Genetic variation and complex rearrangements in Autism Spectrum Disordersimplications for genetic counseling

Resumo

The etiology of Autism Spectrum Disorders (ASD) remains unknown for most of the cases, in spite of its strong genetic component. A greater knowledge of its genetic basis would result in many benefits, including specific genetic counseling for families and, eventually, the development of personalized therapeutic strategies. In this thesis, we have applied several recent sequencing technologies and adapted pipelines to its study. We have investigated the role of rare variants and its transcriptional consequences and explored the contribution of complex rearrangements to its missing heritability. In addition, we have studied second-hit susceptibility genetic factors in a group of individuals with Williams-Beuren syndrome, a genomic disorder associated with a mirror phenotype. Finally, we have explored parental knowledge and the effect of genetic counseling in affected families. Our results reveal that both highly penetrant mutations and inherited variants of milder effect contribute to its susceptibility, following monogenic and oligogenic or multifactorial models, respectively. Each of them may contribute to part of the variability and may explain a subset of cases.