Patterns of genetic changes found in mental retardation
Dutch and British researchers have shed more light on the connection between genes and mental retardation or intellectual disability. Thanks to their work, they shrank the list of genes whose changes trigger this disorder from thousands to several dozen. The findings are published in the open-access journal Public Library of Science (PLoS) Genetics. The results of the study are part of the ANEUPLOIDY ('Understanding the importance of gene dosage imbalance in human health using genetics, functional genomics and systems biology') project, which is funded under the EU's 'Life sciences, genomics and biotechnology for health' Thematic area of the Sixth Framework Programme (FP6). Financing for ANEUPLOIDY, which will end in November 2010, stands at EUR 12 million. The project aims to fuel the understanding of the molecular basis and pathogenetic mechanisms of aneuploidies (cells that have extra copies or missing copies of specific chromosomes). The researchers from the Radboud University Nijmegen Medical Centre in the Netherlands and the UK Medical Research Council at the University of Oxford noted that between 1% and 3% of the population is affected by mental retardation (also known as developmental or intellectual disability, this condition is characterised by subnormal intellectual functioning and impaired adaptive behaviour during one's developmental years). Various, yet individually rare DNA (deoxyribonucleic acid) deletions and duplications, lead to this disease. 'Mental retardation is defined as an overall intelligence quotient lower than 70, and is associated with functional deficits in adaptive behaviour, such as daily living skills, social skills and communication,' the authors write. 'This disorder results from extraordinarily heterogeneous environmental and genetic causes. Genetic changes underlying mental retardation are still poorly resolved, especially for the autosomes that provide the largest contribution to disease aetiology.' According to the team, microscopically visible chromosomal changes detected by routine chromosome analysis are responsible for mental retardation in 5% to 10% of patients. Such changes 'represent gains or losses of more than 5 [to] 10 Mb of DNA and affect many genes, thereby almost inevitably leading to developmental abnormalities during embryogenesis [formation and development of the embryo]', the research shows. Researchers agree that cognitive impairment is the most common effect of these variants. However, other abnormalities including dysmorphic features and heart defects are also linked with the variants. Identifying the DNA changes responsible for mental retardation was not easy to do because these changes are not concentrated in a small number of genes. For this study, the researchers obtained DNA from more than 150 people with mental retardation and compared it with descriptions of 5,000 mice whose genomes each had single genes disrupted. The DNA changes linked to mental retardation had many more genes whose loss in mice also impacted the nervous system. According to them, the extensive data from humans and mice were key in revealing a relatively small set of genes that contribute significantly to mental retardation in humans. Ultimately, the results offer solid evidence that genomic deletions and duplications are at the root of what triggers mental retardation. 'In conclusion, it appears that our approach identified a large number of interesting and plausible novel candidate genes for both mental retardation and associated clinical phenotypes,' the researchers wrote.