2014 ASHG: Implementing an Augmented Clinical Exome and Reference Improvements to Enhance Diagnostic Yield and Discovery

Clinical exome sequencing is increasingly used for solving diagnostic odyssey cases in children with suspected genetic syndromes and cancer. The complex process of going from DNA sample to clinical report involves multiple, technologically, scientifically, and medically complex steps; despite early success, significant improvements can be made to increase the overall diagnostic yield of exome sequencing tests. To improve diagnostic yield, we have developed an augmented exome approach to increase gene finishing as well as sensitivity and specificity of exome sequencing to achieve clinical grade performance. Furthermore, we explore methods of enhancing the informatics pipeline performance through human reference improvements.