Identification of genetic factors involved in autism spectrum disorders and dyslexia

• Main Author: Huguet, Guillaume
• Other Authors: Génétique Humaine et Fonctions Cognitives, Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS), Université René Descartes - Paris V, Thomas Bourgeron
• Format: Doctoral or Postdoctoral Thesis
• Language: French
• Published: HAL CCSD 2013
• Subjects: Genetics; Dyslexia; Autism; CNV; Synapse; Genes; Mutations; Selection pressure; Génétique; Dyslexie; Autisme; Gènes; Pression de sélection; [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology; Faroe Islands
• Online Access: https://theses.hal.science/tel-01124276; https://theses.hal.science/tel-01124276/document; https://theses.hal.science/tel-01124276/file/2013PA05T078.pdf

Autism spectrum disorders (ASD) affect 1% of the general population. These disorders are characterized by deficits in social communication as well as stereotyped behaviors and restricted interests. Several genes involved in the determination of ASD have been identified, such as NLGN3-4, NRXN1-3 and SHANK1-3. In the previous years, ASD have been considered as a complex set of monogenic disorders. Recent studies on the complete genome nevertheless suggest the presence of modifier genes ("multiple hits model"). Dyslexia is characterized by difficulties in learning to read and write. It affects 5-15 % of the general population. Genetic factors involved remain unknown. Only candidate genes or loci have been identified. My thesis had two main objectives: pursuing the identification of genetic factors involved in ASD, and discovering a first genetic factor for dyslexia. I therefore studied two types of populations: on the one hand a group of patients with ASD (N > 600) from France, Sweden and the Faroe Islands, and on the other hand another group of patients with dyslexia (N > 200) from France, and more specifically a family of 11 people followed over 3 generations. I used both Illumina microarrays technology (600K and 5M) and the complete human genome sequencing to conduct linkage and association analyses. Regarding ASD, CNVs (copy number variants) analyses allowed me to confirm the association of several synaptic genes with autism and to identify new candidate genes. In particular, the study of a population of 30 patients from the Faroe Islands confirmed the involvement of NLGN1 and NRXN1 genes in autism and identified a new candidate gene, IQSEC3. At the same time, I explored PRRT2 located in 16p11.2. PRRT2 encodes a member of the synaptic SNARE complex that allows the release of synaptic vesicles. I have not been able to demonstrate any association with ASD, but I showed that this gene, which is important for some neurological diseases, was under different selection pressures according to the population ...