Integrated genetic and epigenetic diagnosis of facioscapulohumeral muscular dystrophy using Oxford Nanopore long-read sequencing.

Simultaneous long-read characterisation of D4Z4 repeat size, haplotype, single-molecule methylation and genomic structure.

Facioscapulohumeral muscular dystrophy is genetically and epigenetically complex, and full characterisation of the D4Z4 repeat array remains difficult. The authors apply Oxford Nanopore long-read sequencing to three patients, one unaffected control and a trio family to measure repeat size, haplotype, methylation and genomic structure in a single assay. Results are validated by Southern blotting, single-molecule optical mapping and bisulfite sequencing. Methylation profiling shows reduced and heterogeneous methylation across individual D4Z4 repeats. Haplotype-resolved assembly identifies, in the trio family, a deletion outside the D4Z4 region and precisely localises its breakpoint.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The clinical argument is a single assay replacing several complementary techniques: size, methylation and structure in the same read. Concordance with reference methods is reported, but on three patients, one control and one trio: diagnostic sensitivity and specificity remain to be established in a cohort. Long-read is positioned here as an alternative to conventional approaches, not yet as a validated test.

Analysis by Dr Thibaut Benquey