Sequence based analysis of neurodevelopmental disorders

Halvardson, J. 2016. Sequence based analysis of neurodevelopmental disorders. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1231. 62 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9597-8. In this thesis the main focus is the use of methods and applications of next generation sequencing in order to study three of the most common neurodevelopmental disorders: intellectual disability, epilepsy and schizophrenia. A large fraction of the genes in our genome produce several distinct transcript isoforms through the process of splicing and there is an increasing amount of evidence pinpointing mutations affecting splicing as a mechanism of disease. In Paper I we used exome capture of RNA in combination with sequencing in order to enrich for coding sequences. We show that this approach enables us to detect lowly expressed transcript and splice events that would have been missed in regular RNA sequencing using the same coverage. In Paper II we selectively depleted the different transcripts of Quaking (QKI), a gene previously associated to schizophrenia. Using RNA sequencing we show that the effects of depletion differ between transcripts and that the QKI gene is a potential regulator of the Glial Fibrillary Acidic Protein (GFAP), a gene implicated in several diseases in the central nervous system. De-novo mutations are frequently reported to be causative in neurodevelopmental disorders with a strong genetic component, such as epilepsy and intellectual disability. In Paper III we used exome sequencing in family trios where the child was diagnosed with both intellectual disability and epilepsy, focusing on finding de-novo mutations. We identified several previously unknown disease causing mutations in genes previously known to cause disease and used previously published interaction and mutation data to prioritize novel candidate genes. The most interesting result from this study are the implication of the HECW2 gene as a candidate gene in intellectual disability and epilepsy. In Paper IV we used RNA sequencing of post mortem brain tissue in a large cohort of schizophrenics and controls. In this study we could show that the immune system and more specifically the complement system was dysregulated in a large fraction of patients. Further, using co-expression network we also found some evidence suggesting genes involved in axon development and maintenance. Jonatan Halvardson, Department of Immunology, Genetics and Pathology, Rudbecklaboratoriet, Uppsala University, SE-751 85 Uppsala, Sweden. © Jonatan Halvardson 2016 ISSN 1651-6206 ISBN 978-91-554-9597-8 urn:nbn:se:uu:diva-287407 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-287407)