London Calling 2023: Nanopore sequencing reveals retrotransposon insertions or complex genetic mechanisms in four rare disorders

Up to 50% of cases with rare diseases lack a molecular diagnosis due to the limitations of current sequencing methods. Oxford Nanopore sequencing has emerged as a promising tool to overcome this gap and improve our understanding of the molecular mechanisms of rare diseases. We used Oxford Nanopore sequencing in 17 unresolved cases with four different rare disorders using PromethION or MinION with enrichment of targeted genes using adaptive sampling. Nanopore sequencing identified the molecular mechanisms in six cases, detecting retrotransposon insertions (three SVA elements and one LINE element) affecting SERPINC1, PEX1, and GYS2, which are responsible for antithrombin deficiency, peroxisomal  disease, and glycogen storage disease. A complex structural variant in ITGB3 was detected in two cases with Glanzmann thrombasthenia. These results support that Oxford Nanopore sequencing is a suitable method to facilitate the molecular diagnosis of rare diseases and retrotransposon insertions may be underestimated due to the use of previous molecular methods.