Multi-Omics and IPSCs to Improve the Diagnosis of Rare Intellectual Disabilities
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 发起方
- 入组人数
- 7
- 试验地点
- 6
- 主要终点
- To evaluate the relevance and effectiveness of a multi-omics approach to the diagnosis of ID of unknown genetic origin.
研究概览
简要总结
Background Genetic factors play a major role in intellectual disability (ID) but the underlying cause is not determined in many cases.
This proposal is the continuation of the previous interregional project HUGODIMS, the aim of which was to perform whole exome sequencing (WES) in 69 thoroughly selected simplex ID parent-child trios. Thanks to HUGODIMS consortium, the underlying genetic cause of ID was determined or highly suspected in 48 cases (69.5%) and 7 novel ID genes were identified.
Hypothesis Investigators hypothesize that an approach combining genomics, transcriptomics, metabolomics and morphological analyses performed on induced pluripotent stem cell (iPSC)-derived neural cells would improve diagnosis of ID. The current proposal is therefore a proof-of concept project aiming at assessing the relevance and effectiveness of this multi-omics approach.
Aims and Methods Ten individuals with ID recruited through HUGODIMS, in whom WES have failed to identify pathogenic variants will be included.
The workflow is the following:
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Whole genome sequencing (WGS) (Nantes) of these 10 negative trios.
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Bio-informatics analyses
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In 3 WGS negative cases, 3 positive controls bearing distinct mutations in CAMK2a (a novel ID gene identified thanks to HUGODIMS), and 3 healthy negative controls:
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Derivation of induced pluripotent stem cell (iPSC)-derived neural progenitors (iPSC core facility at Nantes)
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Targeted and non-targeted metabolomics analyses performed on iPSC-derived neuronal cells (Angers)
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RNA sequencing performed on the 9 cell lines (Rennes)
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Morphological analyses of differentiated neuronal cell lines derived from 3 affected individuals and 3 positive controls bearing CMK2a mutations (Tours)
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Integration and validation of data from multi-omics and morphological approaches
Expected results and impact Investigatrors expect that this approach combining multi-omics and iPSC will help to improve diagnosis and understanding of genetic ID of unknown cause
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Diagnostic
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •3 Whole Genome Sequencing negative cases
- •3 positive controls bearing distinct mutations in CAMK2a
排除标准
- •no informed consent/refusal
结局指标
主要结局
To evaluate the relevance and effectiveness of a multi-omics approach to the diagnosis of ID of unknown genetic origin.
时间窗: Day 1
Whole genome sequencing : de novo variants in non-coding regions of the genome, WGS will be performed using the HiSeq X Five System 5; Bionformatics analysis of WGS data; neuronal progenitors derived from iPSC
次要结局
- The assessment of metabolomics consequences of CAMK2a mutations in human neuronal progenitors and differentiated neuronal cell lines(Day 1)
- The assessment of morphological consequences of CAMK2a mutations in human neuronal progenitors and differentiated neuronal cell lines(Day 1)