Diverse mutational mechanisms cause pathogenic subtelomeric rearrangements

Yue Luo, Karen E. Hermetz, Jodi M. Jackson, Jennifer G. Mulle, Anne Dodd, Karen D. Tsuchiya, Blake C. Ballif, Lisa G. Shaffer, Jannine D. Cody, David H. Ledbetter, Christa L. Martin, M. Katharine Rudd

Research output: Contribution to journalArticlepeer-review

34 Scopus citations


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.

Original languageEnglish (US)
Article numberddr293
Pages (from-to)3769-3778
Number of pages10
JournalHuman molecular genetics
Issue number19
StatePublished - Oct 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Diverse mutational mechanisms cause pathogenic subtelomeric rearrangements'. Together they form a unique fingerprint.

Cite this