Oxford Nanopore and Genomics England announce new strategic research project to resolve undiagnosed rare disease cases

Oxford Nanopore sequencing technology will be used in a pioneering new collaboration with Genomics England, to sequence as many as 7,500 samples from participants of the landmark 100,000 Genomes Project with a range of genetic or suspected genetic disorders. The programme aims to improve diagnostic outcomes for participants with rare conditions, including those who have not yet received a diagnosis through short-read only sequencing methods. The programme will also further aim to develop an accredited lab workflow and data analysis pipelines to support the clinical use of human whole genome sequence data generated using nanopore sequencing.

The study will use nanopore whole genome sequencing for three distinct objectives: to uncover new diagnoses in participants who have yet to be diagnosed, to finalise genetic characterisation 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 characterise improvements in insights using nanopore sequencing. The dataset will also be of great value 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, made possible by Oxford Nanopore technology’s ability to sequence fragments of any length. The sample cohort will be inclusive of singleton samples and duo/trio families.

Eurofins Genomics will be the service provider for the sequencing, in the UK. Eurofins Genomics brings a rich legacy of managing extensive population genomic initiatives across the globe, employing cutting-edge sequencing and predictive genomics methodologies. The incorporation of long-read, high-throughput capabilities will significantly expedite the integration of long-read technologies in both diagnostic and applied sectors. This advancement is set to be fortified by the commencement of procedures aimed at securing clinical accreditation for the pipeline.

The project will use Oxford Nanopore’s high-throughput sequencing device, the PromethION 48, which provides rapid characterisation of large genomes, delivering scalability for large projects with low infrastructure requirements. Combined with the latest “Q20+” chemistry, comprised of Kit 14 and R10.4.1 flow cells, Oxford Nanopore delivers complete and accurate genomic data, at scale.

Oxford Nanopore’s ability to sequence any DNA/RNA fragment length from short to ultra-long, allows for characterisation of more genetic variation that includes single nucleotide variants, insertions/deletions, complex copy number variations and structural variations. This has been highlighted in a recent Nature Methods paper, in which a team contributing to the National Institutes of Health (NIH) Center for Alzheimer’s and Related Dementias (CARD) shared an end-to-end pipeline for nanopore sequencing that produces comprehensive, state-of-the-art single nucleotide polymorphism (SNP), structural variant and methylation calls. 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 characterised at a whole genome scale in rare disease cohorts and is often only analysed in targeted tests or EPIC arrays. This offers the first large scale database of rare disease patients that will be characterised 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.

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.

Gordon Sanghera, CEO, Oxford Nanopore Technologies, commented:  

“We are delighted to be extending our collaboration with Genomics England into rare disease research, in addition to our current cancer programmes. The combination of very high single-molecule accuracy with the ability to reach all parts of the genome and characterise all types of genetic variation, mean that nanopore sequencing can deliver comprehensive whole genome analysis and will reveal that what’s missing matters.” 

Professor Matt Brown, CSO, Genomics England, commented: 

“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. We’re excited to work with Oxford Nanopore to explore the potential for long-read and epigenetic sequencing to improve our understanding of the causes of rare conditions and help us to build the world’s largest dataset with comprehensive genomic profiling to support diagnosis for patients and families affected by rare genetic conditions.” 

Note to editors: The ground-breaking 100,000 Genomes Project, led by Genomics England and NHS England, was established in 2013 to sequence 100,000 whole genomes from NHS patients affected by rare conditions and cancer.

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