A rapid ONT-based sequencing approach to capture complete Ataxia-Mutomes (AtaxiaMutSeq)

Hereditary ataxias are complicated neurological disorders with enormous genetic heterogeneity as well as the diverse genetic mechanism. Among different genetic mechanism, tandem nucleotide repeat expansion (TNRex) are the most common cause for genetic ataxias followed by single nucleotide variations in over 200 genes. The detection and the diagnosis of tandem nucleotide repeats in clinics and laboratories has been at large common in comparison with SNVs owing to the large number of the mutations in the respective genes they are found. The widely used platforms for detection of these mutations are capillary electrophoresis and Next generation sequencing based targeted gene panel or clinical or whole exome sequencing. Long read sequencers have been proven useful for detection of tandem nucleotide repeat expansions. We have evolved a method to detect in one experiment and on single platform the detection of TNRex and SNVs on Oxford Nanopre Technology using adaptive sequencing approach. We were able to optimize the target region sequencing of both TNR loci and SNV-loci and validate the capture of both by detection of FXN-GAA repeats and pathogenic SNVs in SETX