Grant: Operating Grant

Chromosomal imbalance is the most frequently recognized cause of intellectual disability, but mutations that alter the sequence and function of genes without causing chromosomal imbalance are probably an even more frequent cause. Mutations of about 300 genes that can produce intellectual disability have been identified, but it is likely that there are actually thousands of such "intellectual disability genes". Clinical methods are available to test for mutations of a specific gene that is suspected of being involved in a particular child, but it is impractical and prohibitively expensive to test for mutations of all of the different genes that might be responsible. Consequently, the cause of the intellectual disability in most affected children remains unknown. Massively parallel genomic sequencing, a newly-developed technology, provides a potential solution to this problem. Massively parallel sequencing can test for alterations of thousands of genes at once. We will use this method to look for mutations that cause intellectual disability in 25 affected children who have at least one similarly affected sibling but in whom no recognizable cause has been found by standard clinical assessment. We will then test the genes discovered in the familial cases in 200 unrelated children with intellectual disability to look for other instances that are caused by mutations of the same genes. This project will help to establish massively parallel genomic sequencing as a highly sensitive and cost-effective test for the evaluation of children with intellectual disability. Clinical implementation of this technology should improve the care of children with intellectual disability and permit more effective genetic counselling for affected families.