Clinical trial NCT03635294: Multi-Omics and IPSCs to Improve Diagnosis of Rare Intellectual Disabilities
Official title: Multi-Omics and IPSCs to Improve the Diagnosis of Rare Intellectual Disabilities
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Rare Intellectual Disabilities
Lead sponsor: University Hospital, Angers
Sponsor class: OTHER_GOV
First posted: 2018-08-17
Enrollment: 7
Sex: ALL
Minimum age (years): 2
Maximum age (years): 25
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: DIAGNOSTIC

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. 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


Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

* no informed consent/refusal

Primary outcomes:
measure: To evaluate the relevance and effectiveness of a multi-omics approach to the diagnosis of ID of unknown genetic origin.
timeFrame: Day 1
Secondary outcomes:
measure: The assessment of metabolomics consequences of CAMK2a mutations in human neuronal progenitors and differentiated neuronal cell lines
timeFrame: Day 1
measure: The assessment of morphological consequences of CAMK2a mutations in human neuronal progenitors and differentiated neuronal cell lines
timeFrame: Day 1
Other outcomes:
Locations:
city: Angers
country: France
facility: CHU Angers
city: Bron
country: France
facility: HCL Lyon
city: Dijon
country: France
facility: CHU de Bourgogne
city: Nantes
country: France
facility: CHU Nantes
city: Poitiers
country: France
facility: CHU Poitiers
city: Rennes
country: France
facility: CHU Rennes
Study officials:
References: