Supervisor: Professor Ants Kurg, University of Tartu
Opponent: Dr Reinhard Ullmann, Max Planck Institute for Molecular Genetics, Germany
Intellectual disability (ID) is a neurodevelopmental disorder with a population prevalence of approximately 2% and high socio-economical burden on the patients' families and the society. Due to the heterogeneous aetiology of ID, disease-causative factors have remained unknown in about half of patients with cognitive impairment. Over the recent years, the biotechnological progress in human genomics has enabled a whole-genome approaches to study the genetic background of diseases and revealed small chromosomal gains and losses - DNA copy number variations (CNVs) - as one of the major contributors to the aetiology of developmental disorders. However, these CNVs can also be harmless variants in the human genome or act as susceptibility factors for common diseases and phenotypic traits. Moreover, numerous CNVs initially detected in patients with brain-related disorders also occur with lower frequency in apparently normal individuals. Thus, challenging the assessment of the consequence of CNVs on individual's health and development. The current study was the first comprehensive effort to investigate genomic causes of cognitive impairment and associated complex phenotypes in Estonian patients with unexplained ID and general population individuals. As a result of the study, genetic diagnosis was established in 18 investigated families (the diagnostic yield of 23%) and rare CNVs of neuropsychological relevance were found in 19 Estonian general population individuals. By participating in collaborative investigations, the core clinical features were established for novel genomic disorders associated with regions 7q11.23 and 16p11.2 in the human genome. In summary, the results of this study demonstrated the importance of rare CNVs in the aetiology of neurodevelopmental disorders and proved that whole-genome screening for genomic rearrangments is an effective tool in research and diagnostics.