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Presenter: Dr. Alistair Pagnamenta, Wellcome Trust Centre for Human Genetics, University of Oxford

Molecular diagnosis of intellectual disability disorders has typically consisted of sequential testing of candidate genes known to be associated with disease phenotypes but cannot always detect the causative mechanism. A better approach involves use of sequencing for greater diagnostic yield. Here we will examine a few different cases of early-onset epilepsy and hyperphosphatasia with intellectual disability (Mabry syndrome), an autosomal recessive form of ID, where different strategies were used to ascertain the molecular basis of the disorders. For hyperphosphatasia with ID, autozygosity mapping and exome sequencing was used for some cases and a targeted sequencing approach in other cases, with both methods leading to convergent findings – mutations in PGAP3. In an Ohtahara Syndrome case, use of WGS revealed paternal isodisomy of Chr9 leading to homozygosity of a missense mutation as the causative agent. We were able to identify novel genes for ID disorders using WGS in concert with traditional arrays and have demonstrated that WGS can provide comprehensive and rapid molecular diagnosis for patients with complex genetic diseases.