- ICH GCP
- Amerikanska kliniska prövningsregistret
- Klinisk prövning NCT03635294
Multi-Omics and IPSCs to Improve Diagnosis of Rare Intellectual Disabilities (MIDRID)
Multi-Omics and IPSCs to Improve the Diagnosis of Rare Intellectual Disabilities
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
Studieöversikt
Status
Betingelser
Intervention / Behandling
Studietyp
Inskrivning (Förväntat)
Fas
- Inte tillämpbar
Kontakter och platser
Studiekontakt
- Namn: Dominique BONNEAU
- Telefonnummer: 0241353883
- E-post: dobonneau@chu-angers.fr
Studera Kontakt Backup
- Namn: Dominique BONNEAU
- Telefonnummer: 0241353883
Studieorter
-
-
-
Angers, Frankrike
- Har inte rekryterat ännu
- CHU Angers
-
Kontakt:
- Dominique Bonneau
-
Bron, Frankrike
- Rekrytering
- HCL LYON
-
Kontakt:
- Gaetan Lesca
-
Dijon, Frankrike
- Har inte rekryterat ännu
- CHU de Bourgogne
-
Kontakt:
- Anne-Sophie Denommée-Pichon
-
Nantes, Frankrike
- Avslutad
- CHU Nantes
-
Poitiers, Frankrike
- Avslutad
- CHU Poitiers
-
Rennes, Frankrike
- Avslutad
- CHU Rennes
-
-
Deltagandekriterier
Urvalskriterier
Åldrar som är berättigade till studier
Tar emot friska volontärer
Kön som är behöriga för studier
Beskrivning
Inclusion Criteria:
- 3 Whole Genome Sequencing negative cases
- 3 positive controls bearing distinct mutations in CAMK2a
Exclusion Criteria:
- no informed consent/refusal
Studieplan
Hur är studien utformad?
Designdetaljer
- Primärt syfte: Diagnostisk
- Tilldelning: N/A
- Interventionsmodell: Enskild gruppuppgift
- Maskning: Ingen (Open Label)
Vapen och interventioner
Deltagargrupp / Arm |
Intervention / Behandling |
---|---|
Experimentell: Blood sample
Blood sample for analyses
|
combining genomics, transcriptomics, metabolomics and morphological analyses performed on induced pluripotent stem cell (iPSC)-derived neural cells
|
Vad mäter studien?
Primära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
---|---|---|
To evaluate the relevance and effectiveness of a multi-omics approach to the diagnosis of ID of unknown genetic origin.
Tidsram: 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
|
Day 1
|
Sekundära resultatmått
Resultatmått |
Åtgärdsbeskrivning |
Tidsram |
---|---|---|
The assessment of metabolomics consequences of CAMK2a mutations in human neuronal progenitors and differentiated neuronal cell lines
Tidsram: Day 1
|
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
|
The assessment of morphological consequences of CAMK2a mutations in human neuronal progenitors and differentiated neuronal cell lines
Tidsram: Day 1
|
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
|
Samarbetspartners och utredare
Sponsor
Studieavstämningsdatum
Studera stora datum
Studiestart (Faktisk)
Primärt slutförande (Förväntat)
Avslutad studie (Förväntat)
Studieregistreringsdatum
Först inskickad
Först inskickad som uppfyllde QC-kriterierna
Första postat (Faktisk)
Uppdateringar av studier
Senaste uppdatering publicerad (Faktisk)
Senaste inskickade uppdateringen som uppfyllde QC-kriterierna
Senast verifierad
Mer information
Termer relaterade till denna studie
Ytterligare relevanta MeSH-villkor
Andra studie-ID-nummer
- 49RC17_0224
Plan för individuella deltagardata (IPD)
Planerar du att dela individuella deltagardata (IPD)?
Läkemedels- och apparatinformation, studiedokument
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