Grant: CIHR Fellowship

Intellectual disability (ID) is a life-long and debilitating condition with deficits in cognitive functioning and social skills, often with behavioural issues such as autism, epilepsy and other disabilities. ID affects 2-3% of children globally making it one of the most common disorders. As a disease category, its health care cost is massive-almost equal to the combined economic impact of stroke, heart disease and cancer. Moreover ID places a profound psychological burden on a family with an affected child. In about half of children with ID, no cause is recognized, exacerbating the emotional trauma for the family and hindering patient care. The highest yielding current diagnostic test for ID is microarray, which detects gains or losses of genetic material called copy number variants (CNVs) in 15% of patients. In addition to CNVs, DNA sequence changes or mutations are known in about 300 genes that cause ID. Testing for these mutations must be done one-by-one in a time-consuming and expensive process.Medical management is immediately improved once a diagnosis is established, often leading to educational and social support for the family. A new technology, 'next generation sequencing' or NGS is able to read the child's entire DNA sequence in a single test. NGS can also detect CNVs, making it a powerful and comprehensive screen for a causative genetic change. We will use NGS to look for causative mutations in 10 affected children in whom no recognizable cause has been found by standard assessment, and both their normal parents. Testing both parents, will enable us to distinguish inherited normal genetic change events from mutations that have newly arisen in the child and are likely disease causing. We will then test the genes identified in 50 unrelated children with ID, to establish their frequency. This project will potentially diagnose patients with ID, discover new genes for the disease and help establish NGS as a tool in routine clinical testing.