MOLECULAR ANALYSIS OF AN ARGENTINE DYSTROPHINOPATHY COHORT: DIAGNOSTIC ALGORITHM, GENETIC ASSESSMENT AND DMD GENE CHARACTERIZATION?

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

Milan

Congreso; EUROPEAN HUMAN GENETICS CONFERENCE IN CONJUNCTION WITH THE EUROPEAN MEETING ON PSYCHOSOCIAL ASPECTS OF GENETICS. (ESHG / EMPAG); 2018

ESHG / EMPAG

Molecular analysis of an argentine dystrophinopathy cohort: diagnostic algorithm, genetic assessment and DMD gene characterizationL.N. Luce1,2, M.M. Carcione1,2, C. Mazzanti1,2, I. Szijan, F. Giliberto1,21Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Cátedra de Genética. Buenos Aires, Argentina.2CONICET - Universidad de Buenos Aires, Instituto de Inmunología, Genética y Metabolismo (INIGEM). Buenos Aires, Argentina.Introduction: Dystrophinopathies are X-linked recessive diseases caused by mutations in DMD gene. Hitherto there is no effective treatment for these pathologies, which enhances the importance of performing genetic assessment in order to detect mutation carriers and prevent diseased newborns. However, two mutation-specific gene therapies were recently approved: Exon 51 Skipping (Eteplirsen) and Premature Stop Codon Read-through (Ataluren). Therefore, accurate detection and characterization of the causing mutation is essential to allow genetic counseling, patient follow-up and determine the suitable gene therapy. Materials and Methods: We have analyzed 200 boys with clinical diagnosis of Dystrophinopathy, 12 symptomatic women, 240 females at-risk of being carriers and 15 prenatal diagnoses. A diagnostic algorithm was designed for each case, implementing MLPA, PCR, Whole Exome Sequencing, Sanger Sequencing, STRs segregation analysis and HUMARA assay.Results: The selected strategy allowed disease confirmation in 71.7% (152/212) of the affected boys and symptomatic females. 12 were candidates for Eteplirsen, while 22 were suitable for Ataluren. On the other hand, we were able to establish as carriers 72/255 women/fetuses, while could exclude from being carriers/affected 143/255. As for gene characterization, we could establish an association between the most frequent deletion/duplication intron breakpoints and the abundance of STR loci and, we have detected 3 haplotypes blocks within the SNPs identified by the Exome technique. Conclusions: In the present work, we have characterized a Dystrophinopathy argentine population and contributed to the understanding of the genetic/molecular basis of these pathologiesThis study was supported by PTC Therapeutics and University of Buenos Aires, Argentina.