1000 Trio exomes; Insights into severe developmental disorders. M. Van KOGELENBERG, T. Fitzgerald, W. Jones, J. C. Barret, M. Hurles on behalf of the DDD project The Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
The UK-based Deciphering Developmental Disorders (DDD) project aims to delineate the genetic architecture in children with undiagnosed severe developmental disorders. The study employs a high throughput approach that aims to recruit 12.000 children with developmental disorders and their parents via all of the 24 Regional Genetics Services in the UK and republic of Ireland.
The clinically diverse patient cohort in this study requires the consideration of both inherited and de novo disease models. Our approach is focused on detecting sequence variants in all coding exons, known enhancers, and the most highly conserved non-coding element. De novo exome variants where systematically validated by capillary sequencing which detected ~0.88 coding or splice de novo mutations (DNM) per trio.
Here we intend to present an overview of the exome data analysis in 1000 patient-parent trios. This includes various types of burden analysis such as the detection of a significant enrichment of loss of function DNM variants, in addition to DNM protein altering variants being more frequently present in dosage sensitive genes. Further, we will discuss the significance of identifying variants in known monoallelic disease genes, as well as the detection of recurrent functional DNM in both known disease genes (19) and genes not previously associated with human disease (26).
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