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

LEONELA LUCE; CARCIONE, MICAELA; MAZZANTI, CHIARA; DIANA PARMA; FERRER MARCELA; , SZIJAN IRENE; FLORENCIA GILIBERTO,

Mendoza

Congreso; ALAG 2019 XVII Congreso Latinoamericano de Genética, XLVII Congreso Argentino de Genética, LII Reunión Anual de la Sociedad de Genética de Chile, VI Congreso de la Sociedad Uruguaya de Genética, V Congreso Latinoamericano de Genética Humana y V Simposio L; 2019

Molecular analysis of an argentine dystrophinopathy cohort: diagnostic algorithm, genetic assessment and DMD gene characterizationLuce, Leonela1,2; Carcione, Micaela1,2; Mazzanti, Chiara1,2; Parma, Diana1,2; Ferrer, Marcela3; Szijan, Irene1; Giliberto, Florencia1,2.1.Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Genética. Buenos Aires, Argentina.2.CONICET - Universidad de Buenos Aires, Instituto de Inmunología, Genética y Metabolismo (INIGEM). Buenos Aires, Argentina.3.Servicio de Neurología, Hospital de Clínicas ?José de San Martín?.Dystrophinopathies are X-linked recessive diseases caused by mutations in DMD gene. Hitherto there is no effective treatment, thus is it of utmost importance to provide genetic assessment so as to detect female carriers and prevent diseased newborns. Recently, 2 mutation-specific gene therapies were approved: Exon 51 Skipping and Premature Stop Codon (PTC) Readthrough. Therefore, accurate detection and characterization of the causing mutation is essential to allow diagnosis confirmation, follow-up and determine the suitable gene therapy.We analysed 358 boys with clinical diagnosis of Dystrophinopathy, 12 symptomatic women, 176 individuals at-risk of being carriers and 17 prenatal diagnoses. We designed a diagnostic algorithm for each case, using MLPA, PCR, WES, Sanger Sequencing, STR segregation and HUMARA assay.The selected strategy allowed diagnosis confirmation in 79,4% of the affected boys and symptomatic women. Regarding treatment, 18 were candidates for Exon 51 Skipping and 53 for PTC Readthrough. Furthermore, we diagnosed 11 boys with Limb-Girdle Muscular Dystrophies, diseases frequently misdiagnosed as Dystrophinopathy. Moreover, we established as carriers 60 women/fetuses and excluded 83 from being carriers/affected. As for gene characterization, we established an association between the large mutations intron breakpoints and the STR abundance and we detected 3 haplotypes blocks within the identified SNPs.Here, we have characterized a Dystrophinopathy argentine population and contributed to the understanding of the genetic/molecular basis of these pathologies.