Maximizing the power of genomic sequencing in pediatric rare disease

Abstract At Boston Children’s Hospital, patients receive CLIA-grade short-read whole-exome and -genome sequencing through the Children’s Rare Disease Cohort initiative, which includes more than 50 specialized research studies covering hundreds of rare diseases. Data for over 13,800 patients and their families have been harmonized and analyzed with a wide range of interpretation tools. Many of these patients, who would otherwise be ineligible for clinical genetic testing, have received actionable clinical findings from this study. Overall, 35% of patients have either had a genetic finding clinically confirmed and returned or a candidate variant being further researched. To shed light on the remaining unsolved cases, we initiated more in-depth analysis using long-read sequencing on hundreds of patients and their families in collaboration with Oxford Nanopore Technologies. Extracted DNA of undiagnosed patients with rare diseases and their direct relatives are being sequenced using Oxford Nanopore long-read whole-genome sequencing (LR WGS) methodologies. SNVs/small indels, CNVs, SVs, and STRs are identified through the EPI2ME human-variation workflow. The resulting variants are being processed through an in-house tertiary pipeline tailored for long-read data and integrated into our genomic learning system via the GeneDx Discovery Platform. This workflow allows easy access to annotated and filtered data by research groups and greatly facilitates pathogenic variant identification. Analysis of these data will be presented during the meeting and will support emerging recommendations for research-informed clinical care in support of pediatric rare diseases. Biography Wanqing Shao completed her PhD under Dr. Julia Zeitlinger at the Stowers Institute, utilizing genomic approaches to study polymerase II pausing. She then pursued postdoctoral training at Washington University School of Medicine under Dr. Ting Wang, developing computational tools to unravel transcriptional and epigenetic landscapes of transposable elements. Currently, Wanqing is a Genomic Scientist at Boston Children's Hospital, where she leads and engages in computational analyses for the Children's Rare Disease Cohort initiative.