Research Questions and Objectives:
1. Identify and characterize XY individuals with large in-frame deletions in the DMD (a large gene that encodes a protein lost in Duchenne muscular dystrophy, D.M.D.) who remain minimally symptomatic, including their laboratory, clinical, and motor phenotypes.
2. Determine the molecular characteristics and affected functional domains of these deletions.
3. Look for known genetic modifiers of DMD in these individuals that may explain tolerance of large deletions with minimal symptoms.
4. Extend analysis to other large disease-causing genes (ATM, TTN) to identify potential regions for therapeutic targeting.
Scientific Rationale: D.M.D. is caused by mutations in the DMD gene encoding dystrophin (427 kDa), presenting challenges for gene therapy using AAV vectors (~4.7 kb capacity). Some individuals with large in-frame DMD deletions exhibit minimal symptoms, suggesting portions of the protein may be dispensable.
Exon skipping approaches using antisense oligonucleotides create in-frame transcripts producing internally deleted but partially functional dystrophin. Understanding which deletions maintain function is crucial for therapeutic development.
In our group’s analysis of gnomAD-v4-SV (63,046 individuals), we identified 8 males with large in-frame DMD deletions likely to be minimally symptomatic. We extrapolate 30-50 such individuals in the UK Biobank cohort. These cases would provide insights for:
1. Designing optimized microdystrophins for gene therapy
2. Estimating efficacy of internally deleted dystrophins from exon skipping
3. Informing regulatory endpoints for dystrophin restoration therapies
This approach extends to other large disease-causing genes with delivery challenges, including ATM (ataxia-telangiectasia) and TTN (cardiomyopathies), potentially enabling new “miniaturization” strategies compatible with AAV delivery.