The effect of genetic factors on the severity of the ASD phenotype

Autism spectrum disorder (ASD) is a developmental disorder characterized by impairments in social communication and interaction on the one hand, and restricted and repetitive behaviours and interests, including hyper- of hyporeactivity to sensory input, on the other hand. ASD covers a phenotypically and genetically heterogeneous group of syndromes, but the overal risk of developing ASD has a strong genetic component. However, the genetics of autism are complex with, for example, both rare mutations and common variants, inherited risk and de novo mutations, and genes with a major impact and variants with a small contribution in play. It is unclear to what extent the genetic variation in ASD accounts for the phenotypical variation. Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by a loss of function mutation in the NF1 gene. The disorder is clinically defined by café-au-lait macules, intertriginous freckling, and various benign and malignant tumours. Patients with NF1 have a higher prevalence of neurodevelopmental complications, including a lower IQ, specific learning disorders, ADHD, and ASD. This finding suggests that NF1 mutations are involved in the development of ASD, making NF1 an interesting monogenic syndrome to study the influence of a rare genetic mutation on the presence, severity and variability of the ASD phenotype.
In this study we compare the clinical phenotype of patients with NF1 (aged 3 to 16 years) to that of a group of the same age with idiopathic ASD, using questionnaires, interviews, and observations. Phenotypical data concern the ASD core symptoms, but also anxiety, mood, motor development, executive functioning, adaptive behavior, intelligence, and parental stress. In a second phase, we compare both populations on experimental measures of social processing, visual processing, attention, and executive functioning.