Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and verbal and non-verbal communication (DSM-5, 2013), affecting approximately 2% of the general population. In 5 to 40% of cases, genetic factors are identified as the cause of these disorders, with prevalence depending on the technique used (exomes and/or SNP arrays) and the associated intellectual deficit. In the majority of cases, the etiology remains unknown. Studies of microdeletions/microduplications (copy number variants) or Whole Exome Sequencing and Whole Genome Sequencing (Single Nucleotide Variants) show the involvement of numerous genes in the predisposition to autism. ASD remains a genetically heterogeneous disorder, as more than 250 genes have been associated with ASD to date.
The main objective of the project is to continue identifying genetic factors, and also to understand the biological mechanisms involved in the emergence of autistic symptoms.
Identifying biological pathways is an essential step in developing new therapeutic strategies. In addition, one of the major challenges of this study is to better understand the phenotype/genotype relationships in ASD. This requires in-depth knowledge of the phenotypic characteristics of participants with ASD and their families, as well as neurotypical populations. This study combines the scientific expertise of researchers specializing in molecular biology, phenotypic exploration (clinical, cognitive, MRI, EEG, biochemistry, immunology), and the use of pre-therapeutic cellular models (iPSCs, neural precursors, organoids).
The objective of this work is the identification of numerous genes associated with ASD and involved in synaptic formation and regulation: NLGN3-4, SHANK1 and SHANK3, CNTN-6, and CNTNAP4. This work was combined with in-depth phenotypic explorations of ASD participants and their relatives. It has made it possible to clarify the neuroanatomical characteristics of participants with ASD and their genetic substrate, as well as the underlying cognitive processes.
All of this work opens up new prospects for identifying new therapeutic targets using preclinical cell models (IPSCs Induced pluripotent stem cells, neural progenitors, organoids) developed in particular by I-Stem and Human Technopole.