Targeted long-read sequencing enables comprehensive analysis of the genetic and epigenetic landscape of inherited myopathies.

Targeted long-read assay + bioinformatics framework capturing short variants, structural variants, repeat expansions and epigenetic signatures (D4Z4 contraction/hypomethylation)

Variants causing inherited myopathies are highly heterogeneous (short variants, structural variants, repeat expansions, complex events such as the FSHD D4Z4 contraction/hypomethylation), often hard to characterise with standard NGS. The authors develop a targeted long-read assay and analysis framework capturing the full set of implicated genes, variants and epigenetic signatures. Applied to a patient cohort, it demonstrates analytical validity and improved resolution over existing methods. It yields a new genetic diagnosis in 35.5% (11/31) of patients who remained undiagnosed after standard clinical genetic testing.

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

A striking result: a single long-read assay replaces the patchwork of myopathy analyses (including the notoriously difficult FSHD) and recovers a third of unresolved cases. A concrete illustration of long-read value in diagnostics — consolidating multiple assays with improved yield, directly transferable to routine practice.

Analysis by Dr Thibaut Benquey