Long-read whole-genome sequencing for the genetic diagnosis of dystrophinopathies

The precise genetic diagnosis of dystrophinopathies can be challenging, largely due to rare deep intronic variants and more complex structural variants (SVs). We report on the genetic characterization of a dystrophinopathy patient. He remained without a genetic diagnosis after routine genetic testing, dystrophin protein and mRNA analysis, and short- and long-read wholeDMDgene sequencing. We finally identified a novel complex SV inDMDvia long-read whole-genome sequencing. The variant consists of a large-scale (similar to 1Mb) inversion/deletion-insertion rearrangement mediated by LINE-1s. Our study shows that long-read whole-genome sequencing can serve as a clinical diagnostic tool for genetically unsolved dystrophinopathies.