Dystrophinopathy patients with non-contiguous molecular alterations: diagnosis and characterization of the genetic mechanisms involved

LEONELA LUCE; CARCIONE, MICAELA;; MAZZANTI, CHIARA; , SZIJAN IRENE; SEBASTIÁN MENAZZI; FRANCIPANE L. ;; JULIÁN NEVADO; PABLO LAPUNZINA; LILIANA ROSSETTI; PAMELA RADIC; ABELLEYRO MIGUEL M; CARLOS DE BRASI; FLORENCIA GILIBERTO

Berlín

Congreso; 53º European Human Genetics Virtual Conference. 2020; 2020

Introduction: Dystrophinopathies are neuromuscular X-linked recessive diseases caused by DMD mutations. Molecular alterations in this gene are large deletions/duplicand small mutations in the remaining. Several authors reported the occurrence of non-contiguous rearrangements within the same DMD allele, with frequencies up to 4aims to characterize the incidence of complex rearrangements in an Argentinian dystrophinopathy cohort and unravel the causing molecular mechanisms. Materialsanalyzed 437 boys with clinical diagnosis of Dystrophinopathy. The following techniques were implemented: MLPA, WES, WGS, PCR-Sanger Sequencing, CGH Array andcases, breakpoints were precisely determined, so we performed a bioinformatic screening of microhomologies, interspersed repeats, secondary structures and recombsurrounding each breakpoint. Results: We detected 6 patients carrying complex rearrangements in DMD: 2 deletions-duplications, 3 non-contiguous duplications and 120pb insertion. These accounted for 1.4% of our cohort. In a deletion-duplication case, familial segregation and bioinformatics analysis suggested that the duplication wevent caused by Fork Stalling and Template Switching (FoSTeS), while the deletion occurred secondly by Non-homologous end joining. Furthermore, bioinformatic screplus insertion propose that the deletion was due to Microhomology-mediated end joining, while the insertion arose by FoSTeS. Conclusions: Our findings widen the umolecular events that may take place in DMD and characterize the occurrence of complex rearrangements in our dystrophinopathy cohort.This study was supported byUniversity of Buenos Aires.