While early genetic diagnosis can guide critical care management, the turnaround time for whole genome based diagnostic testing is months. Recent programs in neonatal populations have reduced turnaround to days and shown that rapid genetic diagnosis enhances patient care and reduces healthcare costs. Yet, most critical care decisions need to be made in hours.We developed a whole genome sequencing approach designed to provide a genetic diagnosis within hours. Optimized highly parallel nanopore sequencing was coupled with high-performance cloud computing to implement near real-time basecalling and alignment followed by accelerated variant calling. A custom scheme for variant prioritization took minutes to rank variants likely to be deleterious allowing efficient manual review and classification. We performed whole genome sequencing on 12 patients from the critical care units of Stanford hospitals. In 10 cases, the pipeline produced diagnostic results faster than all previously published clinical genome analyses. Per patient, DNA extraction, library preparation, and nanopore sequencing across 48 flow cells generated 173–236 GigaBases of sequencing data in as little as 1:50 hours. After optimization, the average turnaround time was 7:58 hours. A pathogenic or likely pathogenic variant was identified in five out of 12 patients (42%). After confirmation in a CLIA laboratory, clinical management was altered in every case. We developed an approach to make a genetic diagnosis from whole genome sequencing in hours, returning actionable, cost-saving diagnostic information on critical care timescales.
1. Explain how genetic diagnosis can impact clinical care.
2. Discuss advances in sequencing technologies and how they can be applied in a clinical setting.
3. Discuss the basics of Nanopore sequencing.