Mutations in RNF135, a gene within the NF1 microdeletion region, cause phenotypic abnormalities including overgrowth

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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.

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Figure 1: Mutations and clinical features associated with RNF135 and comparison with NF1 microdeletion cases.

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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).

Author information

J.D., D.C. and K.C. undertook the mutation screening and MLPA analysis. K.B. undertook the RNF135 expression analysis. K.T.B contributed to exclusion of known overgrowth genes. D.C., K.T.B., B.B., J.B., D.J., M.M., S.M., E.R., V.C.-D. and T.C. provided clinical information and samples from individuals with RNF135 mutations. N.R. designed the study and wrote the paper.

Correspondence to Nazneen Rahman.

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