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Multi-Omics and IPSCs to Improve Diagnosis of Rare Intellectual Disabilities (MIDRID)

Primary Purpose

Rare Intellectual Disabilities

Status
Unknown status
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Blood sample
Sponsored by
University Hospital, Angers
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Rare Intellectual Disabilities

Eligibility Criteria

2 Years - 25 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • 3 Whole Genome Sequencing negative cases
  • 3 positive controls bearing distinct mutations in CAMK2a

Exclusion Criteria:

  • no informed consent/refusal

Sites / Locations

  • CHU Angers
  • HCL LyonRecruiting
  • CHU de Bourgogne
  • CHU Nantes
  • CHU Poitiers
  • CHU Rennes

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Blood sample

Arm Description

Blood sample for analyses

Outcomes

Primary Outcome Measures

To evaluate the relevance and effectiveness of a multi-omics approach to the diagnosis of ID of unknown genetic origin.
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

Secondary Outcome Measures

The assessment of metabolomics consequences of CAMK2a mutations in human neuronal progenitors and differentiated neuronal cell lines
Coupled to high-resolution mass spectrometry ; Transcriptomics analyses: quality of the RNA will be evaluated with the Bioanalyzer (Agilent) on the basis of the RIN (RNA integrity number) as well as by taking into account the DV200, i.e. the percentage of RNA fragments with more than 200 nucleotides Non-targeted metabolomic analyses will be performed using a method based on ultra-high-performance liquid chromatography Flow injection analysis-tandem mass spectrometry for quantifying acylcarnitines, glycerophospholipids, sphingolipids and sugar, whereas liquid chromatography
The assessment of morphological consequences of CAMK2a mutations in human neuronal progenitors and differentiated neuronal cell lines
immunocytochemistry and protein expression approaches using confocal microscopy and Western blotting with antibodies specific for proteins expressed in neurons (MAP2, Tubulin beta 3, PSD95, SNAP25), astrocytes (GFAP) or oligodendrocytes (Gal-C)

Full Information

First Posted
August 10, 2018
Last Updated
January 2, 2020
Sponsor
University Hospital, Angers
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1. Study Identification

Unique Protocol Identification Number
NCT03635294
Brief Title
Multi-Omics and IPSCs to Improve Diagnosis of Rare Intellectual Disabilities
Acronym
MIDRID
Official Title
Multi-Omics and IPSCs to Improve the Diagnosis of Rare Intellectual Disabilities
Study Type
Interventional

2. Study Status

Record Verification Date
January 2020
Overall Recruitment Status
Unknown status
Study Start Date
January 9, 2019 (Actual)
Primary Completion Date
March 2020 (Anticipated)
Study Completion Date
March 2020 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University Hospital, Angers

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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: Whole genome sequencing (WGS) (Nantes) of these 10 negative trios. Bio-informatics analyses 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: Derivation of induced pluripotent stem cell (iPSC)-derived neural progenitors (iPSC core facility at Nantes) Targeted and non-targeted metabolomics analyses performed on iPSC-derived neuronal cells (Angers) RNA sequencing performed on the 9 cell lines (Rennes) Morphological analyses of differentiated neuronal cell lines derived from 3 affected individuals and 3 positive controls bearing CMK2a mutations (Tours) 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Rare Intellectual Disabilities

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
6 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Blood sample
Arm Type
Experimental
Arm Description
Blood sample for analyses
Intervention Type
Other
Intervention Name(s)
Blood sample
Intervention Description
combining genomics, transcriptomics, metabolomics and morphological analyses performed on induced pluripotent stem cell (iPSC)-derived neural cells
Primary Outcome Measure Information:
Title
To evaluate the relevance and effectiveness of a multi-omics approach to the diagnosis of ID of unknown genetic origin.
Description
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
Time Frame
Day 1
Secondary Outcome Measure Information:
Title
The assessment of metabolomics consequences of CAMK2a mutations in human neuronal progenitors and differentiated neuronal cell lines
Description
Coupled to high-resolution mass spectrometry ; Transcriptomics analyses: quality of the RNA will be evaluated with the Bioanalyzer (Agilent) on the basis of the RIN (RNA integrity number) as well as by taking into account the DV200, i.e. the percentage of RNA fragments with more than 200 nucleotides Non-targeted metabolomic analyses will be performed using a method based on ultra-high-performance liquid chromatography Flow injection analysis-tandem mass spectrometry for quantifying acylcarnitines, glycerophospholipids, sphingolipids and sugar, whereas liquid chromatography
Time Frame
Day 1
Title
The assessment of morphological consequences of CAMK2a mutations in human neuronal progenitors and differentiated neuronal cell lines
Description
immunocytochemistry and protein expression approaches using confocal microscopy and Western blotting with antibodies specific for proteins expressed in neurons (MAP2, Tubulin beta 3, PSD95, SNAP25), astrocytes (GFAP) or oligodendrocytes (Gal-C)
Time Frame
Day 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
2 Years
Maximum Age & Unit of Time
25 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 3 Whole Genome Sequencing negative cases 3 positive controls bearing distinct mutations in CAMK2a Exclusion Criteria: no informed consent/refusal
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Dominique BONNEAU
Phone
0241353883
Email
dobonneau@chu-angers.fr
First Name & Middle Initial & Last Name or Official Title & Degree
Dominique BONNEAU
Phone
0241353883
Facility Information:
Facility Name
CHU Angers
City
Angers
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dominique Bonneau
Facility Name
HCL Lyon
City
Bron
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gaëtan Lesca
Facility Name
CHU de Bourgogne
City
Dijon
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Anne-Sophie Denommée-Pichon
Facility Name
CHU Nantes
City
Nantes
Country
France
Individual Site Status
Completed
Facility Name
CHU Poitiers
City
Poitiers
Country
France
Individual Site Status
Completed
Facility Name
CHU Rennes
City
Rennes
Country
France
Individual Site Status
Completed

12. IPD Sharing Statement

Plan to Share IPD
No

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Multi-Omics and IPSCs to Improve Diagnosis of Rare Intellectual Disabilities

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