London Calling 2023: Nanopore sequencing as a potential diagnostic tool for genetic diseases in the Middle East

Despite a comprehensive suite of diagnostic tools — including short-read, whole-exome, and whole-genome sequencing, chromosomal microarrays, targeted methylation, and repeat testing — the cumulative diagnostic yield in a Middle Eastern cohort with rare diseases (n = 1,000) was 32.5%, leaving two-thirds of patients without diagnoses and likely missing possible personalized treatment and/or management plans. This incomplete diagnostic yield may be due to the inherent limitations of current technologies in accurately and comprehensively querying complete sets of all possible disease-causing variants in our  genomes.

Here, we demonstrate the potential utility of Oxford Nanopore sequencing as a single comprehensive tool in routine clinical practice. Using previously characterized clinical samples, we optimized a long-read, whole-genome sequencing pipeline, which we then applied to a cohort of patients with negative results using current technologies and demonstrated the additional value of nanopore sequencing. We also optimized a targeted Oxford Nanopore assay to analyse SMN1 and SMN2 and demonstrated its potential feasibility in clinical settings.