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This thesis addresses young adults with Alström syndrome (AS). AS causes acquired deafblindness, a severe, progressive, combined auditory and visual impairment affecting daily life and self-reliance to a degree that full participation depends on help from others and society. AS is an autosomal, recessively inherited single-gene disorder that affects the ALMS1 gene. AS has a multi-systemic pathology including a high incidence of additional multiple endocrine abnormalities, cardiomyopathy, pulmonary fibrosis, restrictive lung disease and progressive hepatic and renal failure leading to reduced life expectancy. The focus in the present thesis is on the development of Theory-of-mind (ToM) and on how ToM relates to the development of certain cognitive skills and the characteristics of the individual social network. ToM refers to the ability to understand the thoughts and feelings of others. The results reveal that individuals with AS displayed a significantly higher degree of heterogeneity in the performance of ToM tasks, and some individuals with AS performed on an equal level with nondisabled individuals. ToM performance was predicted by verbal ability and executive functioning (EF), whereas working memory capacity (WM) proved to be an indirect predictor. Later onset of visual loss further characterized AS individuals with better ToM. The sizes of the social networks of individuals with AS were smaller relative to those of nondisabled individuals, and many of the acquaintances were professionals working with individuals with AS. The number of friends correlated with ToM performance. Methods to improve verbal ability and EF, and interventions to enhance social participation in childhood of individuals with AS might prove to be fruitful. In addition assistive technology to establish and maintain friendships in adulthood is required.

Certaines maladies héréditaires monogéniques sont caractérisées par une grande hétérogénéité génétique. Chez des individus présentant un phénotype clinique similaire, les mutations causales peuvent être retrouvées dans un des gènes parmi un sous-ensemble décrits comme impliqués dans la maladie. Cette hétérogénéité génétique limite considérablement les offres diagnostiques pour les patients, et une majorité reste sans diagnostic moléculaire. Nous avons développé une approche diagnostique alternative par séquençage à haut débit ciblé (ciblant spécifiquement les régions codantes des gènes d’intérêt par capture d’exons), au travers de trois pathologies génétiquement hétérogènes : le syndrome de Bardet-Biedl (19 gènes décrits), les leucodystrophies (50 gènes), et la déficience intellectuelle (>400 gènes). Au vu de son efficacité dans le syndrome de Bardet-Biedl et la déficience intellectuelle (80% et 25% de mutations détectées respectivement, soit des taux nettement supérieurs à ceux des méthodes précédentes), elle est depuis appliquée en routine diagnostique. Au-delà du diagnostic, cette approche permet de manière non biaisée de revoir la contribution de chacun des gènes dans la pathologie et donc d’identifier les gènes récurrents, et d’établir de nouvelles corrélations génotype/phénotype. / Some monogenic disorders are characterized by a vast genetic heterogeneity. In individuals with similar clinical phenotype, causative mutations can be found in one gene from a subset described as implicated in the disease. Such genetic heterogeneity limits considerably the diagnostic offer for the patients, and a majority is left without molecular diagnosis. We developed an alternative diagnostic approach by targeted high throughput sequencing (specific to the coding regions of genes of interest by a technique of exon capture) through three genetically heterogeneous disorders: Bardet-Biedl syndrome (19 genes reported), leukodystrophies (50 genes), and intellectual disability (>400 genes). In light of its efficiency, this approach has since been implemented in diagnostic routine for Bardet-Biedl syndrome and intellectual disability (80% and 25% of diagnostic yields respectively, significantly higher than those of previous methods). Beyond diagnosis, this approach allows unbiased means to assess the contribution of each gene in the disease and highlight recurrent genes, and establish new correlations genotype to phenotype, overall providing much insight in the genetics of a particular disease.