Nicole Nehls, Tze Sheng Yap, Talya Salant, Mark Aronson, Gordon Schiff, Suzanne Olbricht, Swapna Reddy, Scot B Sternberg, Timothy S Anderson, Russell S Phillips, James C Benneyan
Systems engineering analysis of diagnostic referral closed-loop processes
BMJ open quality
rare dna alterations cause heritable diseases partially resolvable clinical nextgeneration sequencing due difficulty detecting structural variation sv genomic contexts longread high fidelity genome sequencing hifigs detects svs increased sensitivity enables assembling personal graph genomes leverage standard reference genomes public assemblies n 94 large collection hifigs data rare disease program genomic answers kids ga4k n 574 assemblies build graph genome representing unified sv callset ga4k identify common variation prioritize svs likely cause genetic disease maf 001 using graphs obtain higher level reproducibility standard reference approach observe 200000 sv alleles unique ga4k including nearly 1000 rare variants impact coding sequence improved specificity rare svs isolate 30 candidate svs phenotypically prioritized genes including known disease svs isolate novel diagnostic sv kmt2e demonstrating use personal assemblies coupled pangenome graphs rare disease genomics community may interrogate pangenome additional assemblies discover new svs within allele frequency spectrum relevant genetic diseases