P.21 - Genotype-phenotype associations in a large cohort of Duchenne muscular dystrophy patients

Abstract

Phenotype heterogeneity within the DMD population has long been noted but until recently there has been a relative dearth of understanding of the relationship between genotype and phenotype. Prior studies have suggested some genotype-specific phenotypic variations (exon 3–7 deletions, exon 44 skippable genotypes, exon 53 skippable genotypes). Genotype-phenotype associations were evaluated with regard to age at loss of ambulation within the Cincinnati Children's Hospital Medical Center (CCHMC) DMD Natural History Database (n = 574) with focus on genotypes amenable to exon skipping therapies and genotypes with significant patient numbers. Survival analysis was performed comparing genotypes of interest against the rest of the cohort. Kaplan-Meier curves were generated and log-rank tests were performed. Specific genotype groups analyzed included exon skippable genotypes (44, 45, 50, 51, 53, 55), deletions (exons 3–7, 8–11), duplications (exon 2), splice mutations, nonsense mutations and non-stop codon point mutations. Deletion of exons 3–7 (80% ambulating >17 years, CI 9.8-∞, p = 0.004) and exon 44 skippable genotypes (median age 20.5, CI 11.9-∞, p = 0.005) were associated with a later age of loss of ambulation. Exon 51 skippable genotypes (median age 11.0, CI 9.5–12.5, p = 0.0001) were associated with an earlier age of loss of ambulation. Exon 8–11 deletions, exon 2 duplications, splice mutations, non-sense mutations, non-stop codon point mutations and genotypes amenable to skipping of exons 45, 50, 53, 55 were not significantly different from the rest of the cohort (respectively). In conclusion, deletion of exons 3–7 and exon 44 skippable genotypes are associated with a later age of loss of ambulation. Exon 51 skippable genotypes are associated with an earlier age of loss of ambulation. These genotype-specific phenotypic variations can have significant impact on the success of future DMD clinical trials.