17q11 microdeletions that encompass NF1 cause 5%–10% of cases of neurofibromatosis type 1, and individuals with microdeletions are typically taller than individuals with intragenic NF1 mutations, suggesting that deletion of a neighboring gene might promote human growth. We identified mutations in RNF135, which is within the NF1 microdeletion region, in six families characterized by overgrowth, learning disability, dysmorphic features and variable additional features. These data identify RNF135 as causative of a new overgrowth syndrome and demonstrate that RNF135 haploinsufficiency contributes to the phenotype of NF1 microdeletion cases.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Ferner, R.E. et al. J. Med. Genet. 44, 81–88 (2007).
Messiaen, L.M. et al. Hum. Mutat. 15, 541–555 (2000).
Kluwe, L. et al. Hum. Mutat. 23, 111–116 (2004).
De Raedt, T. et al. Nat. Genet. 38, 1419–1423 (2006).
Tonsgard, J.H. et al. Am. J. Med. Genet. 73, 80–86 (1997).
Spiegel, M. et al. Eur. J. Hum. Genet. 13, 883–888 (2005).
Devriendt, K. & Vermeesch, J.R. Hum. Genomics 1, 126–133 (2004).
Butler, M.G. et al. J. Med. Genet. 42, 318–321 (2005).
Joazeiro, C.A.P. & Weissman, A.M. Cell 102, 549–552 (2000).
Rhodes, D.A. et al. Immunology 116, 411–417 (2005).
Quaderi, N.A. et al. Nat. Genet. 17, 285–291 (1997).
Venturin, M. et al. J. Med. Genet. 41, 35–31 (2004).
De Raedt, T. et al. Am. J. Hum. Genet. 72, 1288–1292 (2003).
Cohen, M., Neri, G. & Weksberg, R. Overgrowth Syndromes (Oxford Univ. Press, New York, 2002).
Van Asperen, C.J. et al. J. Med. Genet. 35, 323–327 (1998).
We thank the participating families who were recruited to the study by the Childhood Overgrowth Collaboration, which includes the following contributors: M. Addor, A. Al Swaid, J. Amiel, 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, S. Cavani, M. Cecconi, 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, D.R. Magali, N. Dennis, A. Dobbie, P. Edery, F. Elmslie, F. Faravelli, H. Firth, R. Fischetto, D. FitzPatrick, F. Forzano, N. Foulds, J. Franklin, A. Fryer, S. Garcia, C. Gardiner, C. Garrett, B. Gener, R. Gibbons, Y. Gillerot, G. Gillessen-Kaesbach, D. Goudie, M. Grasso, A. Henderson, J. Hirst, S. Hodgson, S. Holder, T. Homfrey, H. Hughes, B. Kerr, A. Kumar, D. Kumar, D. Lacombe, W. Lam, M. Le Merrer, N. Leonard, J. Liebelt, P. Lunt, S. Lynch, S. Lyonnet, A. Magee, M. Malacarne, S. Mansour, M. McEntagart, S. Majore, S. McKee, C. McKeown, P. Meinecke, K. Metcalfe, D. Milani, S. Mohammad, A. Munnich, A. Murray, A. Nemeth, G. Neri, S. Odent, 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, A. Saggar-Malik, H. Santos, G. Scarano, G.B. Schaeffer, A. Schulze, A. Selicorni, A. Shaw, M. Silengo, S. Smithson, M. Splitt, F. Stewart, H. Stewart, M. Suri, E. Sweeney, K. Tatton-Brown, I.K. Temple, E. Thompson, M. Tischkowitz, J. Tolmie, S. Turkmen, P. Turnpenny, L. Van Maldergem, P. Vasudevan, I. Vaz, D. Waggoner, C. Verellen, G. Viot, E. Wakeling, D. Weaver, K. White, L. Wilson, P. Zack, G. Zampino, A. Zankl. We are grateful to S. Huson and L. Side for providing photographs of individuals with NF1 microdeletions. We are very grateful to J. Shipley and A. Mcintyre for providing DNA from Chinese individuals without overgrowth. The research was supported by the Child Growth Foundation, the Institute of Cancer Research and the Medical Research Council (UK).
The authors declare no competing financial interests.
About this article
Biomolecular NMR Assignments (2019)
RNF135 is a positive regulator of IFN expression and involved in RIG-I signaling pathway by targeting RIG-I
Fish & Shellfish Immunology (2019)
Assessing the Pathogenicity, Penetrance, and Expressivity of Putative Disease-Causing Variants in a Population Setting
The American Journal of Human Genetics (2019)
Genetics in Medicine (2019)
Frontiers in Immunology (2018)