P.335Phenotypic and Genomic Characterization As Predictors of DMD 45 to 55 Multi-Exon Skipping Therapy

Duchenne and Becker muscular dystrophy (DMD and BMD) are X-linked myopathies characterized by a progressive muscular dystrophy with or without cardiomyopathy. As described in literature, 63% of DMD patients are eligible to a multi-exon skipping therapy, thus becoming BMD patients with exons 45 to 55 deletion (BMDdel45-55). Precision medicine approaches are currently in development and/or clinical testing. Interestingly, emerging regulatory actors as long non-coding RNA (lncRNA) are localized in 44 and 55 introns (Bovolenta et al., 2012). The specific neo-introns of each BMDdel45-55 patient could create or modify the lncRNA and/or RNA non-coding sequences and result in a various clinical outcome. Here we present a population of 54 "skip-equivalent" BMDdel45-55 patients. The objective is to identify modifier factors involved in phenotypic variability in these patients. We performed first a phenotypic characterization showing that 100% patients have BMD phenotype. Interestingly, 67% display the first signs age <16 y.o. The most disabling complains are the walking/running difficulties (65 %) and in 16 patients 50% have dilatative cardiomyopathy. Then we established the profile of lncRNA presence in 38/54 patients at genomic level in healthy subjects, muscle biopsies of BMDdel45-55 and DMD patients and human immortalized myoblasts displaying a deletion of 45-52 exons in DMD gene (Myo-45-52). We identified one cluster associating a smaller number of lncRNAs with a "milder" phenotype. In addition, in Myo-45-52 the profile of lncRNA expression underlined two lacking lncRNA. The WGS in 19/54 patients allowed precise identification of the deletion breakpoints underling specific sequence different for all analyzed patients. This study allowed us to describe phenotypic and genomic profile in the largest reported cohort of BMDdel45-55 patients. Genomic data profiling would have a favorable contribution in the design of these therapeutic approaches.