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Original article
Multiple mechanisms are implicated in the generation of 5q35 microdeletions in Sotos syndrome
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  1. K Tatton-Brown1,
  2. J Douglas1,
  3. K Coleman1,
  4. G Baujat2,
  5. K Chandler3,
  6. A Clarke4,
  7. A Collins5,
  8. S Davies4,
  9. F Faravelli6,
  10. H Firth7,
  11. C Garrett8,
  12. H Hughes4,
  13. B Kerr3,
  14. J Liebelt9,
  15. W Reardon10,
  16. G B Schaefer11,
  17. M Splitt12,
  18. I K Temple5,
  19. D Waggoner11,
  20. D D Weaver13,
  21. L Wilson14,
  22. T Cole15,
  23. V Cormier-Daire2,
  24. A Irrthum1,
  25. N Rahman1,
  26. on behalf of the Childhood Overgrowth Collaboration
  1. 1Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, UK
  2. 2Department of Medical Genetics, Hopital Necker Enfants Malades, Paris, France
  3. 3Regional Genetics Service, St Mary’s Hospital, Manchester, UK
  4. 4Institute of Medical Genetics, University Hospital of Wales, Cardiff, UK
  5. 5Department of Human Genetics, Southampton University Hospital, Southampton, UK
  6. 6Laboratorio di Genetica Umana, Ospedali Galliera de Genova, Genova, Italy
  7. 7Medical Genetics, Addenbrooke’s Hospital, Cambridge, UK
  8. 8Kennedy Galton Centre, Northwick Park Hospital, Harrow, UK
  9. 9South Australian Clinical Genetics Service, North Adelaide, Australia
  10. 10National Centre for Medical Genetics, Our Lady’s Hospital for Sick Children, Crumlin, Dublin 12, Ireland
  11. 11University of Nebraska Medical Center, Omaha, NE, USA
  12. 12Department of Clinical Genetics, Guy’s and St Thomas’ Hospital NHS Trust, London, UK
  13. 13Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, USA
  14. 14Great Ormond Street Hospital for Sick Children, London, UK
  15. 15Clinical Genetics Unit, Birmingham Women’s Hospital, Birmingham, UK
  1. Correspondence to:
 Dr N Rahman
 Section of Cancer Genetics, Brookes Lawley Building, Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey SM2 5NG, UK; nazneen.rahmanicr.ac.uk

Abstract

Background: Sotos syndrome (MIM 117550) is characterised by learning difficulties, overgrowth, and a typical facial appearance. Microdeletions at 5q35.3, encompassing NSD1, are responsible for ∼10% of non-Japanese cases of Sotos. In contrast, a recurrent ∼2 Mb microdeletion has been reported as responsible for ∼50% of Japanese cases of Sotos.

Methods: We screened 471 cases for NSD1 mutations and deletions and identified 23 with 5q35 microdeletions. We investigated the deletion size, parent of origin, and mechanism of generation in these and a further 10 cases identified from published reports. We used “in silico” analyses to investigate whether repetitive elements that could generate microdeletions flank NSD1.

Results: Three repetitive elements flanking NSD1, designated REPcen, REPmid, and REPtel, were identified. Up to 18 cases may have the same sized deletion, but at least eight unique deletion sizes were identified, ranging from 0.4 to 5 Mb. In most instances, the microdeletion arose through interchromosomal rearrangements of the paternally inherited chromosome.

Conclusions: Frequency, size, and mechanism of generation of 5q35 microdeletions differ between Japanese and non-Japanese cases of Sotos. Our microdeletions were identified from a large case series with a broad range of phenotypes, suggesting that sample selection variability is unlikely as a sole explanation for these differences and that variation in genomic architecture might be a contributory factor. Non-allelic homologous recombination between REPcen and REPtel may have generated up to 18 microdeletion cases in our series. However, at least 15 cannot be mediated by these repeats, including at least seven deletions of different sizes, implicating multiple mechanisms in the generation of 5q35 microdeletions.

  • MLPA, multiplex ligation dependent probe amplification
  • NAHR, non-allelic homologous recombination
  • 5q35
  • NSD1
  • Sotos
  • microdeletions
  • overgrowth

https://doi.org/10.1136/jmg.2004.027755

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    Footnotes

    • The Childhood Overgrowth Collaboration includes the following contributors: M Addor, A Al Swaid, S Andries, H Archer, A Barnicoat, M Barrow, J Barwell, G Baujat, K Becker, J Berg, B Bernhard, M Bhat, M Bitner, E Blair, A Brady, L Brueton, K Chandler, C Christensen, A Clarke, J Clayton-Smith, T Cole, L Colleaux, A Colley, A Collins, V Cormier-Daire, S Danda, S Davies, R Day, De Roy Magali, N Dennis, A Dobbie, F Elmslie, F Faravelli, H Firth, D Fitzpatrick, N Foulds, J Franklin, A Fryer, S Garcia, C Gardiner, C Garrett, B Gener, R Gibbons, Y Gillerot, D Goudie, A Henderson, J Hirst, S Hodgson, S Holder, T Homfrey, H Hughes, B Kerr, A Kumar, D Kumar, W Lam, N Leonard, J Liebelt, P Lunt, S Lynch, A Magee, S Mansour, M McEntagart, C McKeown, S McKee, K Metcalfe, S Mohammad, A Murray, A Nemeth, S Park, M Patton, E Penny, D Pilz, B Plecko, C Pollitt, S Price, O Quarrell, A Raas-Rothschild, N Rahman, W Raith, J Rankin, L Raymond, W Reardon, E Reid, E Rosser, D Ruddy, H Santos, GB Schaeffer, A Schulze, A Shaw, S Smithson, M Splitt, F Stewart, H Stewart, M Suri, E Sweeney, K Tatton-Brown, I K Temple, E Thompson, M Tischowitz, J Tolmie, S Turkmen, P Turnpenny, Van Maldergem, P Vasudevan, I Vaz, D Waggoner, C Verellen, E Wakeling, D Weaver, K White, L Wilson, R Winter, P Zack, A Zankl.

    • Competing interests: none declared