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

N/ANot Yet RecruitingNCT07755098

Centre Hospitalier Universitaire Dijon132 enrolled

Overview

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.

Interventions

Re-analysis of available srGS dataDIAGNOSTIC_TEST

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

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

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.

srGS sequencingDIAGNOSTIC_TEST

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

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

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

Eligibility

Sex: ALL

Medical Language ↔ Plain English

Inclusion Criteria: * Index case (minor or adult) with severe to profound intellectual disability or syndromic neurodevelopmental disorder without an identified molecular diagnosis. - Index case with a negative srGS result. * Sample collection possible from the index case (blood and skin biopsy) and their biological parent(s) (blood) if material is not otherwise available. * Signed consent from the adult index case, or from the legal representatives or guardian (as applicable) of a minor index case, and from their parent(s). Exclusion Criteria: * \- Index case or parent(s) not affiliated with or not covered by a social security scheme. * Diagnostic hypothesis considered highly probable, for which an available targeted molecular test costs less than the proposed strategy. * Suspicion of an acquired cause for the symptoms. * Minor parent(s). * Parent subject to a legal protection measure, or incapacitated or otherwise unable to provide informed consent. * Pregnant, birthing, or breastfeeding woman. * Participant (index case or parent) who has previously undergone allogeneic hematopoietic stem cell transplantation, rendering blood sample analysis uninformative.

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

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

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