosis of Genetic Neurodevelomental Disorders

Summary

Neurodevelopmental disorders (NDDs), including intellectual disability (ID), represent the most common indication for genetic testing. Affecting up to 3% of the general population, NDDs are characterized by significant clinical and genetic heterogeneity. Although short-read genome sequencing (srGS) has driven major advances through the France Genomic Medicine 2025 Plan (PFMG2025), a substantial proportion of patients still lack a molecular diagnosis.

These results are partly explained by the limitations of short-read genome sequencing (srGS). Although effective in many cases, this technology performs poorly in detecting complex structural rearrangements, anomalies within repetitive or GC-rich regions, epigenetic variations, and certain intronic variants. Furthermore, srGS does not allow for the direct assessment of the functional impact of genetic variations on splicing or gene expression. Following a negative srGS result, periodic reanalysis of sequencing data via the PFMG2025 laboratories (AURAGEN and SeqOIA) is the only diagnostic option currently available in routine practice. However, these reanalyses are constrained by financial and staffing limitations as well as strict eligibility criteria, making it difficult for many patients-particularly those with stable neurodevelopmental disorders (NDDs)-to obtain a diagnosis. Moreover, they often consist merely of a data review without bioinformatic updates, and the turnaround times-frequently exceeding one year-contribute to the diagnostic odyssey. Utilizing updated pipelines tailored to the specific characteristics of NDDs for the re-examination of srGS data could serve as an initial source of new diagnoses.

Complementary technologies-such as messenger RNA sequencing (mRNA-seq), optical genome mapping (OGM), and long-read genome sequencing (lrGS)-are available and offer solutions to overcome the limitations of short-read genome sequencing (srGS). In particular, they enable the identification of complex structural variants and the assessment of the functional impact of point variants. Despite their potential, their routine use remains limited due to cost and technical complexity.

Our study proposes a combined strategy to address the limitations of current approaches and improve the diagnosis of neurodevelopmental disorders (NDDs) that remain unresolved after short-read genome sequencing (srGS). It begins with a re-analysis of sequencing data using customized bioinformatics pipelines tailored to the patients' specific clinical profiles. In cases of inconclusive results, innovative multi-omics analyses (mRNA-seq, OGM, and long-read genome sequencing/lrGS) will be employed to investigate complex genetic variants. As multi-omics approaches are not currently integrated into the PFMG2025 framework, the project's findings will be crucial in demonstrating their added value for NDD diagnosis and could pave the way for their inclusion in a future PFMG. By anticipating these developments, NextOmix will help define the diagnostic strategies of the future, aligned with technological advancements and patient needs.

Conditions

• Intellectual Disability
• Neurodevelopmental Disorder (Diagnosis)
• srGS
• lrGS
• Short-read Genome Sequencing
• Long-read Genome Sequencing

Interventions

DIAGNOSTIC_TEST

Re-analysis of available srGS data

Re-analysis of available srGS data without further analysis, as the results were positive for the causal diagnosis.

DIAGNOSTIC_TEST

Re-analysis of available srGS data, followed by complementary analyses (lrGS sequencing, mRNA, and GMOs)

Re-analysis of available srGS data followed by additional analyses (lrGS sequencing, mRNA-seq, and GMO testing), as the srGS data are negative for the causal diagnosis.

DIAGNOSTIC_TEST

srGS sequencing

New srGS sequencing without additional analyses, as it is positive for the causal diagnosis.

DIAGNOSTIC_TEST

Short-read sequencing (srGS) followed by long-read sequencing (lrGS,), mRNA-sequencing and GMO testing

New srGS sequencing followed by additional analyses (lrGS sequencing, mRNA-seq, and GMO testing) because the srGS data are negative for the causal diagnosis.

Sponsors & Collaborators

• Centre Hospitalier Universitaire Dijon

  lead OTHER

Study Design

Allocation

NA

Purpose

DIAGNOSTIC

Masking

SINGLE

Model

SINGLE_GROUP

Eligibility

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2026-09-30

Primary Completion

2029-03-31

Completion

2029-03-31

Countries

• France

Study Locations