National German initiative partners with Oxford Nanopore to advance research of rare diseases with nanopore-based genome sequencing

Collaboration will provide four German centres of excellence with Oxford Nanopore sequencing tools as part of a pilot to demonstrate increased rates of diagnosis and improved patient outcomes using long-read technology  

Oxford Nanopore Technologies plc (Oxford Nanopore) today announced a research collaboration agreement with the ‘Clinical Long-read Genome Initiative’ (lonGER), a new national German programme developed to evaluate the clinical and research applications of comprehensive nanopore-based sequencing to advance the understanding of rare disease.

Scientists within four German research university medical centres –  Uniklinik RWTH Aachen (Ingo Kurth, Florian Kraft), Institute of Medical and Human Genetics, Charité – Universitätsmedizin Berlin, and Berlin Institute of Health at Charité (BIH) (Nadja Ehmke, Janine Altmüller, Manuel Holtgrewe), Medical Scholl Hannover (Bernd Auber, Gunnar Schmidt), University of Tübingen (Tobias Haack, Stephan Ossowski)  — will use Oxford Nanopore’s technology to evaluate the advantages of technology that can sequence any length DNA fragments, from short to ultra-long, when establishing firm genetic disease characterisation. The universities will study a multi-centre cohort of patients with unsolved rare diseases, e.g. neurological, neurodevelopmental and imprinting disorders.

The two-year pilot study will explore the benefits and feasibility of nanopore-based genome sequencing in German clinical practice, with a broader aim to provide a blueprint for implementation across Germany’s sequencing centres.

The work is expected to be performed on PromethION P2 and P24 devices. P24 is capable of running up to 24 flow cells at once and is therefore uniquely designed to enable accelerated sequencing and to deliver ultra-rapid analysis. This will enable the researchers to identify different classes of disease-causing variants simultaneously using the latest high-accuracy chemistry, including single nucleotide variations (SNVs), structural variations (SVs) and also methylation, all in one assay.

This study builds on structured diagnostic processes established and evaluated within the TRANSLATE-NAMSE (TNAMSE) study, which was a three-year prospective study in Germany that involved more than 200 clinicians and scientists and was designed to assess the clinical value of exome sequencing in the ultra-rare disease population. TNAMSE was completed using short-read sequencing technology.

More complete rare disease data  

Oxford Nanopore’s technology is well suited to serve lonGER’s aim of improving clinical outcomes by using its ability to sequence any-length fragments of DNA from short to ultra long. This has been shown to demonstrate specific advantages over short reads in the study of genetic diseases.

The long read capabilities of nanopore sequencing enable phasing of genetic variants, which is important for clinical interpretation of the genome in terms of identifying compound heterozygous variants and parental origin. It is also able to resolve “dark” regions that cannot be accessed by short reads, which accounts for up to 8% of the genome and could contain clinically relevant variants. Long nanopore sequencing reads are also able to resolve SVs much more comprehensively – historically an important yet understudied type of human genetic variation as it has been challenging for traditional sequencing technologies.

Oxford Nanopore’s ability to scale with plug-and-play benchtop sequencers and ‘out of the box’ workflows also means this pipeline could easily be deployed at other sites. Additionally, the ability to sequence as the samples come in, with no need for batching, provides an extra layer of flexibility that will support the needs of the research consortium.

Gordon Sanghera, CEO, Oxford Nanopore Technologies, commented:  

“We are delighted to be collaborating with this broad, dedicated team to focus on rare disease translational research. Oxford Nanopore’s any read length sequencing technology shows that what you’re missing matters as it can deliver comprehensive insights across the whole genome. Together with the lonGER consortium, we can unlock the potential of nanopore sequencing technology to drive breakthrough discoveries and transform the lives of those affected by these rare diseases.”

Bernd Auber, Head of Genomics Laboratory, Department of Human Genetics, Hannover Medical School, commented: 

“By overcoming the limitations of short read sequencing, scalable sequencing technology with long read capabilities has the potential to improve the accuracy and completeness of genomic analysis, uncovering novel disease mechanisms of rare disorders. In critically ill children, for example phasing of genetic variants using a rapid long read sequencing approach could be very helpful in diagnostics and personalised treatment of pediatric ICU patients.”

Nadja Ehmke, Head of Clinical Genomics Unit, Institute of Medical and Human Genetics, Charité – Universitätsmedizin Berlin, commented:  

“We believe that the introduction of long-read genome sequencing into clinical routine will allow us to further close the diagnostic gap in patients with monogenic diseases. For the first time, we can sequence complex regions, determine structural variants and perform haplotype-based analyses. In addition, detection of methylation patterns is possible. This allows us to better understand disease mechanisms and develop therapies.”

Tobias Haack, Deputy Director, Institute of Medical Genetics and Applied Genomics, University of Tübingen, commented: 

“Beyond the improved accuracy of genomic variation detection, the organisational structure of our consortium, combined with streamlined processes, will provide the data background crucial to the clinical interpretation of etiologically unclear variants and gene-disease associations. Translating this multicenter concept into firm diagnoses will rely on established networks and the shared expertise of multidisciplinary teams of clinicians, geneticists, and translational researchers.”

Florian Kraft, Group Leader Long-Read Sequencing, Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen, commented: 

“We are very excited about analysing the genomes of patients with rare disease using nanopore sequencing and think that this can shape the future of research and diagnostics in this field. The new V14 chemistry together with the PromethION P24 is really a game changer for the application of long read sequencing in the clinical routine. We see a huge improvement in accuracy and a dramatic decrease for DNA input, along with about 50x genomic coverage from a single PromethION Flow Cell. The better data quality will facilitate the elucidation of pathomechanisms behind rare genetic disorders.”

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