Integration of New Generation Multi-omics Analyses for the Diagnosis of Genetic Neurodevelomental Disorders (NEXTOMIX)
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.
研究概览
地位
研究类型
注册 (估计的)
阶段
- 不适用
联系人和位置
学习联系方式
- 姓名：Benoit MAZEL
- 电话号码：+33 03.80.29.53.13
- 邮箱：benoit.mazel@chu-dijon.fr
学习地点
-
-
-
Dijon、法国、21000
- CHU Dijon Bourgogne
-
接触：
- Louis ARNOULD, Pr
- 电话号码：+33 03.80.29.34.53
- 邮箱：Louis.arnould@chu-dijon.fr
-
-
参与标准
资格标准
适合学习的年龄
- 孩子
- 成人
- 年长者
接受健康志愿者
描述
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.
学习计划
研究是如何设计的？
设计细节
- 主要用途：诊断
- 分配：不适用
- 介入模型：单组作业
- 屏蔽：单身的
武器和干预
参与者组/臂 |
干预/治疗 |
|---|---|
|
其他：Patient with severe to profound intellectual disability
|
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 additional analyses (lrGS sequencing, mRNA-seq, and GMO testing), as the srGS data are negative for the causal diagnosis.
New srGS sequencing without additional analyses, as it is positive for the causal diagnosis.
New srGS sequencing followed by additional analyses (lrGS sequencing, mRNA-seq, and GMO testing) because the srGS data are negative for the causal diagnosis.
|
|
其他：Patient with a syndromic neurodevelopmental disorder with intellectual disability
|
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 additional analyses (lrGS sequencing, mRNA-seq, and GMO testing), as the srGS data are negative for the causal diagnosis.
New srGS sequencing without additional analyses, as it is positive for the causal diagnosis.
New srGS sequencing followed by additional analyses (lrGS sequencing, mRNA-seq, and GMO testing) because the srGS data are negative for the causal diagnosis.
|
|
其他：Patient with a syndromic neurodevelopmental disorder without intellectual disability
|
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 additional analyses (lrGS sequencing, mRNA-seq, and GMO testing), as the srGS data are negative for the causal diagnosis.
New srGS sequencing without additional analyses, as it is positive for the causal diagnosis.
New srGS sequencing followed by additional analyses (lrGS sequencing, mRNA-seq, and GMO testing) because the srGS data are negative for the causal diagnosis.
|
研究衡量的是什么？
主要结果指标
结果测量 |
措施说明 |
大体时间 |
|---|---|---|
|
Identification of a causative diagnosis (class 4 or 5 variant according to American College of Medical Genetics criteria) explaining the phenotype and validated during a multidisciplinary team meeting.
大体时间：Between 4 and 12 months
|
Identification of a causative diagnosis (class 4 or 5 variant according to American College of Medical Genetics criteria) explaining the phenotype and validated during a multidisciplinary team meeting.
|
Between 4 and 12 months
|
合作者和调查者
研究记录日期
研究主要日期
学习开始 (估计的)
初级完成 (估计的)
研究完成 (估计的)
研究注册日期
首次提交
首先提交符合 QC 标准的
首次发布 (实际的)
研究记录更新
最后更新发布 (实际的)
上次提交的符合 QC 标准的更新
最后验证
更多信息
此信息直接从 clinicaltrials.gov 网站检索，没有任何更改。如果您有任何更改、删除或更新研究详细信息的请求，请联系 register@clinicaltrials.gov. clinicaltrials.gov 上实施更改，我们的网站上也会自动更新.