DIFFERENTIAL MOLECULAR ALGORITHM FOR DUCHENNE MUSCULAR DYSTROPHY. COMPARATIVE STUDY OF LATIN AMERICA MUTATION FREQUENCIES WITH THERAPEUTIC TARGET

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

Congreso; REUNIÓN ANUAL DE SOCIEDAD DE BIOCIENCIAS SAIC-SAI-AAFE-NANOMED.AR 2021 REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2021

17-20 Noviembre 2021 | MODALIDAD VIRTUALDIFFERENTIAL MOLECULAR ALGORITHM FOR DUCHENNE MUSCULAR DYSTROPHY. COMPARATIVE STUDY OF LATIN AMERICA MUTATION FREQUENCIES WITH THERAPEUTIC TARGETCarcione, Micaela1,2; Mazzanti, Chiara1,2;Luce, Leonela1,2; Giliberto, Florencia1,2*.1Laboratorio 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.Dystrophinopathies cover a spectrum of rare progressive X-linked muscle diseases, arising from DMD mutations. They are among the most common neuromuscular diseases, being Duchenne Muscular Dystrophy (DMD) the most severe form. Despite that there is still no cure for these diseases, advances are being made for the development of DMD therapies. Some are already approved: exon skipping and premature stop codon read-through (Ataluren). We aimed to characterize the mutational spectrum of DMD in an Argentinian cohort, to identify candidates for available treatments and, to conduct a comparative analysis of the Latin American (LA) frequencies of mutations amenable for available DMD therapies. We studied 400 patients with dystrophinopathy, implementing a diagnostic algorithm including: MLPA/PCR/Sanger/Exome/in-silico panels and bioinformatics. We performed a meta-analysis of LA’s metrics for DMD available therapies. The algorithm resulted effective for achieving differential diagnosis, reaching a 97% detection rate. Therefore, 371 patients with genetic confirmation of dystrophinopathy resulted candidates for corticosteroid treatment, 20 were eligible for exon skipping 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 the skipping of only one exon. According to the meta-analysis, only 4 LA countries (Argentina, Brazil, Colombia and Mexico) complete the molecular algorithm for dystrophinopathies. In conclusion, this manuscript describes the theragnosis carried out in Argentinian dystrophinopathy patients. The implemented molecular algorithm proved to be efficient for the achievement of differential diagnosis, which plays a crucial role in patient management, determination of standard of care and genetic counselling. Finally, this work contributes with the international efforts to characterize the frequencies and variants of LA, pillars of drug development and theragnosis.