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Non-hotspot-related breakpoints of common deletions in Sotos syndrome are located within destabilised DNA regions
  1. R Visser2,
  2. O Shimokawa1,
  3. N Harada1,
  4. N Niikawa1,
  5. N Matsumoto2
  1. 1Department of Human Genetics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
  2. 2Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  1. Correspondence to:
 Dr Naomichi Matsumoto
 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Fukuura 3-9, Kanazawa-ku, Yokohama 236-0004, Japan;


Background: Sotos syndrome (SoS) is a disorder characterised by excessive growth, typical craniofacial features, and developmental retardation. It is caused by haploinsuffiency of NSD1 at 5q35. There is a 3.0 kb recombination hotspot in which the breakpoints of around 80% of SoS patients with a common deletion can be mapped.

Objective: To identify deletion breakpoints located outside the SoS recombination hotspot.

Methods: A screening system for the directly orientated segments of the SoS LCRs was developed for 10 SoS patients with a common deletion who were negative for the SoS hotspot. Deletion-junction fragments were analysed for DNA duplex stability and their relation to scaffold/matrix attachment regions (S/MARs). These features were compared with the SoS hotspot and recombination hotspots of other genomic disorders.

Results: The breakpoint was mapped in four SoS patients, two with a deletion in the maternally derived chromosome. These breakpoint regions were located ∼2.5 kb, ∼9.6 kb, ∼27.2, and ∼27.7 kb telomeric to the SoS hotspot and were confined to 164 bp, 46 bp, 256 bp, and 124 bp, respectively. Two of the regions were mapped within Alu elements. All crossover events were found to have occurred within or adjacent to a highly destabilised DNA duplex with a high S/MAR probability. In contrast, the SoS hotspot and other genomic disorders’ recombination hotspots were mapped to stabilised DNA helix regions, flanked by destabilised regions with high probability of containing S/MAR elements.

Conclusions: The data suggest that a specific chromatin structure may increase susceptibility for recurrent crossover events and thus predispose to recombination hotspots in genomic disorders.

  • AF4, ALL-1 fused chromosome 4
  • CMT1A, Charcot-Marie-Tooth disease type 1A
  • DLCR, distal low copy repeat
  • HNPP, hereditary neuropathy with liability to pressure palsies
  • LCR, low copy repeat
  • MLL, mixed lineage leukaemia gene
  • NAHR, non-allelic homologous recombination
  • NF1, neurofibromatosis type 1
  • NSD1, nuclear receptor binding, SET domain containing protein 1
  • PLCR, proximal low copy repeat
  • PSV, paralogous sequence variant
  • RB1, retinoblastoma 1 gene
  • SIDD, stress induced destabilisation duplex
  • S/MAR, scaffold/matrix attachment region
  • SMS, Smith-Magenis syndrome
  • SoS, Sotos syndrome
  • Sotos syndrome
  • low copy repeats
  • homologous recombination
  • stress induced destabilisation duplex (SIDD)

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  • Competing interests: none declared