IMEX   05356
INSTITUTO DE MEDICINA EXPERIMENTAL
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
BEYOND CLASSIC MOLECULAR ALTERATIONS: NON-CONTIGUOUS MUTATIONS IN DMD GENE
Autor/es:
LUCE, L; SZIJAN I; NEVADO, J; RADIC CP; GILIBERTO F; CARCIONE, M; MENAZZI, S; LAPUNZINA, P; ABELLEYRO MM; MAZZANTI, C; FRANCIPANE L ; ROSSETTI LC; DE BRASI CD
Lugar:
CABA
Reunión:
Congreso; LXV REUNIÓN ANUAL DE LA SOCIEDAD ARGENTINA DE INVESTIGACIÓN CLÍNICA (SAIC); 2020
Institución organizadora:
SAIC
Resumen:
Introduction: Dystrophinopathies are neuromuscular X-linked reces-sive diseases caused by DMD mutations. Molecular alterations inthis gene are large deletions/duplications in 80% of cases and smallvariants in the remaining. Several authors reported the occurrenceof non-contiguous rearrangements within the same DMD allele, withfrequencies up to 4%. The present work aims to characterize theincidence of complex rearrangements in an Argentinian dystrophi-nopathy cohort and unravel the causing molecular mechanisms.Materials and Methods: We analyzed 437 boys with clinical diagno-sis of Dystrophinopathy. The following techniques were implement-ed: MLPA, WES, WGS, PCR-Sanger Sequencing, CGH Array andHUMARA assay. In 2 cases, breakpoints were precisely determined,so we performed a bioinformatic screening of microhomologies, in-terspersed repeats, secondary structures and recombinogenic mo-tifs 50pb surrounding each breakpoint.Results: We detected 6 patients carrying complex rearrangementsin DMD: 2 deletions-duplications, 3 non-contiguous duplications and1 large deletion plus a 20pb insertion. These accounted for 1.4% ofour cohort. In a deletion-duplication case, familial segregation andbioinformatics analysis suggested that the duplication was the firstmutagenic event caused by Fork Stalling and Template Switching(FoSTeS), while the deletion occurred secondly by Non-homologousend joining. Furthermore, bioinformatic screening of the deletionplus insertion propose that the deletion was due to Microhomolo-gy-mediated end joining, while the insertion arose by FoSTeS.Conclusions: Our findings widen the understanding of the molecularevents that may take place in DMD and characterize the occurrence