NM_004006.3(DMD):c.2916T>G (p.Tyr972Ter)

Exon skipping using antisense oligonucleotides (ASOs) targeting the exon containing the c.2916T>G nonsense mutation is a plausible therapeutic strategy for this DMD variant. The premature stop codon at p.Tyr972Ter truncates dystrophin in the central rod domain, but skipping the affected exon (exon 22) could restore the reading frame and produce a partially functional, internally deleted dystrophin—analogous to the milder Becker muscular dystrophy phenotype. Multiple exon-skipping ASOs have received FDA approval for other DMD exons (eteplirsen for exon 51, golodirsen for exon 53, viltolarsen for exon 53, casimersen for exon 45), establishing clinical precedent for this modality.

1. The c.2916T>G variant introduces a premature stop codon (p.Tyr972Ter) in exon 22 of the DMD gene, classified as Pathogenic in ClinVar. The mutation falls in the spectrin-like repeat region of the dystrophin rod domain. 2. Exon-skipping ASOs have demonstrated partial dystrophin restoration in DMD patients with out-of-frame deletions: eteplirsen (exon 51), golodirsen and viltolarsen (exon 53), and casimersen (exon 45) have FDA approval, though with modest functional benefit. 3. For nonsense mutations, skipping the exon containing the stop codon can restore the reading frame if the flanking exons maintain frame compatibility. Exon 22 skipping in DMD has been explored in preclinical models. 4. Translational read-through compounds (e.g., ataluren) represent an alternative RNA-level approach for nonsense mutations, though clinical efficacy data for ataluren remain limited and its EU approval was not renewed in 2024.

1. Exon-skipping efficiency for exon 22 specifically has limited clinical data compared to the more commonly targeted exons (51, 53, 45). ASO design, delivery, and tissue penetration in cardiac muscle remain significant challenges. 2. The resulting internally deleted dystrophin from exon 22 skipping may have variable functionality depending on the structural role of the skipped region in the rod domain. 3. Systemic delivery to both skeletal and cardiac muscle is a persistent bottleneck—current ASOs show preferential skeletal muscle uptake with limited cardiac penetration. 4. Long-term efficacy and durability data for exon-skipping therapies remain limited, with modest dystrophin restoration levels (typically <5-10% of normal) in approved products. 5. This analysis is based on general exon-skipping principles applied to this specific variant; dedicated preclinical validation for exon 22 skipping with this particular nonsense mutation would be needed.