Since 2012, at Baylor College of Medicine (BCM), the Baylor-Johns Hopkins Center for Mendelian Genomics has initiated collaborations with nearly 275 investigators in 18 countries to identify novel disease genes in patients with hypothesized Mendelian disease and to describe the full extent of phenotypic expression of established Mendelian diseases (i.e. phenotypic expansion).
Towards this effort, the Baylor College of Medicine Human Genome Sequencing Center (BCM-HGSC) has generated more than 20 Tb of whole exome data for more than 300 phenotypes using its high-throughput multiplexed exome pipeline.
Whole exome sequencing (WES) is favored for the molecular analysis of Mendelian disorders because of its efficiency, cost effectiveness and the opportunity for novel gene/mutation discovery. Samples were multiplexed for both capture and sequencing, and full-length blocking oligos were employed for hybridization to enhance on target specificity. Using this format, ~10 Gb was generated for each sample to provide ~90% of the target bases at 20X coverage or greater. This pipeline, producing 3,000 capture libraries per month, is automated from library construction through annotated VCF generation in part using the ‘Mercury’ analysis pipeline. We have so far enrolled more than 4,000 subjects for the WES studies and completed sequencing for more than 2,500, resulting in the identification of disease causing mutations in 162 known and 91 novel genes.