Expression Profiling and Population Structure Analysis of Copy Number Variants (CNVs) in Autism Spectrum Disorder (ASD): 1st Triennium Post Doc Fellowship Report

Pires Carreira da Conceição, Inês Susana

http://hdl.handle.net/10400.18/2208

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Authors

Pires Carreira da Conceição, Inês Susana

Abstract(s)

Autism Spectrum Disorder (ASD) is a common complex behavioral disorder with significant clinical heterogeneity and unclear etiology. Assessment protocols and diagnostic instruments are complex to implement, and not widely used by most clinical practitioners or pediatricians worldwide. It is well known that educational interventions, language and behavioral therapies may significantly improve the patient’s quality of life, and are particularly beneficial when initiated at a young age. While the contribution of genetic factors for ASD etiology has been clearly established by family and twin studies, common risk genes accounting for a high proportion of autism heritability have not yet been identified1. At the same time, the increased burden of rare variants in ASD is increasingly recognized from genomic screening in large population samples. The latest genome wide association studies (GWAS) have failed to find common risk variants with a significant impact, however all have shown an excess of rare and heterogeneous structural variants designated Copy Number Variants (CNV). The significance of most of these rare CNVs for etiological diagnosis of ASD still needs to be properly addressed. The importance of rare variation in autism has also been supported by the many reports of rare mutations in synaptic candidate genes (such as SHANK, MET, NLGN, NRNX amongst others). It seems likely that both common low risk genes and rare, high penetrance, variants will converge in a restricted number of biological pathways. Our group is part of the international consortium Autism Genome Project (AGP), which gathers more than 100 scientists in 13 investigation centers. Recently it has been conducting a Genome Wide Association Study (GWAS), with more than 3000 families of autistic patients, including 342 Portuguese families. In this GWAS analysis, almost 40.000 CNVs were identified in patients and parents, the functional consequences and relevance of these CNVs is being analyzed. Also, the correlation between genetic and clinical data in a large scale sample is uncommon, but very important for a better characterization of the pathology. Our sample has the major advantage of a detailed clinical evaluation following the Autism Speaks project funded The Autism Trio Collection (TASC) project.