The genomic region responsible for the muscular dystrophy FSHD (facioscapulohumeral dystrophy) is remarkably large and complex: 3-kb repeats arranged in a tandem array of up to 100 repeat units. Structural variants and epigenetic variants can cause FSHD, which affects 1 in 20,000 people. In order to diagnose as well as to understand the mechanisms of FSHD, it is crucial to (epi)genetically characterise this repetitive region. However diagnosis in Australia still relies on Southen blotting, an expensive, low-throughput and information-poor technique.
Using ultra-long nanopore sequencing and targeted sequencing, we reveal the complex genetics and epigenetics at play in FSHD. This allows us to count repeat numbers, distinguish alleles and reveal the epigenetic state of the macrosatellite region in patients. This technique has the potential to make FSHD diagnosis both much faster and much more informative, and shed light on the mechanisms of macrosatellite repeat epigenetic regulation in health and disease.