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Background Currently patients in England with suspected monogenic disorders will undergo NHS genetic testing which can include Whole Genome Sequencing (WGS) using short read sequencing (SRS) technology. More than 50% of patients remain undiagnosed. We aim to evaluate the utility of Nanopore long-read sequencing (LRS) to increase the diagnostic rate for these patients with no molecular diagnosis despite standard-of-care testing.Material and Methods We performed trio Oxford Nanopore LRS WGS of 27 individuals likely to have a monogenic disorder who have no molecular diagnosis, despite reaching the ceiling of investigation as defined by NHS England within the National Genomic Test Directory. We used a range of existing software to study participants’ genomes for potentially disease-causing variants.Results We have identified the molecular aetiology in an additional 11% of patients including a diagnosis of Coffin Siris syndrome, Familial Adenomatous Polyposis and Roifman syndrome. We will discuss the patient phenotypes, bioinformatic pipeline, downstream analysis tools and why these variants were not previously identified. Finally, we will consider the feasibility of implementation of LRS into diagnostic testing.Conclusion Nanopore LRS has increased the diagnostic rate for patients with likely monogenic disorders who have reached the ceiling for investigation in the NHS.