NM_004006.3(DMD):c.8547+2T>C

For DMD c.8547+2T>C, a likely pathogenic splice donor variant at the intron 59 boundary that disrupts normal pre-mRNA splicing and is predicted to cause out-of-frame exon skipping or intron retention leading to Duchenne phenotype, antisense oligonucleotide-mediated exon skipping represents the most variant-class-appropriate RNA therapy approach. The c.8547+2T>C variant destroys the canonical GT splice donor of exon 59. Therapeutic exon skipping using phosphorodiamidate morpholino oligomers (PMOs) could target exon 59 (or adjacent exons depending on reading frame analysis) to restore an in-frame transcript encoding a Becker-like internally deleted but partially functional dystrophin. Four exon-skipping ASOs are FDA-approved for DMD (eteplirsen for exon 51, golodirsen for exon 53, viltolarsen for exon 53, casimersen for exon 45), validating the platform.

Exon-skipping ASOs for DMD have demonstrated proof-of-concept across multiple exon targets. Eteplirsen (Exondys 51) received accelerated FDA approval in 2016 based on modest dystrophin restoration (~0.9% of normal by Western blot). Viltolarsen (Viltepso, exon 53 skipping) showed ~5.7% dystrophin restoration at 24 weeks in the Phase 2 trial (PMID: 32981936). The reading frame rule (Monaco et al., 1988) predicts that in-frame deletions within the central rod domain produce milder Becker phenotype rather than severe Duchenne. For exon 59, which encodes part of spectrin-like repeat 22-23 near the C-terminal region, skipping feasibility depends on whether removal maintains an open reading frame with the adjacent exons 58 and 60. Next-generation peptide-conjugated PMOs (PPMOs) are in clinical development with substantially improved tissue penetration to cardiac and skeletal muscle compared to unconjugated PMOs.

Current exon-skipping ASOs achieve low levels of dystrophin restoration (typically 1-5% of normal), which may be below the threshold needed for meaningful clinical benefit (~15-20% is thought necessary based on Becker dystrophy genotype-phenotype studies). All approved exon-skipping ASOs required accelerated approval pathways based on the surrogate endpoint of dystrophin protein restoration rather than functional clinical endpoints. Confirmatory trials have shown inconsistent functional benefit. ASO therapy requires lifelong weekly IV infusions (for PMOs) or subcutaneous injections, creating substantial treatment burden and cost. For c.8547+2T>C specifically, the amenability to exon 59 skipping requires detailed reading frame analysis — not all splice-site variants in this region will produce a functional protein with exon 59 removal. PPMOs (peptide-PMOs) under development by Sarepta and others may improve tissue delivery and dystrophin restoration levels, but are not yet approved.