UBC Theses and Dissertations
Autism spectrum disorders : identification of novel microdeletions and microduplications and their associated phenotypes Riendeau, Noémie
Background: Autism Spectrum Disorders (ASDs) are common, heritable neurobiologic conditions of unknown etiology confounded by significant clinical and genetic heterogeneity. In recent years, array CGH technology has been used to rapidly screen the genome for pathogenic copy number variants (PCNVs) associated with ASDs and data from 6 studies suggests that PCNVs contribute to ASD pathogenesis in 6-27% of cases. However, the role of PCNVs in ASDs remains poorly understood, due to the absence of comprehensive phenotyping of ASD subjects. Methods: To address this, we collected detailed clinical, medical, physical and morphologic information on all subjects and investigated whether these phenotypes would be good indicators of PCNV risk. We studied somatic phenotypes, as opposed to behavioural indices that change over time and with treatment, in an attempt to provide better evidence for the biological/embryological origin of ASDs and help define new ASD syndromes. Results: Seven disease-specific and potentially pathogenic CNVs were uncovered in 6/40 patients (15%). Two changes were de novo and 5 were inherited from normal parents, but had never been reported in normal populations before. All PCNVs were discovered in individuals without family history of autism, ranged in sizes from 175kb to 2.5Mb, and revealed 9 good candidate genes. Our results suggest that whilst no single phenotypic feature investigated associates with PCNV risk, there is an indication that the presence of phenotypic abnormalities involving multiple body areas may be a better indicator of PCNVs in ASDs than the presence or number of minor physical anomalies alone. In addition, our findings lend support to the idea that complex autism, involving significant dysmorphology, is etiologically distinct from essential autism, with an increased prevalence of ID, seizures and health problems, and a higher proportion of individuals without family history of ASDs. Conclusion: We identified novel areas of chromosomal imbalance associated with ASDs and provide detailed phenotypic information for every subject for which these new PCNVs were detected. The extensive phenotyping of affected individuals carrying clinically relevant CNVs is needed in order to understand their role in the etiology of autism and ultimately provide earlier and more reliable means for ASD diagnosis and treatment.
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