A unique case of severe out of frame dystrophin mutation converted to a milder in frame phenotype due to canonical splice site within intron 7


Genetic Testing

Poster Number: 91


Ava Lin, MD, PhD, Stanley Nelson, MD, Steven Moore, MD, Jacinda Sampson, MD, PhD, Carly Siskind, MS, LCGC, John Day, MD, PhD, Carolina Tesi-Rocha, MD


1. Stanford University, 2. University of California-Los Angeles, 3. The University of Iowa, 4. Stanford, 5. Stanford University, 6. Stanford, 7. Stanford University

We report a unique case of a predicted out of frame deletion in dystrophin converted to an in frame milder phenotype through a canonical alternate splice site within intron 7. This unique boy was 8 years of age at time of presentation, with normal motor development and previously quite active in sports. Around 6-7 years of age, he started to demonstrates signs of toe walking, increased difficulty in keeping up with peers when running and signs of proximal weakness (started to use arms to push when getting up after bending over, stairs became more challenging, etc). On examination he had mild proximal weakness, only needing 2 seconds to rise from floor but nearly a full Gower’s sign. Creatine kinase level is greater than 22,000. Genetic testing shows a partial deletion of exon 8, predicted to be an out of frame construct, despite the comparatively milder findings clinically. Muscle biopsy showed typical dystrophic changes with immunofluorescence staining indicating reconstitution of his sequence downstream of exon 8, befitting his milder clinical picture. RNAseq showed utilization of a canonical splice site within intron 7, which results in the partial inclusion of intron 7, making an in frame construct despite deletion of first 13 codons in exon 8. This case highlights the complex nature of dystrophin splicing regulation.