Genetic basis of intellectual disability and other cognitive disorders – GenCognition

In this project, the knockout mouse is used as a fast and cheap means to find novel intellecual disability genes across the genome, and through well-established collaborations with the Sanger Institute (Hinxton, UK) and the Mouse Clinical Institute (Strasbourg, France).
A pilot screen of abnormal brain morphology has already yielded success with the identification of two genes: Chd7 (Chromodomain Helicase Dna binding protein 7) and Wdr47 (WD repeat domain 47), both associated with corpus callosum agenesis in the mouse. Mutations in Chd7 have previously been reported to be the underlying pathological cause in a majority of patients with CHARGE syndrome. Identification of known Chd7 gene acts as a proof that the screen can detect abnormality in the mouse that translates into human pathology. There is very limited literature on Wdr47, and its role in the development of cognitive disorders and its possible role in axon outgrowth guidance remains to be investigated. Genes identified in the mouse will then be screened for deleterious mutations in relevant human cohorts with intellectual disability, and tested in other functional studies.

So far the main results of the project are:
1) the identification of an additional 21 genes associated with brain defects in the mouse.
2) the development of a cellular model to characterise the function of Wdr47. Interestingly we have also found mutations in the human WDR47 gene in a human cohort with intellectual disability.

This project consists of a multidisciplinary approach to advance our understanding of the genetics of intellectual disability and other cognitive disorders, ultimately aiming to improve diagnosis and treatment. The proposed research integrates large-scale mouse knockout analysis and is grounded in a strong multidisciplinary perspective, combining mouse and human genetics, and developmental neurobiology.

in progress

Intellectual disability (ID) and other cognitive disorders remain one of the least understood and investigated health problems. In fact, it has only recently become apparent that a large number of causative genes remain to be discovered. Current approaches are becoming increasingly difficult as the remaining unidentified genes exist only in small families. Large-scale genome-wide resequencing has been proposed as the future key strategy; however this approach remains very expensive and has highlighted issues confronting large-scale screens, including the difficulties distinguishing causative mutations from other genetic variation. My proposal deals with the problem of the «missing» (as yet unidentified) genes in syndromic forms of ID. The general aim is to identify novel human cognition genes by screening abnormal morphology of the mouse brain. The proposed approach represents a highly innovative and original undertaking, which has high potential to overcome current difficulties and advance our understanding of these devastating disorders, ultimately aiming at improving diagnosis and treatment. I will screen knockout (KO) mice by using EUCOMM (EUropean COnditional Mouse Mutagenesis) program, for neuroanatomical abnormalities, in a high-throughput manner. Preliminary data confirm the power of this approach and its ability to identify genes rapidly: I identified two KO mutants (Wdr47 and Chd7) by screening 100 KO genes during a two-month pilot project. Genes identified in the mouse will then be screened for deleterious mutations in relevant human cohorts with ID, and tested in other functional studies such as expression study of whole transcriptome. The proposed research integrates large-scale mouse knockout analysis and is grounded in a strong multidisciplinary perspective, combining mouse and human genetics, and developmental neurobiology.