From freezer to findings: Oxford Nanopore sequencing for rare disease research | LC 25

Biography

Nathaniel Edisis works with the Children's Rare Disease Research Group at Boston Children’s Hospital, The Manton Center for Orphan Disease Research, and other local scientists to integrate cutting-edge genomics technologies into rare disease research. He is a Research Assistant conducting and overseeing genomic sequencing, including nanopore sequencing, at the Molecular Genetics Core in Boston Children’s Hospital.

Abstract

Researchers have demonstrated the emerging viability of long-read whole-genome sequencing (LR-WGS) as a tool that can identify a wider swath of genetic variation than traditional short-read next-generation sequencing, including larger structural variants (SVs), short-tandem repeat expansions (STRs), and epigenetic variance in DNA methylation. Extracting more information from sequencing data is alluring to the field of rare disease research, where the diagnostic yield is optimistically half of all enrolled patients. The adoption of LR-WGS technology like nanopore sequencing into rare disease research, though, involves certain practical challenges. As our technological milieu shifts to longer, native DNA sequencing, can and should rare disease researchers adopt LR-WGS? The BEACON project aims to answer these questions by using nanopore whole-genome sequencing on up to 1000 patients from the Children’s Rare Disease Collaborative (CRDC) Program at Boston Children’s Hospital with previous negative short-read whole-genome or exome sequencing. At present, we have sequenced the genomes of 499 individuals, including 194 families with a suspected Mendelian mutation. A significant minority (38%) were sequenced using DNA extracted before 25 January 2015. We have identified 37 diagnostic findings from the 168 families that have been analyzed to date and confirmed 27 of 35 findings previously identified by short-read sequencing. This presentation will pertain to the lessons learned, challenges, and tricks of high-throughput nanopore sequencing for rare disease research with varying sample input along with associated findings from the BEACON project.