Faculty of Medicine

The study will utilize whole exome sequencing using the Illumina Genome Analyzer pipeline at the Michael Smith Genome Sciences Centre. The resulting data will be analysed bioinformatically to identify candidate autosomal recessive ID loci as defined by those with coding segment mutations that are predicted to inactivate or otherwise adversely alter gene function of both alleles. Putative autosomal recessive ID loci detected by sequencing will then be confirmed in the proband, affected sib(s) and both parents by resequencing using conventional Sanger technology.

Once these mutations have been confirmed in the family, they will be tested for in a cohort of 200 unrelated children with idiopathic ID to determine the frequency of pathogenic mutations of these loci as causes of idiopathic ID. Finally, the absence of these candidate ID mutations in normal populations will be determined by analysis of the publicly available genome sequences of more than 1200 unaffected individuals.

The aim of this study was to identify pathogenic copy number variants by performing AGH with 100 K and than 500 K Affymetrix GeneChip® arrays on 200 children with moderate to severe cognitive impairment of unknown cause. In addition to intellectual disability, the children also had a major malformation or multiple minor anomalies. A further aim of this study was to establish the clinical utility of Array Genomic Hybridization as a tool to identify microdeletions or duplications as a potential cause of intellectual disability. While conventional cytogenetic techniques identify an abnormality in about 10% of children with cognitive impairment, studies such as this have found that 15-20% of children with apparently 'normal' karyotypes can be shown to have a genomic imbalance.