SUMMARYWhole genome sequencing (WGS) is championed by the UK National Health Service (NHS) to identify genetic variants that cause particular diseases. The full potential of WGS has yet to be realised as early data analytic steps prioritise protein-coding genes, and effectively ignore the less well annotated non-coding genome which is rich in transcribed and critical regulatory regions. To address, we developed a filter, which we call GROFFFY, and validated in WGS data from hereditary haemorrhagic telangiectasia patients within the 100,000 Genomes Project. Before filter application, the mean number of DNA variants compared to human reference sequence GRCh38 was 4,867,167 (range 4,786,039-5,070,340), and one-third lay within intergenic areas. GROFFFY removed a mean of 2,812,015 variants per DNA. In combination with allele frequency and other filters, GROFFFY enabled a 99.56% reduction in variant number. The proportion of intergenic variants was maintained, and no pathogenic variants in disease genes were lost. We conclude that the filter applied to NHS diagnostic samples in the 100,000 Genomes pipeline offers an efficient method to prioritise intergenic, intronic and coding gDNA variants. Reducing the overwhelming number of variants while retaining functional genome variation of importance to patients, enhances the near-term value of WGS in clinical diagnostics.
S67 Whole genome sequencing of patients with pulmonary arteriovenous malformations and hereditary haemorrhagic telangiectasia