Identification of recurrent type-2 NF1 microdeletions reveals a mitotic nonallelic homologous recombination hotspot underlying a human genomic disorder

Hum Mutat. 2012 Nov;33(11):1599-609. doi: 10.1002/humu.22171. Epub 2012 Aug 20.


Nonallelic homologous recombination (NAHR) is one of the major mechanisms underlying copy number variation in the human genome. Although several disease-associated meiotic NAHR breakpoints have been analyzed in great detail, hotspots for mitotic NAHR are not well characterized. Type-2 NF1 microdeletions, which are predominantly of postzygotic origin, constitute a highly informative model with which to investigate the features of mitotic NAHR. Here, a custom-designed MLPA- and PCR-based approach was used to identify 23 novel NAHR-mediated type-2 NF1 deletions. Breakpoint analysis of these 23 type-2 deletions, together with 17 NAHR-mediated type-2 deletions identified previously, revealed that the breakpoints are nonuniformly distributed within the paralogous SUZ12 and SUZ12P sequences. Further, the analysis of this large group of type-2 deletions revealed breakpoint recurrence within short segments (ranging in size from 57 to 253-bp) as well as the existence of a novel NAHR hotspot of 1.9-kb (termed PRS4). This hotspot harbored 20% (8/40) of the type-2 deletion breakpoints and contains the 253-bp recurrent breakpoint region BR6 in which four independent type-2 deletion breakpoints were identified. Our findings indicate that a combination of an open chromatin conformation and short non-B DNA-forming repeats may predispose to recurrent mitotic NAHR events between SUZ12 and its pseudogene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Chromosome Deletion
  • Chromosomes, Human, Pair 17 / genetics
  • Craniofacial Abnormalities / genetics*
  • DNA Breaks
  • DNA Copy Number Variations
  • Genes, Neurofibromatosis 1*
  • Homologous Recombination
  • Humans
  • Intellectual Disability / genetics*
  • Learning Disabilities / genetics*
  • Mitosis / genetics
  • Molecular Sequence Data
  • Mosaicism
  • Multiplex Polymerase Chain Reaction
  • Neurofibromatoses / genetics*
  • Neurofibromatosis 1 / genetics
  • Polycomb Repressive Complex 2 / genetics
  • Pseudogenes
  • Sequence Deletion*
  • Sequence Homology, Nucleic Acid


  • SUZ12 protein, human
  • Polycomb Repressive Complex 2

Supplementary concepts

  • NF1 Microdeletion Syndrome