Molecular analysis of an argentine dystrophinopathy cohort: diagnostic algorithm, genetic assessment and DMD gene characterization

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

Congreso; SAIC-SAI-SAFIS 2018 REUNIÓN CONJUNTA DE LAS SOCIEDADES DE BIOCIENCIAS LXIII REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA; 2018

(112) MOLECULAR ANALYSIS OF AN ARGENTINE DYSTROPHINOPATHYCOHORT: DIAGNOSTIC ALGORITHM,GENETIC ASSESSMENT AND DMD GENE CHARACTERIZATIONLeonela Luce2, 1, Micaela Carcione1, 2, Chiara Mazzanti1, 2,Diana Parma1, Marcela Ferrer, Irene Szijan, Florencia Giliberto1,21Universidad de Buenos Aires, Facultad de Farmacia yBioquímica, Cátedra de Genética. Buenos Aires, Argentina., 2CONICET - Universidad de Buenos Aires, Instituto deInmunología, Genética y Metabolismo (INIGEM). Buenos Aires,Argentina.Introduction: Dystrophinopathies are X-linked recessive diseasescaused by mutations in DMD gene. Hitherto there is no effectivetreatment for these pathologies, which enhances the importance ofperforming genetic assessment in order to detect mutation carriersand prevent diseased newborns. However, two mutation-specificgene therapies were recently approved: Exon 51 Skipping (Eteplirsen)and Premature Stop Codon Read-through (Ataluren). Therefore,accurate detection and characterization of the causing mutation isessential to allow genetic counseling, patient follow-up and determinethe suitable gene therapy.Materials and Methods: We have analyzed 200 boys with clinical diagnosisof Dystrophinopathy, 12 symptomatic women, 240 femalesat-risk of being carriers and 15 prenatal diagnoses. A diagnosticalgorithm was designed for each case, implementing MLPA, PCR,Whole Exome Sequencing, Sanger Sequencing, STRs segregationanalysis and HUMARA assay.Results: The selected strategy allowed disease confirmation in71.7% (152/212) of the affected boys and symptomatic females. 12were candidates for Eteplirsen, while 22 were suitable for Ataluren.On the other hand, we were able to establish as carriers 72/255women/fetuses, while could exclude from being carriers/affected143/255. As for gene characterization, we could establish an associationbetween the most frequent deletion/duplication intron breakpointsand the abundance of STR loci and, we have detected 3 haplotypesblocks within the SNPs identified by the Exome technique.Conclusions: In the present work, we have characterized a Dystrophinopathyargentine population and contributed to the understandingof the genetic/molecular basis of these pathologies. This studywas supported by PTC Therapeutics and University of Buenos Aires,Argentina.