title: Complex genomic rearrangements in the dystrophin gene due to replication-based mechanisms.
abstract: Genomic rearrangements such as intragenic deletions and duplications are the most prevalent type of mutations in the dystrophin gene resulting in Duchenne and Becker muscular dystrophy (D/BMD). These copy number variations (CNVs) are nonrecurrent and can result from either nonhomologous end joining (NHEJ) or microhomology-mediated replication-dependent recombination (MMRDR). We characterized five DMD patients with complex genomic rearrangements using a combination of MLPA/mRNA transcript analysis/custom array comparative hybridization arrays (CGH) and breakpoint sequence analysis to investigate the mechanisms for these rearrangements. Two patients had complex rearrangements that involved microhomologies at breakpoints. One patient had a noncontiguous insertion of 89.7 kb chromosome 4 into intron 43 of DMD involving three breakpoints with 2-5 bp microhomology at the junctions. A second patient had an inversion of exon 44 flanked by intronic deletions with two breakpoint junctions each showing 2 bp microhomology. The third patient was a female with an inherited deletion of exon 47 in DMD on the maternal allele and a de novo noncontiguous duplication of exons 45-49 in DMD and MID1 on the paternal allele. The other two patients harbored complex noncontiguous duplications within the dystrophin gene. We propose a replication-based mechanisms for all five complex DMD rearrangements. This study identifies additional underlying mechanisms in DMD, and provides insight into the molecular bases of these genomic rearrangements.
authors.affiliation: Department of Immunology, Genetics and Pathology, The Rudbeck Laboratory, Uppsala University Uppsala, Sweden ; The Centre for Applied Genomics, The Hospital for Sick Children Toronto, Ontario, Canada.
authors.forename: Berivan
authors.initials: B
authors.lastname: Baskin
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children Toronto, Ontario, Canada ; Department of Laboratory Medicine and Pathology, University of Toronto Toronto, Ontario, Canada ; Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada.
authors.forename: Dimitri J
authors.initials: DJ
authors.lastname: Stavropoulos
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children Toronto, Ontario, Canada.
authors.forename: Paige A
authors.initials: PA
authors.lastname: Rebeiro
authors.affiliation: Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Orr
authors.affiliation: Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Li
authors.affiliation: Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada.
authors.forename: Leslie
authors.initials: L
authors.lastname: Steele
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children Toronto, Ontario, Canada ; Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: Division of Medical Genetics, Royal University Hospital & University of Saskatchewan Saskatoon, Saskatchewan, Canada.
authors.forename: Edmond G
authors.initials: EG
authors.lastname: Lemire
authors.affiliation: Department of Genetics, Children's Hospital of Eastern Ontario Ottawa, Ontario, Canada.
authors.forename: Kym M
authors.initials: KM
authors.lastname: Boycott
authors.affiliation: Department of Medical Genetics, Child and Family Research Institute, The University of British Columbia Vancouver, British Columbia, Canada.
authors.forename: William
authors.initials: W
authors.lastname: Gibson
authors.affiliation: The Centre for Applied Genomics, The Hospital for Sick Children Toronto, Ontario, Canada ; Division of Molecular Genetics, The Hospital for Sick Children Toronto, Ontario, Canada ; Department of Molecular Genetics, The University of Toronto Toronto, Ontario, Canada.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Ray
keywords: Duchenne muscular dystrophy; MMRDR; dystrophin; mRNA; rearrangement; replication