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

NCT03635294 | Completed

• 1 other identifier: 49RC17_0224
• Study Type: interventional
• Target: 7
• Locations: 1 country
• Sites: 6

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:

1. 1.Whole genome sequencing (WGS) (Nantes) of these 10 negative trios.
2. 2.Bio-informatics analyses
3. 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:
4. 4.Derivation of induced pluripotent stem cell (iPSC)-derived neural progenitors (iPSC core facility at Nantes)
5. 5.Targeted and non-targeted metabolomics analyses performed on iPSC-derived neuronal cells (Angers)
6. 6.RNA sequencing performed on the 9 cell lines (Rennes)
7. 7.Morphological analyses of differentiated neuronal cell lines derived from 3 affected individuals and 3 positive controls bearing CMK2a mutations (Tours)
8. 8.Integration and validation of data from multi-omics and morphological approaches

Conditions

Rare Intellectual Disabilities

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (2)

• 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

Study Arms (1)

Blood sample

EXPERIMENTAL

Blood sample for analyses

Other: Blood sample

Interventions

Blood sample OTHER

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

Blood sample

Eligibility Criteria

• Age: 2 Years - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

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

You may not qualify if:

• no informed consent/refusal

Sponsors & Collaborators

• University Hospital, Angers: lead

Study Sites (6)

CHU Angers

Angers, France

Location

HCL Lyon

Bron, France

Location

CHU de Bourgogne

Dijon, France

Location

CHU Nantes

Nantes, France

Location

CHU Poitiers

Poitiers, France

Location

CHU Rennes

Rennes, France

Location

MeSH Terms

Interventions

Blood Specimen Collection

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER GOV
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 10, 2018
• First Posted: August 17, 2018
• Study Start: January 9, 2019
• Primary Completion: February 11, 2020
• Study Completion: February 11, 2020
• Last Updated: August 14, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

FR (6)