title: Diverse mutational mechanisms cause pathogenic subtelomeric rearrangements.
abstract: Chromosome rearrangements are a significant cause of intellectual disability and birth defects. Subtelomeric rearrangements, including deletions, duplications and translocations of chromosome ends, were first discovered over 40 years ago and are now recognized as being responsible for several genetic syndromes. Unlike the deletions and duplications that cause some genomic disorders, subtelomeric rearrangements do not typically have recurrent breakpoints and involve many different chromosome ends. To capture the molecular mechanisms responsible for this heterogeneous class of chromosome abnormality, we coupled high-resolution array CGH with breakpoint junction sequencing of a diverse collection of subtelomeric rearrangements. We analyzed 102 breakpoints corresponding to 78 rearrangements involving 28 chromosome ends. Sequencing 21 breakpoint junctions revealed signatures of non-homologous end-joining, non-allelic homologous recombination between interspersed repeats and DNA replication processes. Thus, subtelomeric rearrangements arise from diverse mutational mechanisms. In addition, we find hotspots of subtelomeric breakage at the end of chromosomes 9q and 22q; these sites may correspond to genomic regions that are particularly susceptible to double-strand breaks. Finally, fine-mapping the smallest subtelomeric rearrangements has narrowed the critical regions for some chromosomal disorders.
authors: Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, GA 30322, USA.
authors: Yue
authors: Y
authors: Luo
authors: Karen E
authors: KE
authors: Hermetz
authors: Jodi M
authors: JM
authors: Jackson
authors: Jennifer G
authors: JG
authors: Mulle
authors: Anne
authors: A
authors: Dodd
authors: Karen D
authors: KD
authors: Tsuchiya
authors: Blake C
authors: BC
authors: Ballif
authors: Lisa G
authors: LG
authors: Shaffer
authors: Jannine D
authors: JD
authors: Cody
authors: David H
authors: DH
authors: Ledbetter
authors: Christa L
authors: CL
authors: Martin
authors: M Katharine
authors: MK
authors: Rudd
mesh_terms: D001483:Base Sequence; D002869:Chromosome Aberrations; D019457:Chromosome Breakage; D025063:Chromosome Disorders / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011995:Recombination, Genetic; D016615:Telomere / Q000235:genetics* / Q000378:metabolism