The genetic architecture of autism is complex made of a combination of common and rare variants. Our previous studies pointed at one biological pathway associated with autism related to the synapse. Among the causative genes, synaptic cell adhesion molecules (neuroligins and neurexins) and scaffolding proteins (SHANK) are crucial for synapse formation/maintenance as well as correct balance between inhibitory and excitatory synaptic currents. These findings significantly advanced our knowledge on the possible causes of autism. However, they also (unintentionally) contributed to the emergence of a simplistic conception of autism as a binary trait: mutated vs. non-mutated or affected vs. non-affected. This simplification neglects the large phenotypic heterogeneity of autism, whose genetic architecture –like most complex diseases –cannot be reduced to a single gene. In this presentation, I will discuss our recent results coming from human studies in large populations and genetic isolates as well as mouse studies that shed new light on the inheritance of autism and some of the underlying mechanisms. Finally, I will illustrate how we are currently studyingResilienceto understand why some carriers of deleterious mutations seem to be protected (The Resilients) while others are severely affected.
Neurogenycs conference "Tackling the genetic and synaptic heterogeneity in autism from risk to resilience"
Thomas BOURGERON est à l’origine de la découverte des premières mutations des gènes NLGN3, NLGN4X et SHANK3 dans l’autisme, soulignant le rôle principal de la synapse neuronale dans la pathologie. Actuellement, son laboratoire rassemble des psychiatres, neuroscientifiques et généticiens qui poursuivent l’objectif de compréhension de l’interaction entre les variants génétiques fréquents et rares dans l’autisme. Il dirige le workpackage «génétique» pour le projet PARIS et l’étudeAIMS2-TRIALS, le plus grand projet européen dédié à la recherche translationnelle sur l’autisme. Il est co-investigateur principal (avec Olivier Gascuel) du projet INCEPTION de l’Institut Pasteur qui utilise la biologie intégrative comme outil de compréhension de l’émergence de maladies dans les populations et les individus.. Son objectif est d’approfondir les connaissances sur la pathologie afin d’améliorer le diagnostic, les soins et l’intégration des personnes atteintes d’autisme et de troubles neurodéveloppementaux.