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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT03635294
Other study ID # 49RC17_0224
Secondary ID
Status Recruiting
Phase N/A
First received
Last updated
Start date January 9, 2019
Est. completion date March 2020

Study information

Verified date January 2020
Source University Hospital, Angers
Contact Dominique BONNEAU
Phone 0241353883
Email dobonneau@chu-angers.fr
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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:

1. Whole genome sequencing (WGS) (Nantes) of these 10 negative trios.

2. Bio-informatics analyses

3. 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:

1. Derivation of induced pluripotent stem cell (iPSC)-derived neural progenitors (iPSC core facility at Nantes)

2. Targeted and non-targeted metabolomics analyses performed on iPSC-derived neuronal cells (Angers)

3. RNA sequencing performed on the 9 cell lines (Rennes)

4. Morphological analyses of differentiated neuronal cell lines derived from 3 affected individuals and 3 positive controls bearing CMK2a mutations (Tours)

5. 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


Recruitment information / eligibility

Status Recruiting
Enrollment 6
Est. completion date March 2020
Est. primary completion date March 2020
Accepts healthy volunteers No
Gender All
Age group 2 Years to 25 Years
Eligibility Inclusion Criteria:

- 3 Whole Genome Sequencing negative cases

- 3 positive controls bearing distinct mutations in CAMK2a

Exclusion Criteria:

- no informed consent/refusal

Study Design


Intervention

Other:
Blood sample
combining genomics, transcriptomics, metabolomics and morphological analyses performed on induced pluripotent stem cell (iPSC)-derived neural cells

Locations

Country Name City State
France CHU Angers Angers
France HCL Lyon Bron
France CHU de Bourgogne Dijon
France CHU Nantes Nantes
France CHU Poitiers Poitiers
France CHU Rennes Rennes

Sponsors (1)

Lead Sponsor Collaborator
University Hospital, Angers

Country where clinical trial is conducted

France, 

Outcome

Type Measure Description Time frame Safety issue
Primary 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 Day 1
Secondary 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 Day 1
Secondary 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) Day 1