Differential molecular algorithm for DUCHENNE MUSCULAR DYSTROPHY. Comparative study of mutation frequencies with therapeutic target from Latin America

MAZZANTI, CHIARA; LEONELA LUCE; CARCIONE, MICAELA;; GILIBERTO, FLORENCIA

Congreso; V International Congress in translational medicine (IMBS); 2021

DIFFERENTIAL MOLECULAR ALGORITHM FOR DUCHENNE MUSCULAR DYSTROPHY. COMPARATIVE STUDY OF MUTATION FREQUENCIES WITH THERAPEUTIC TARGET FROM LATIN AMERICA.Mazzanti, Chiara1,2; Luce, Leonela1,2; Carcione, Micaela1,2; Giliberto, Florencia1,2*.1 Laboratorio de Distrofinopatías, Cátedra de Genética, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.2 Instituto de Inmunología, Genética y Metabolismo (INIGEM), CONICET - Universidad de Buenos Aires, Buenos Aires, Argentina.Background and aimsDystrophinopathies are a spectrum of rare progressive X-linked muscle diseases caused by mutations in DMD. They are one of the most common pediatric muscular dystrophies, with Duchenne muscular dystrophy (DMD) being the most severe form. While there is no cure for these diseases, great advances are being made in the development of therapies. Some of which are already conditionally approved: exon skipping and premature stop codon readthrough (Ataluren). The present work aims to characterize the mutational spectrum of DMD in an Argentine cohort, to identify candidates for the available mutation-dependent treatments and to perform a comparative analysis of the Latin American frequencies of mutations treatable with the available therapies.MethodsWe studied 400 patients with a dystrophinopathy clinical diagnosis. The molecular diagnostic algorithm included: MLPA / PCR / Sanger / Exoma / in-silico panels and bioinformatics. We also performed a meta-analysis of Latin American metrics for available DMD therapies.ResultsThe algorithm used was effective in achieving a differential diagnosis, reaching a detection rate of 97%. In 371 patients the dystrophinopathy diagnosis was confirmed, of which 20 applied for exon skipping therapy of exon 51, 21 for exon 53, 12 for exon 45 and another 70 for Ataluren. We determined that 87.5% of DMD patients will restore the reading frame with single exon skipping. According to the meta-analysis, only Argentina, Brazil, Colombia and Mexico complete the molecular algorithm.ConclusionsThe molecular algorithm implemented proved to be effective in reaching the differential diagnosis, which plays a crucial role in patient management, determining the standard of care, and genetic counseling. Finally, this work contributes to the international efforts aiming to characterize frequencies and variants in Latin America, one of the pillars for drug development.