Accelerated identification of disease-causing variants with ultra-rapid nanopore genome sequencing

• Published in: Nature biotechnology Vol. 40; no. 7; pp. 1035 - 1041
• Main Authors: Goenka, Sneha D., Gorzynski, John E., Shafin, Kishwar, Fisk, Dianna G., Pesout, Trevor, Jensen, Tanner D., Monlong, Jean, Chang, Pi-Chuan, Baid, Gunjan, Bernstein, Jonathan A., Christle, Jeffrey W., Dalton, Karen P., Garalde, Daniel R., Grove, Megan E., Guillory, Joseph, Kolesnikov, Alexey, Nattestad, Maria, Ruzhnikov, Maura R. Z., Samadi, Mehrzad, Sethia, Ankit, Spiteri, Elizabeth, Wright, Christopher J., Xiong, Katherine, Zhu, Tong, Jain, Miten, Sedlazeck, Fritz J., Carroll, Andrew, Paten, Benedict, Ashley, Euan A.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2022; Nature Publishing Group
• Subjects: 631/114; 631/208/514/1948; 692/308/2056; Agriculture; Annotations; Bioinformatics; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Chromosome Mapping; Cloud computing; Gene sequencing; Genetic disorders; Genomes; High-Throughput Nucleotide Sequencing - methods; Humans; Life Sciences; Nanopore Sequencing; Nanopores; Sample preparation; Whole genome sequencing; Whole Genome Sequencing - methods
• ISSN: 1087-0156; 1546-1696; 1546-1696
• DOI: 10.1038/s41587-022-01221-5

Whole-genome sequencing (WGS) can identify variants that cause genetic disease, but the time required for sequencing and analysis has been a barrier to its use in acutely ill patients. In the present study, we develop an approach for ultra-rapid nanopore WGS that combines an optimized sample preparation protocol, distributing sequencing over 48 flow cells, near real-time base calling and alignment, accelerated variant calling and fast variant filtration for efficient manual review. Application to two example clinical cases identified a candidate variant in <8 h from sample preparation to variant identification. We show that this framework provides accurate variant calls and efficient prioritization, and accelerates diagnostic clinical genome sequencing twofold compared with previous approaches. A streamlined sequencing process enables identification of disease-causing variants in the clinic within 8 hours.