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Oxford Nanopore and Genomics England are teaming up to sequence up to 7,500 samples from people with a range of genetic or suspected genetic disorders to improve diagnostic outcomes in rare diseases. Building on Genomics England’s landmark 100,000 Genomes Project, this effort also aims to develop an accredited lab workflow and data analysis pipelines for clinical use of human whole genome sequence data. 

“The combination of very high single-molecule accuracy with the ability to reach all parts of the genome and characterize all types of genetic variation, mean that nanopore sequencing can deliver comprehensive whole genome analysis and will reveal that what’s missing matters,” said Gordon Sanghera, CEO, Oxford Nanopore Technologies.

The study will use nanopore whole genome sequencing to uncover new diagnoses in participants and to finalize genetic characterization and heritability within families for partially diagnosed participants. And finally, to identify potentially missed variants and highlight improvements over other, short-read-only technology. 

The ultimate goal of this proof-of-concept study will be to generate datasets that provide insights using nanopore sequencing. The dataset should also be useful in any disease where genetics plays a role, including common diseases, enabling researchers to look easily in the one dataset to study how genetic variation can influence health and disease. 

This project will be part of a wider multiomic study led by Genomics England—including genomic, transcriptomic, epigenetic, proteomic and metabolomic analysis—to support the understanding of multiomic research in rare cases that are difficult to resolve. Whole genome sequencing will be performed on all samples and a subset will also have full-length RNA sequencing. The sample cohort will be inclusive of singleton samples and duo/trio families. 

Once the project is complete, the data will be stored in the National Genomic Research Library, creating the world’s largest global dataset with genetic and epigenetic profiling for rare disease. 

Professor Matt Brown, CSO, Genomics England, said, “Over the last decade we’ve seen incredible technological and scientific advances across genomic research. This vast progress means we now have a wealth of tools at our disposal to study rare genetic conditions.” 

Oxford Nanopore reports that its technology allows for characterization of more genetic variation that includes single nucleotide variants, insertions/deletions, complex copy number variations and structural variations, as highlighted in a recent Nature Methods paper.

In the paper, the team describe how this makes large-scale, long, native DNA sequencing projects feasible due to the lower cost and higher throughput of Oxford Nanopore’s PromethION when compared with alternative sequencing methods.   

To date, methylation has not been characterized at a whole genome scale in rare disease cohorts and is often only analyzed in targeted tests or EPIC arrays. This effort offers the first large scale database of rare disease patients that will be characterized epigenetically and will be made available to the research community to investigate the importance of methylation as a type of variation and to shed light on mechanism of action.

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