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227 results on '"Goodship, J. A."'

1. Large-scale discovery of novel genetic causes of developmental disorders

Author

Fitzgerald, T. W., Gerety, S. S., Jones, W. D., van Kogelenberg, M., King, D. A., McRae, J., Morley, K. I., Parthiban, V., Al-Turki, S., Ambridge, K., Barrett, D. M., Bayzetinova, T., Clayton, S., Coomber, E. L., Gribble, S., Jones, P., Krishnappa, N., Mason, L. E., Middleton, A., Miller, R., Prigmore, E., Rajan, D., Sifrim, A., Tivey, A. R., Ahmed, M., Akawi, N., Andrews, R., Anjum, U., Archer, H., Armstrong, R., Balasubramanian, M., Banerjee, R., Baralle, D., Batstone, P., Baty, D., Bennett, C., Berg, J., Bernhard, B., Bevan, A. P., Blair, E., Blyth, M., Bohanna, D., Bourdon, L., Bourn, D., Brady, A., Bragin, E., Brewer, C., Brueton, L., Brunstrom, K., Bumpstead, S. J., Bunyan, D. J., Burn, J., Burton, J., Canham, N., Castle, B., Chandler, K., Clasper, S., Clayton-Smith, J., Cole, T., Collins, A., Collinson, M. N., Connell, F., Cooper, N., Cox, H., Cresswell, L., Cross, G., Crow, Y., DʼAlessandro, M., Dabir, T., Davidson, R., Davies, S., Dean, J., Deshpande, C., Devlin, G., Dixit, A., Dominiczak, A., Donnelly, C., Donnelly, D., Douglas, A., Duncan, A., Eason, J., Edkins, S., Ellard, S., Ellis, P., Elmslie, F., Evans, K., Everest, S., Fendick, T., Fisher, R., Flinter, F., Foulds, N., Fryer, A., Fu, B., Gardiner, C., Gaunt, L., Ghali, N., Gibbons, R., Pereira, Gomes S. L., Goodship, J., Goudie, D., Gray, E., Greene, P., Greenhalgh, L., Harrison, L., Hawkins, R., Hellens, S., Henderson, A., Hobson, E., Holden, S., Holder, S., Hollingsworth, G., Homfray, T., Humphreys, M., Hurst, J., Ingram, S., Irving, M., Jarvis, J., Jenkins, L., Johnson, D., Jones, D., Jones, E., Josifova, D., Joss, S., Kaemba, B., Kazembe, S., Kerr, B., Kini, U., Kinning, E., Kirby, G., Kirk, C., Kivuva, E., Kraus, A., Kumar, D., Lachlan, K., Lam, W., Lampe, A., Langman, C., Lees, M., Lim, D., Lowther, G., Lynch, S. A., Magee, A., Maher, E., Mansour, S., Marks, K., Martin, K., Maye, U., McCann, E., McConnell, V., McEntagart, M., McGowan, R., McKay, K., McKee, S., McMullan, D. J., McNerlan, S., Mehta, S., Metcalfe, K., Miles, E., Mohammed, S., Montgomery, T., Moore, D., Morgan, S., Morris, A., Morton, J., Mugalaasi, H., Murday, V., Nevitt, L., Newbury-Ecob, R., Norman, A., OʼShea, R., Ogilvie, C., Park, S., Parker, M. J., Patel, C., Paterson, J., Payne, S., Phipps, J., Pilz, D. T., Porteous, D., Pratt, N., Prescott, K., Price, S., Pridham, A., Procter, A., Purnell, H., Ragge, N., Rankin, J., Raymond, L., Rice, D., Robert, L., Roberts, E., Roberts, G., Roberts, J., Roberts, P., Ross, A., Rosser, E., Saggar, A., Samant, S., Sandford, R., Sarkar, A., Schweiger, S., Scott, C., Scott, R., Selby, A., Seller, A., Sequeira, C., Shannon, N., Sharif, S., Shaw-Smith, C., Shearing, E., Shears, D., Simonic, I., Simpkin, D., Singzon, R., Skitt, Z., Smith, A., Smith, B., Smith, K., Smithson, S., Sneddon, L., Splitt, M., Squires, M., Stewart, F., Stewart, H., Suri, M., Sutton, V., Swaminathan, G. J., Sweeney, E., Tatton-Brown, K., Taylor, C., Taylor, R., Tein, M., Temple, I. K., Thomson, J., Tolmie, J., Torokwa, A., Treacy, B., Turner, C., Turnpenny, P., Tysoe, C., Vandersteen, A., Vasudevan, P., Vogt, J., Wakeling, E., Walker, D., Waters, J., Weber, A., Wellesley, D., Whiteford, M., Widaa, S., Wilcox, S., Williams, D., Williams, N., Woods, G., Wragg, C., Wright, M., Yang, F., Yau, M., Carter, N. P., Parker, M., Firth, H. V., FitzPatrick, D. R., Wright, C. F., Barrett, J. C., and Hurles, M. E.

Published
2015
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2. Impact of postoperative non-steroidal anti-inflammatory drugs on adverse events after gastrointestinal surgery

Author

Chapman, S. J., Glasbey, J., Kelly, M., Khatri, C., Nepogodiev, D., Fitzgerald, J. E. F., Bhangu, A., Harrison, E. M., Adams, R., Patel, K., Retchless, A. R., Elsaddig, M., Curtis, A. E., McMahon, R., Mittapalli, D., Ferguson, L. A., Gentry, S. V., Kong, C. Y. N., Naqvi, Z., Amin, H., Chaudhry, B., Burke, J., Henderson, I., Trecarten, S., Clements, J. M., Drake, T. M., Wild, J. R. L., Venkatesh, H., Butters, N., Ahmeidat, H., Goergen, N., Black, D., Robertson, K., Jama, G. M., McGuire, S. A., Ahl, R., Suri, T. S., Kuo, R., Fadhlillah, M., Mills, H., Mitchell, R., Goodship, J., Tan, M., Barker, T., Wright, T., Mohamad, W., Hanna, N., Laing, G., Warnock, M. W. C., Baird-Fraser, P. R., Logan, T., Young, F. M., Fane De Salis, A. C., McHugh, R., Hickson, C., Paszkiewicz, J., Anderson, L. B., Neeson, D., Mohan, M., Narang, Y., Brophy, T., Punj, R., Majumdar, S., Kauser, S., Jong, G., Palkhi, E., Finch, D., Mitchell, H., Carter, N., Viyasar, T., Sammut, T., Cook, N., Powell, M. M., Horne, S., Allen, J. L. Y., Marshall, D., McIntyre, C., S Koh, D. T., Shi, J., Reid, T., Armugam, N. P., Luck, J., Fozard, T., OʼCallaghan, J., Copley, P. C., Tilliriou, V., Aiyer, R., Yazdi, A., Wiltshire, A., Blower, E., Jewitt, C., Cheung, L. K., Fourali, S., Rahimi, Y., Velho, R., Taylor, C., Satterthwaite, L., Eze, N. V., Johnston, J. P. M., McCain, R. S., Hess, E. C. F., Thumbadoo, R. P., Turner, E. J. H., Wookey, R., Morris, R., Gasteratos, K., Heywood, E., Simpson, S. J., Rai, Z., Kazzazi, D., Ducey, J., Livesey, M. J., Finan, C., Staunton, E., Haddad, S. D., Karanjia, R., Bokobza, I., Ahmed, M., Howell, J., Grainger, C., Woo, A., McDowall, M., Bulley, F., Keating, R., Tan, B., Sng, S., Brown, C., Aidoo-Micah, G., Champsi, A., Ellis, R., Darwazeh, S., Polson, R., Chan, J. Z., Chong, B. F. H. K., Park, J. H., Kong, C. Y., Mogan, Y. P., Stevens, S., Sekhon, H. K., McIntosh, R., Ochiltree, D. W., Jamieson, P. D., Naumann, D. N., Bowley, D. M., Howell, G., Clark, T., Dear, K., James, L., Upchurch, E., Wilson, H., Hughes, M., Modayur, S. M., Datta, U., Chen, J. H. C., Williams, L. J. L., Selby, J., Prabhudesai, A., Mahomed, K., Shah, H. A., Kong, K., Chandramoorthy, S., Marshall, L., De Kauwe, C., Rana, R., Patel, J., Pezas, T., Ma, J., Stohlner, V., Kinsella, M. S., Gardiner, S. N., Smith, R. A., Glover, M., Akinfala, M., Lee, J. Z. C., Aggarwal, V., Waters, S., Atif, M., Hill, M., Ramasubramoni, A., Jaffry, Z., Sagoo, H., Jeyakumar, J., Kosasih, S., Davis, J., Stanley, G. H. M., Nijran, J., Tang, I., Mehta, K., Fillery, A., Watson, N. F., Shah, D., Naidu, S., Grewal, T. K., Singh, P., Reissis, D., Marusza, C., Pettit, W., Timbrell, S., Woods, R., Phillips, J., Vaughan, R., Dean, S., Gibby, R., Jones, T. F., Rao, R., Torrance, H. D. T., Thirumal, V., McMahon, R. K., Yap, D., Shaw, A., Claireaux, H. A., Pang, Y. L., Narramore, R., Holmes, C., Caldwell, A., Daoub, A., Bibby, L., Hague, A. G., Sykes, M. C., Morar, P., Downes, G., Shah, S., Walimohamed, S., Alsulaimi, A., Biswas, V., Gnaneswaran, B., Davies, N., Narwani, V., Hernon, J., Jumbu, A., Ilyas, M., Johal, G., Atia, F., Williams, A., Chan, C., McAnelly, S., Evans, A., Chan, K. Y., Flegg, K., Carter, S., Coley, J., Khaw, R., Jayakody, N., Jones, B., Fawcett, N., Ghali, C., Jalundhwala, K., Ariyaratnam, P., Colville, H., Walls, M., Lindsay, J., Keane, M., Ban, V. S., Kambasha, C., Sait, S., Tahir, M., Tharakan, R., Voll, J., Shiwani, H., Al-Omran, Y., Hawash, A., McCaughan, V., Shatkar, V., Gohil, K., Greenhalgh, A., Higgins, E., Moody, T., Booth, M. B., Chan, W. H., Shanthakumaran, S., Maple, N., McNish, D., Shahin, B., Nicholas, J., McDermid, R., Narayan, P., Brodie, C., Hurrey, S., Panayi, V., Turner, B., Kopala, K., Winfield, Clayton S. A., Mohamud, A., Venkatesh, A., Hosein, S., Olimpio, C., Gkiousias, V., Kilgour, J. M., Cogbill, E., Ramcham, M., Carr, G., Bannerman, A., Grundy, L., White, S., Beamish, A., Neo, Y. N., Cragg, A. R., Perkins, A., Wynn-Hebden, A., Khan, T., Ali, M., Battersby, C. L. F., Pinto, R. S., Poon, S. S., Patel, M., Patel, P., Shafi, A. M. A., Vedage, D., Ghorbhanian, S., Klimach, S., Bradley, J., de Sausmarez, E., Hayward, P., Naqib, S., Flanigan, C., Shuttleworth, R. H. A., McElvanna, K., Shelton, B., Westbrook, N., Weir, A., Webb, P., Alam, M., Bhanderi, S., Roberts, C., Al-Shakarchi, J., Lu, M., Harvey, J., Chowdhury, M. U., McGow, C., Antoniou, I., Good, D. F., Gerasimova, N., Eragat, M., Pressler, N., Santos, C. R. D., Arshad, W., Patel, H. R., Kassim, Y., Jayaratne, N., Perera, A., Chandramoorthy, L., Quan, V., Ponweera, A., Tadjkarimi, J., Moyes, L., Metcalfe, C., Napier-Hemy, T, Bull, A., Jaffer, Y., Mushtaq, J., Warren, M., Jarrar, Z., Wickenden, R., Kang, M., Holohan, G., Isbister, T., Strachan, E., Varma, R., Simpson, R., Rajasekar, N., Panayiotou, H., Walsh, E., Thacoor, A., Willson, J. M. H., Mustafa, A., Barai, I., Menon, A., Soon, W. C., Thakrar, C., McCurdie, S., Carr, E. C. F., Westwood, K. J., Wardell, H., Weinberg, D., Craig, A. R. J., Khan, F. A. S., Mulla, A., Dann, P., Saleh, M., Pignatelli, I. C., Igbagiri, K. V., Panagoulas, E. V., Tilston, T. W., Thayaparan, A. J., Navaratnam, J., Aryasomayajula, S., Joji, N., Screen, R., Quinn, C., Harrison, R., Arnaout, A., McCartan, N., Allen, W., Gabriel, R., Hartelius, C. F., Makinde, M. L., Sivasubramaniam, S., Spreadborough, P., Lobo, R., Surendran, H., Couch, L., Butters, T., Beale, K., Markiewicz, O., Kennedy, E. D., Neely, D. M., Martin, A., Al-Moasseb, Z. H., Ong, K. K., Letchumanan, S., Lam, W. L., Yapp, L., Skelly, B. L., Stallard, S., Westhuizen, P. V. D., Rafferty, A. R., Lambert, A., Tay, Y. Z., Koshnow, Z., Elamin, O., Shah, A., Kim, E., English, W., Farrell, A., Sharma, J., Rowan, Chudek. D. K., Mullan, B., Brown, R. J., McCarter, J. A., Johnston, D., Symonds, C., Gatfield, W., Messenger, D., Knox, J. D., Jani, P., Trinquet, J., Naqvi, Z. B., Hussain, K., Jaffer, A., McAleer, E., Joshi, H., Cecil, E., Lochrane, A., Woolley, T., Marriott, P., Bolton, W., Balian, V., Scott, A. J., and Tan, Y. H.

Published
2014
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6. Finding Diagnostically Useful Patterns in Quantitative Phenotypic Data

Author

Aitken, Stuart, primary, Firth, Helen V., additional, McRae, Jeremy, additional, Halachev, Mihail, additional, Kini, Usha, additional, Parker, Michael J., additional, Lees, Melissa M., additional, Lachlan, Katherine, additional, Sarkar, Ajoy, additional, Joss, Shelagh, additional, Splitt, Miranda, additional, McKee, Shane, additional, Németh, Andrea H., additional, Scott, Richard H., additional, Wright, Caroline F., additional, Marsh, Joseph A., additional, Hurles, Matthew E., additional, FitzPatrick, David R., additional, Fitzgerald, T.W., additional, Gerety, S.S., additional, Jones, W.D., additional, van Kogelenberg, M., additional, King, D.A., additional, McRae, J., additional, Morley, K.I., additional, Parthiban, V., additional, Al-Turki, S., additional, Ambridge, K., additional, Barrett, D.M., additional, Bayzetinova, T., additional, Clayton, S., additional, Coomber, E.L., additional, Gribble, S., additional, Jones, P., additional, Krishnappa, N., additional, Mason, L.E., additional, Middleton, A., additional, Miller, R., additional, Prigmore, E., additional, Rajan, D., additional, Sifrim, A., additional, Tivey, A.R., additional, Ahmed, M., additional, Akawi, N., additional, Andrews, R., additional, Anjum, U., additional, Archer, H., additional, Armstrong, R., additional, Balasubramanian, M., additional, Banerjee, R., additional, Barelle, D., additional, Batstone, P., additional, Baty, D., additional, Bennett, C., additional, Berg, J., additional, Bernhard, B., additional, Bevan, A.P., additional, Blair, E., additional, Blyth, M., additional, Bohanna, D., additional, Bourdon, L., additional, Bourn, D., additional, Brady, A., additional, Bragin, E., additional, Brewer, C., additional, Brueton, L., additional, Brunstrom, K., additional, Bumpstead, S.J., additional, Bunyan, D.J., additional, Burn, J., additional, Burton, J., additional, Canham, N., additional, Castle, B., additional, Chandler, K., additional, Clasper, S., additional, Clayton-Smith, J., additional, Cole, T., additional, Collins, A., additional, Collinson, M.N., additional, Connell, F., additional, Cooper, N., additional, Cox, H., additional, Cresswell, L., additional, Cross, G., additional, Crow, Y., additional, D’Alessandro, P.M., additional, Dabir, T., additional, Davidson, R., additional, Davies, S., additional, Dean, J., additional, Deshpande, C., additional, Devlin, G., additional, Dixit, A., additional, Dominiczak, A., additional, Donnelly, C., additional, Donnelly, D., additional, Douglas, A., additional, Duncan, A., additional, Eason, J., additional, Edkins, S., additional, Ellard, S., additional, Ellis, P., additional, Elmslie, F., additional, Evans, K., additional, Everest, S., additional, Fendick, T., additional, Fisher, R., additional, Flinter, F., additional, Foulds, N., additional, Fryer, A., additional, Fu, B., additional, Gardiner, C., additional, Gaunt, L., additional, Ghali, N., additional, Gibbons, R., additional, Pereira, S.L. Gomes, additional, Goodship, J., additional, Goudie, D., additional, Gray, E., additional, Greene, P., additional, Greenhalgh, L., additional, Harrison, L., additional, Hawkins, R., additional, Hellens, S., additional, Henderson, A., additional, Hobson, E., additional, Holden, S., additional, Holder, S., additional, Hollingsworth, G., additional, Homfray, T., additional, Humphreys, M., additional, Hurst, J., additional, Ingram, S., additional, Irving, M., additional, Jarvis, J., additional, Jenkins, L., additional, Johnson, D., additional, Jones, D., additional, Jones, E., additional, Josifova, D., additional, Joss, S., additional, Kaemba, B., additional, Kazembe, S., additional, Kerr, B., additional, Kini, U., additional, Kinning, E., additional, Kirby, G., additional, Kirk, C., additional, Kivuva, E., additional, Kraus, A., additional, Kumar, D., additional, Lachlan, K., additional, Lam, W., additional, Lampe, A., additional, Langman, C., additional, Lees, M., additional, Lim, D., additional, Lowther, G., additional, Lynch, S.A., additional, Magee, A., additional, Maher, E., additional, Mansour, S., additional, Marks, K., additional, Martin, K., additional, Maye, U., additional, McCann, E., additional, McConnell, V., additional, McEntagart, M., additional, McGowan, R., additional, McKay, K., additional, McKee, S., additional, McMullan, D.J., additional, McNerlan, S., additional, Mehta, S., additional, Metcalfe, K., additional, Miles, E., additional, Mohammed, S., additional, Montgomery, T., additional, Moore, D., additional, Morgan, S., additional, Morris, A., additional, Morton, J., additional, Mugalaasi, H., additional, Murday, V., additional, Nevitt, L., additional, Newbury-Ecob, R., additional, Norman, A., additional, O’Shea, R., additional, Ogilvie, C., additional, Park, S., additional, Parker, M.J., additional, Patel, C., additional, Paterson, J., additional, Payne, S., additional, Phipps, J., additional, Pilz, D.T., additional, Porteous, D., additional, Pratt, N., additional, Prescott, K., additional, Price, S., additional, Pridham, A., additional, Proctor, A., additional, Purnell, H., additional, Ragge, N., additional, Rankin, J., additional, Raymond, L., additional, Rice, D., additional, Robert, L., additional, Roberts, E., additional, Roberts, G., additional, Roberts, J., additional, Roberts, P., additional, Ross, A., additional, Rosser, E., additional, Saggar, A., additional, Samant, S., additional, Sandford, R., additional, Sarkar, A., additional, Schweiger, S., additional, Scott, C., additional, Scott, R., additional, Selby, A., additional, Seller, A., additional, Sequeira, C., additional, Shannon, N., additional, Sharif, S., additional, Shaw-Smith, C., additional, Shearing, E., additional, Shears, D., additional, Simonic, I., additional, Simpkin, D., additional, Singzon, R., additional, Skitt, Z., additional, Smith, A., additional, Smith, B., additional, Smith, K., additional, Smithson, S., additional, Sneddon, L., additional, Splitt, M., additional, Squires, M., additional, Stewart, F., additional, Stewart, H., additional, Suri, M., additional, Sutton, V., additional, Swaminathan, G.J., additional, Sweeney, E., additional, Tatton-Brown, K., additional, Taylor, C., additional, Taylor, R., additional, Tein, M., additional, Temple, I.K., additional, Thomson, J., additional, Tolmie, J., additional, Torokwa, A., additional, Treacy, B., additional, Turner, C., additional, Turnpenny, P., additional, Tysoe, C., additional, Vandersteen, A., additional, Vasudevan, P., additional, Vogt, J., additional, Wakeling, E., additional, Walker, D., additional, Waters, J., additional, Weber, A., additional, Wellesley, D., additional, Whiteford, M., additional, Widaa, S., additional, Wilcox, S., additional, Williams, D., additional, Williams, N., additional, Woods, G., additional, Wragg, C., additional, Wright, M., additional, Yang, F., additional, Yau, M., additional, Carter, N.P., additional, Parker, M., additional, Firth, H.V., additional, FitzPatrick, D.R., additional, Wright, C.F., additional, Barrett, J.C., additional, and Hurles, M.E., additional

Published
2019
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9. Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield

Author

Thomson, K, Ormondroyd, E, Harper, A, Dent, T, McGuire, K, Baksi, J, Blair, E, Brennan, P, Buchan, R, Bueser, T, Campbell, C, Carr-White, G, Cook, S, Daniels, M, Deevi, S, Goodship, J, Hayesmoore, J, Henderson, A, Lamb, T, Prasad, S, Rayner-Matthews, P, Robert, L, Sneddon, L, Stark, H, Walsh, R, Ware, J, Farrall, M, Watkins, H, Consortium, Nihr Bioresource – Rare Diseases, Wellcome Trust, and British Heart Foundation

Subjects
Adult, Male, Sarcomeres, Adolescent, NIHR BioResource – Rare Diseases Consortium, VARIANTS, GUIDELINES, Article, DISEASE, genetic testing, Young Adult, RARE, evidence-based, Humans, Genetic Association Studies, Aged, Genetics & Heredity, 0604 Genetics, Science & Technology, Whole Genome Sequencing, MUTATIONS, variant interpretation, 1103 Clinical Sciences, Cardiomyopathy, Hypertrophic, Middle Aged, HCM, VUS, Case-Control Studies, Female, Life Sciences & Biomedicine, TASK-FORCE
Abstract

Purpose Increasing numbers of genes are being implicated in Mendelian disorders and incorporated into clinical test panels. However, lack of evidence supporting the gene-disease relationship can hinder interpretation. We explored the utility of testing 51 additional genes for hypertrophic cardiomyopathy (HCM), one of the most commonly tested Mendelian disorders. Methods Using genome sequencing data from 240 sarcomere gene negative HCM cases and 6229 controls, we undertook case-control and individual variant analyses to assess 51 genes that have been proposed for HCM testing. Results We found no evidence to suggest that rare variants in these genes are prevalent causes of HCM. One variant, in a single case, was categorized as likely to be pathogenic. Over 99% of variants were classified as a variant of uncertain significance (VUS) and 54% of cases had one or more VUS. Conclusion For almost all genes, the gene-disease relationship could not be validated and lack of evidence precluded variant interpretation. Thus, the incremental diagnostic yield of extending testing was negligible, and would, we propose, be outweighed by problems that arise with a high rate of uninterpretable findings. These findings highlight the need for rigorous, evidence-based selection of genes for clinical test panels.

Published
2018

20. Spectrum of clinical features associated with interstitial chromosome 22q11 deletions: a European collaborative study

Author

Ryan, A. K., Goodship, J. A., Wilson, D. I., Philip, N., Levy, A., Seidel, H., Schuffenhauer, S., Oechsler, H., Belohradsky, B., Prieur, M., Aurias, A., Raymond, F. L., Clayton-Smith, J., Hatchwell, E., McKeown, C., Beemer, F. A., Dallapiccola, B., Novelli, G., Hurst, J. A., Ignatius, J., Green, A. J., Winter, R. M., Brueton, L., Brondum-Nielsen, K., Stewart, F., Van Essen, T., Patton, M., Paterson, J., and Scambler, P. J.

Published
1997

22. Prevalence and architecture of de novo mutations in developmental disorders

Author

McRae, JF, Clayton, S, Fitzgerald, TW, Kaplanis, J, Prigmore, E, Rajan, D, Sifrim, A, Aitken, S, Akawi, N, Alvi, M, Ambridge, K, Barrett, DM, Bayzetinova, T, Jones, P, Jones, WD, King, D, Krishnappa, N, Mason, LE, Singh, T, Tivey, AR, Ahmed, M, Anjum, U, Archer, H, Armstrong, R, Awada, J, Balasubramanian, M, Banka, S, Baralle, D, Barnicoat, A, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Bitner-Glindzicz, M, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Bradley, L, Brady, A, Brent, S, Brewer, C, Brunstrom, K, Bunyan, DJ, Burn, J, Canham, N, Castle, B, Chandler, K, Chatzimichali, E, Cilliers, D, Clarke, A, Clasper, S, Clayton-Smith, J, Clowes, V, Coates, A, Cole, T, Colgiu, I, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D’Alessandro, M, Dabir, T, Davidson, R, Davies, S, de Vries, D, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dobbie, A, Donaldson, A, Donnai, D, Donnelly, D, Donnelly, C, Douglas, A, Douzgou, S, Duncan, A, Eason, J, Ellard, S, Ellis, I, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fry, A, Fryer, A, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Gill, H, Goodship, J, Goudie, D, Gray, E, Green, A, Greene, P, Greenhalgh, L, Gribble, S, Harrison, R, Harrison, L, Harrison, V, Hawkins, R, He, L, Hellens, S, Henderson, A, Hewitt, S, Hildyard, L, Hobson, E, Holden, S, Holder, M, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Hutton, B, Ingram, S, Irving, M, Islam, L, Jackson, A, Jarvis, J, Jenkins, L, Johnson, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kelsell, R, Kerr, B, Kingston, H, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Kumar, VKA, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Longman, C, Lowther, G, Lynch, SA, Magee, A, Maher, E, Male, A, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, McWilliam, C, Mehta, S, Metcalfe, K, Middleton, A, Miedzybrodzka, Z, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morton, J, Mugalaasi, H, Murday, V, Murphy, H, Naik, S, Nemeth, A, Nevitt, L, Newbury-Ecob, R, Norman, A, O’Shea, R, Ogilvie, C, Ong, K-R, Park, S-M, Parker, MJ, Patel, C, Paterson, J, Payne, S, Perrett, D, Phipps, J, Pilz, DT, Pollard, M, Pottinger, C, Poulton, J, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Quarrell, O, Ragge, N, Rahbari, R, Randall, J, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, J, Roberts, P, Roberts, G, Ross, A, Rosser, E, Saggar, A, Samant, S, Sampson, J, Sandford, R, Sarkar, A, Schweiger, S, Scott, R, Scurr, I, Selby, A, Seller, A, Sequeira, C, Shannon, N, Sharif, S, Shaw-Smith, C, Shearing, E, Shears, D, Sheridan, E, Simonic, I, Singzon, R, Skitt, Z, Smith, A, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Straub, V, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tischkowitz, M, Tomkins, S, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Varghese, V, Vasudevan, P, Vijayarangakannan, P, Vogt, J, Wakeling, E, Wallwark, S, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Wilkinson, E, Williams, D, Williams, N, Wilson, L, Woods, G, Wragg, C, Wright, M, Yates, L, Yau, M, Nellåker, C, Parker, M, Firth, HV, Wright, CF, FitzPatrick, DR, Barrett, JC, and Hurles, ME

Subjects
Male, Parents, Heredity, Developmental Disabilities, GRIN2B, POGZ, Autoantigens, SMAD4, CASK, GATAD2B, 0302 clinical medicine, TRIO, SMARCA2, KCNH1, Average Faces, CTNNB1, SCN1A, Young adult, Casein Kinase II, Child, AUTS2, MEF2C, Exome, ADNP, Exome sequencing, EP300, KCNQ2, KCNQ3, EHMT1, CNKSR2, CREBBP, MYT1L, MED13L, CSNK2A1, Protein Phosphatase 2C, PPP2R1A, ZBTB18, CDKL5, WAC, HNRNPU, Cohort, STXBP1, Medical genetics, SYNGAP1, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Sex characteristics, AHDC1, SCN8A, medicine.medical_specialty, SLC6A1, FOXP1, USP9X, Article, ANKRD11, PUF60, BRAF, 03 medical and health sciences, SATB2, SMC1A, Intellectual Disability, BCL11A, GABRB3, IQSEC2, Humans, TBL1XR1, TCF4, MSL3, TCF20, DNM1, EEF1A2, SUV420H1, DYRK1A, SETD5, COL4A3BP, CTCF, CHD2, R1, CHD4, 030104 developmental biology, NAA10, HDAC8, Mutation, KDM5B, CHAMP1, PhenIcons, 030217 neurology & neurosurgery, Transcription Factors, 0301 basic medicine, ZMYND11, PTEN, De novo mutation, Chromosomal Proteins, Non-Histone, PTPN11, ASXL1, Bioinformatics, medicine.disease_cause, ASXL3, Cohort Studies, DEAD-box RNA Helicases, CHD8, Prevalence, QRICH1, KIF1A, Genetics, Sex Characteristics, GNAI1, Multidisciplinary, WDR45, Middle Aged, KMT2A, PPM1D, MECP2, DNA-Binding Proteins, PPP2R5D, Phenotype, PACS1, ras GTPase-Activating Proteins, DDX3X, Female, FOXG1, SET, Myeloid-Lymphoid Leukemia Protein, Developmental Disease, Adult, KANSL1, Adolescent, NFIX, Nerve Tissue Proteins, PURA, Biology, KAT6B, KAT6A, NSD1, PDHA1, ALG13, Young Adult, Seizures, CDC2 Protein Kinase, medicine, Journal Article, QH426, Homeodomain Proteins, ITPR1, DYNC1H1, GNAO1, Histone-Lysine N-Methyltransferase, Sequence Analysis, DNA, ZC4H2, ARID1B, Repressor Proteins, CNOT3, SCN2A, SLC35A2, CDK13
Abstract

Children with severe, undiagnosed developmental disorders (DDs) are enriched for damaging de novo mutations (DNMs) in developmentally important genes. We exome sequenced 4,294 families with children with DDs, and meta-analysed these data with published data on 3,287 children with similar disorders. We show that the most significant factors influencing the diagnostic yield of de novo mutations are the sex of the child, the relatedness of their parents and the age of both father and mother. We identified 95 genes enriched for damaging de novo mutation at genome-wide significance (P < 5 x 10-7), including fourteen genes for which compelling data for causation was previously lacking. The large number of genome-wide significant findings allow us to demonstrate that, at current cost differentials, exome sequencing has much greater power than genome sequencing for novel gene discovery in genetically heterogeneous disorders. We estimate that 42.5% of our cohort likely carry pathogenic de novo single nucleotide variants (SNVs) and indels in coding sequences, with approximately half operating by a loss-of-function mechanism, and the remainder being gain-of-function. We established that most haploinsufficient developmental disorders have already been identified, but that many gain-of-function disorders remain to be discovered. Extrapolating from the DDD cohort to the general population, we estimate that de novo dominant developmental disorders have an average birth prevalence of 1 in 168 to 1 in 377, depending on parental age.

Published
2017

25. Large-scale discovery of novel genetic causes of developmental disorders

Author

Fitzgerald, TW, Gerety, SS, Jones, WD, van Kogelenberg, M, King, DA, McRae, J, Morley, KI, Parthiban, V, Al-Turki, S, Ambridge, K, Barrett, DM, Bayzetinova, T, Clayton, S, Coomber, EL, Gribble, S, Jones, P, Krishnappa, N, Mason, LE, Middleton, A, Miller, R, Prigmore, E, Rajan, D, Sifrim, A, Tivey, AR, Ahmed, M, Akawi, N, Andrews, R, Anjum, U, Archer, H, Armstrong, R, Balasubramanian, M, Banerjee, R, Baralle, D, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Brady, A, Bragin, E, Brewer, C, Brueton, L, Brunstrom, K, Bumpstead, SJ, Bunyan, DJ, Burn, J, Burton, J, Canham, N, Castle, B, Chandler, K, Clasper, S, Clayton-Smith, J, Cole, T, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D'Alessandro, M, Dabir, T, Davidson, R, Davies, S, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dominiczak, A, Donnelly, C, Donnelly, D, Douglas, A, Duncan, A, Eason, J, Edkins, S, Ellard, S, Ellis, P, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fryer, A, Fu, B, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Pereira, SLG, Goodship, J, Goudie, D, Gray, E, Greene, P, Greenhalgh, L, Harrison, L, Hawkins, R, Hellens, S, Henderson, A, Hobson, E, Holden, S, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Ingram, S, Irving, M, Jarvis, J, Jenkins, L, Johnson, D, Jones, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kerr, B, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Lowther, G, Lynch, SA, Magee, A, Maher, E, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, Mehta, S, Metcalfe, K, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morris, A, Morton, J, Mugalaasi, H, Murday, V, Nevitt, L, Newbury-Ecob, R, Norman, A, O'Shea, R, Ogilvie, C, Park, S, Parker, MJ, Patel, C, Paterson, J, Payne, S, Phipps, J, Pilz, DT, Porteous, D, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Ragge, N, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, G, Roberts, J, Roberts, P, Ross, A, Rosser, E, Saggar, A, Samant, S, Sandford, R, Sarkar, A, Schweier, S, Scott, C, Scott, R, Selby, A, Seller, A, Sequeira, C, Shannon, N, Shanrif, S, Shaw-Smith, C, Shearing, E, Shears, D, Simonic, I, Simpkin, D, Singzon, R, Skitt, Z, Smith, A, Smith, B, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tolmie, J, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Vasudevan, P, Vogt, J, Wakeling, E, Walker, D, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Williams, D, Williams, N, Woods, G, Wragg, C, Wright, M, Yang, F, Yau, M, Carter, NP, Parker, M, Firth, HV, FitzPatrick, DR, Wright, CF, Barrett, JC, Hurles, ME, Fitzgerald, TW, Gerety, SS, Jones, WD, van Kogelenberg, M, King, DA, McRae, J, Morley, KI, Parthiban, V, Al-Turki, S, Ambridge, K, Barrett, DM, Bayzetinova, T, Clayton, S, Coomber, EL, Gribble, S, Jones, P, Krishnappa, N, Mason, LE, Middleton, A, Miller, R, Prigmore, E, Rajan, D, Sifrim, A, Tivey, AR, Ahmed, M, Akawi, N, Andrews, R, Anjum, U, Archer, H, Armstrong, R, Balasubramanian, M, Banerjee, R, Baralle, D, Batstone, P, Baty, D, Bennett, C, Berg, J, Bernhard, B, Bevan, AP, Blair, E, Blyth, M, Bohanna, D, Bourdon, L, Bourn, D, Brady, A, Bragin, E, Brewer, C, Brueton, L, Brunstrom, K, Bumpstead, SJ, Bunyan, DJ, Burn, J, Burton, J, Canham, N, Castle, B, Chandler, K, Clasper, S, Clayton-Smith, J, Cole, T, Collins, A, Collinson, MN, Connell, F, Cooper, N, Cox, H, Cresswell, L, Cross, G, Crow, Y, D'Alessandro, M, Dabir, T, Davidson, R, Davies, S, Dean, J, Deshpande, C, Devlin, G, Dixit, A, Dominiczak, A, Donnelly, C, Donnelly, D, Douglas, A, Duncan, A, Eason, J, Edkins, S, Ellard, S, Ellis, P, Elmslie, F, Evans, K, Everest, S, Fendick, T, Fisher, R, Flinter, F, Foulds, N, Fryer, A, Fu, B, Gardiner, C, Gaunt, L, Ghali, N, Gibbons, R, Pereira, SLG, Goodship, J, Goudie, D, Gray, E, Greene, P, Greenhalgh, L, Harrison, L, Hawkins, R, Hellens, S, Henderson, A, Hobson, E, Holden, S, Holder, S, Hollingsworth, G, Homfray, T, Humphreys, M, Hurst, J, Ingram, S, Irving, M, Jarvis, J, Jenkins, L, Johnson, D, Jones, D, Jones, E, Josifova, D, Joss, S, Kaemba, B, Kazembe, S, Kerr, B, Kini, U, Kinning, E, Kirby, G, Kirk, C, Kivuva, E, Kraus, A, Kumar, D, Lachlan, K, Lam, W, Lampe, A, Langman, C, Lees, M, Lim, D, Lowther, G, Lynch, SA, Magee, A, Maher, E, Mansour, S, Marks, K, Martin, K, Maye, U, McCann, E, McConnell, V, McEntagart, M, McGowan, R, McKay, K, McKee, S, McMullan, DJ, McNerlan, S, Mehta, S, Metcalfe, K, Miles, E, Mohammed, S, Montgomery, T, Moore, D, Morgan, S, Morris, A, Morton, J, Mugalaasi, H, Murday, V, Nevitt, L, Newbury-Ecob, R, Norman, A, O'Shea, R, Ogilvie, C, Park, S, Parker, MJ, Patel, C, Paterson, J, Payne, S, Phipps, J, Pilz, DT, Porteous, D, Pratt, N, Prescott, K, Price, S, Pridham, A, Procter, A, Purnell, H, Ragge, N, Rankin, J, Raymond, L, Rice, D, Robert, L, Roberts, E, Roberts, G, Roberts, J, Roberts, P, Ross, A, Rosser, E, Saggar, A, Samant, S, Sandford, R, Sarkar, A, Schweier, S, Scott, C, Scott, R, Selby, A, Seller, A, Sequeira, C, Shannon, N, Shanrif, S, Shaw-Smith, C, Shearing, E, Shears, D, Simonic, I, Simpkin, D, Singzon, R, Skitt, Z, Smith, A, Smith, B, Smith, K, Smithson, S, Sneddon, L, Splitt, M, Squires, M, Stewart, F, Stewart, H, Suri, M, Sutton, V, Swaminathan, GJ, Sweeney, E, Tatton-Brown, K, Taylor, C, Taylor, R, Tein, M, Temple, IK, Thomson, J, Tolmie, J, Torokwa, A, Treacy, B, Turner, C, Turnpenny, P, Tysoe, C, Vandersteen, A, Vasudevan, P, Vogt, J, Wakeling, E, Walker, D, Waters, J, Weber, A, Wellesley, D, Whiteford, M, Widaa, S, Wilcox, S, Williams, D, Williams, N, Woods, G, Wragg, C, Wright, M, Yang, F, Yau, M, Carter, NP, Parker, M, Firth, HV, FitzPatrick, DR, Wright, CF, Barrett, JC, and Hurles, ME

Abstract

Despite three decades of successful, predominantly phenotype-driven discovery of the genetic causes of monogenic disorders, up to half of children with severe developmental disorders of probable genetic origin remain without a genetic diagnosis. Particularly challenging are those disorders rare enough to have eluded recognition as a discrete clinical entity, those with highly variable clinical manifestations, and those that are difficult to distinguish from other, very similar, disorders. Here we demonstrate the power of using an unbiased genotype-driven approach to identify subsets of patients with similar disorders. By studying 1,133 children with severe, undiagnosed developmental disorders, and their parents, using a combination of exome sequencing and array-based detection of chromosomal rearrangements, we discovered 12 novel genes associated with developmental disorders. These newly implicated genes increase by 10% (from 28% to 31%) the proportion of children that could be diagnosed. Clustering of missense mutations in six of these newly implicated genes suggests that normal development is being perturbed by an activating or dominant-negative mechanism. Our findings demonstrate the value of adopting a comprehensive strategy, both genome-wide and nationwide, to elucidate the underlying causes of rare genetic disorders.

Published
2015

26. Specific variants in WDR35 cause a distinctive form of ellis-van creveld syndrome by disrupting the recruitment of the evc complex and smo into the cilium

Author

Caparrós-Martín, Jose, De Luca, A., Cartault, F., Aglan, M., Temtamy, S., Otaify, G., Mehrez, M., Valencia, M., Vázquez, L., Alessandri, J., Nevado, J., Rueda-Arenas, I., Heath, K., Digilio, M., Dallapiccola, B., Goodship, J., Mill, P., Lapunzina, P., Ruiz-Perez, V., Caparrós-Martín, Jose, De Luca, A., Cartault, F., Aglan, M., Temtamy, S., Otaify, G., Mehrez, M., Valencia, M., Vázquez, L., Alessandri, J., Nevado, J., Rueda-Arenas, I., Heath, K., Digilio, M., Dallapiccola, B., Goodship, J., Mill, P., Lapunzina, P., and Ruiz-Perez, V.

Abstract

© The Author 2015. Published by Oxford University Press. All rights reserved. Most patients with Ellis-van Creveld syndrome (EvC) are identified with pathogenic changes in EVC or EVC2, however further genetic heterogeneity has been suggested. In this report we describe pathogenic splicing variants in WDR35, encoding retrograde intraflagellar transport protein 121 (IFT121), in three families with a clinical diagnosis of EvC but having a distinctive phenotype. To understand why WDR35 variants result in EvC, we analysed EVC, EVC2 and Smoothened (SMO) in IFT-A deficient cells. We found that the three proteins failed to localize to Wdr35 -/- cilia, but not to the cilium of the IFT retrograde motor mutant Dync2h1 -/- , indicating that IFT121 is specifically required for their entry into the ciliary compartment. Furthermore expression of Wdr35 disease cDNAs in Wdr35 -/- fibroblasts revealed that the newly identified variants lead to Hedgehog signalling defects resembling those of Evc -/- and Evc2 -/- mutants. Together our data indicate that splicing variants in WDR35, and possibly in other IFT-A components, underlie a number of EvC cases by disrupting targeting of both the EvC complex and SMO to cilia.

Published
2015

29. Widening the mutation spectrum of EVC and EVC2: ectopic expression of Weyer variants in NIH 3T3 fibroblasts disrupts Hedgehog signaling

Author

Valencia, M, Lapunzina, P, Lim, D, Zannolli, R, Bartholdi, D, Wollnik, B, Al-Ajlouni, O, Eid, S S, Cox, H, Buoni, S, Hayek, J, Martinez-Frias, M L, Perez-Aytes, A, Temtamy, S, Aglan, M, Goodship, J A, Ruiz-Perez, V L, and University of Zurich

Subjects
2716 Genetics (clinical), 1311 Genetics, 10039 Institute of Medical Genetics, 570 Life sciences, biology, 340 Law, 610 Medicine & health, 10218 Institute of Legal Medicine
Published
2009

32. Ebstein's anomaly may be caused by mutations in the sarcomere protein gene MYH7

Author

Engelen, K, Postma, AV, van de Meerakker, JBA, Roos - Hesselink, Jolien, Helderman-van d Enden, ATJM, Vliegen, HW, Rahman, T, Baars, MJH, Sels, JW, Bauer, U, Pickardt, T, Sperling, SR, Moorman, AFM, Keavney, B, Goodship, J, Klaassen, S, Mulder, BJM, Engelen, K, Postma, AV, van de Meerakker, JBA, Roos - Hesselink, Jolien, Helderman-van d Enden, ATJM, Vliegen, HW, Rahman, T, Baars, MJH, Sels, JW, Bauer, U, Pickardt, T, Sperling, SR, Moorman, AFM, Keavney, B, Goodship, J, Klaassen, S, and Mulder, BJM

Abstract

Ebstein's anomaly is a rare congenital heart malformation characterised by adherence of the septal and posterior leaflets of the tricuspid valve to the underlying myocardium. Associated abnormalities of left ventricular morphology and function including left ventricular noncompaction (LVNC) have been observed. An association between Ebstein's anomaly with LVNC and mutations in the sarcomeric protein gene MYH7, encoding beta-myosin heavy chain, has been shown by recent studies. This might represent a specific subtype of Ebstein's anomaly with a Mendelian inheritance pattern. In this review we discuss the association of MYH7 mutations with Ebstein's anomaly and LVNC and its implications for the clinical care for patients and their family members.

Published
2013

33. The ciliary EVC/EVC2 complex interacts with smo and controls hedgehog pathway activity in chondrocytes by regulating Sufu/Gli3 dissociation and Gli3 trafficking in primary cilia

Author

Caparrós-Martín, Jose, Valencia, M., Reytor, E., Pacheco, M., Fernandez, M., Perez-Aytes, A., Gean, E., Lapunzina, P., Peters, H., Goodship, J., Ruiz-Perez, V., Caparrós-Martín, Jose, Valencia, M., Reytor, E., Pacheco, M., Fernandez, M., Perez-Aytes, A., Gean, E., Lapunzina, P., Peters, H., Goodship, J., and Ruiz-Perez, V.

Abstract

Hedgehog (Hh) signaling is involved in patterning and morphogenesis of most organs in the developing mammalian embryo. Despite many advances in understanding core components of the pathway, little is known about how the activity of the Hh pathway is adjusted in organ- and tissue-specific developmental processes. Mutations in EVC or EVC2 disrupt Hh signaling in tooth and bone development. Using mouse models, we show here that Evc and Evc2 are mutually required for localizing to primary cilia and also for maintaining their normal protein levels. Consistent with Evc and Evc2 functioning as a complex, the skeletal phenotypes in either single or double homozygous mutant mice are virtually indistinguishable. Smo translocation to the cilium was normal in Evc2-deficient chondrocytes following Hh activation with the Smo-agonist SAG. However, Gli3 recruitment to cilia tips was reduced and Sufu/Gli3 dissociation was impaired. Interestingly, we found Smo to co-precipitate with Evc/Evc2, indicating that in some cells Hh signaling requires direct interaction of Smo with the Evc/Evc2 complex. Expression of a dominantly acting Evc2 mutation previously identified in Weyer's acrodental dysostosis (Evc2d43) caused mislocalization of Evc/Evc2d43 within the cilium and also reproduced the Gli3-related molecular defects observed in Evc2 -/- chondrocytes. Moreover, Evc silencing in Sufu -/- cells attenuated the output of the Hh pathway, suggesting that Evc/Evc2 also promote Hh signaling in the absence of Sufu. Together our data reveal that the Hh pathway involves Evc/Evc2-dependent modulations that are necessary for normal endochondral bone formation. © The Author 2012. Published by Oxford University Press. All rights reserved.

Published
2013

34. Evc works in chondrocytes and osteoblasts to regulate multiple aspects of growth plate development in the appendicular skeleton and cranial base

Author

Pacheco, M., Valencia, M., Caparrós-Martín, Jose, Mulero, F., Goodship, J., Ruiz-Perez, V., Pacheco, M., Valencia, M., Caparrós-Martín, Jose, Mulero, F., Goodship, J., and Ruiz-Perez, V.

Abstract

Ellis-van Creveld syndrome protein homolog (Evc) was previously shown to mediate expression of Indian hedgehog (Ihh) downstream targets in chondrocytes. Consequently disruption of the Ihh/Pthrp axis was demonstrated in Evc -/- mice, but the full extent of Evc involvement in endochondral development was not totally characterized. Herein we have examined further the Evc -/- growth plate in a homogeneous genetic background and show that Evc promotes chondrocyte proliferation, chondrocyte hypertrophy and the differentiation of osteoblasts in the perichondrium, hence implicating Evc in both Pthrp-dependent and Pthrp-independent Ihh functions. We also demonstrate that Evc, which localizes to osteoblast primary cilia, mediates Hedgehog (Hh) signaling in the osteoblast lineage. In spite of this, bone collar development is mildly affected in Evc -/- mutants. The onset of perichondrial osteoblastogenesis is delayed at the initial stages of endochondral ossification in Evc -/- mice, and in later stages, the leading edge of expression of osteoblast markers and Wnt/ß-catenin signaling components is located closer to the primary spongiosa in the Evc -/- perichondrium owing to impaired osteoblast differentiation. Additionally we have used Ptch1-LacZ reporter mice to learn about the different types of Hh-responsive cells that are present in the perichondrium of normal and Evc -/- mice. Evc mediates Hh target gene expression in inner perichondrial cells, but it is dispensable in the external layers of the perichondrium. Finally, we report cranial base defects in Evc -/- mice and reveal that Evc is essential for intrasphenoidal synchondrosis development. © 2011.

Published
2012

35. De novo nonsense mutations in ASXL1 cause Bohring-Opitz syndrome

Author

Hoischen, A., Bon, B.W. van, Rodriguez-Santiago, B., Gilissen, C.F.H.A., Vissers, L.E.L.M., Vries, P.F. de, Janssen, I.M., Lier, B. van, Hastings, R., Smithson, S.F., Newbury-Ecob, R., Kjaergaard, S., Goodship, J., McGowan, R., Bartholdi, D., Rauch, A., Peippo, M., Cobben, J.M., Wieczorek, D., Gillessen-Kaesbach, G., Veltman, J.A., Brunner, H.G., Vries, L.B.A. de, Hoischen, A., Bon, B.W. van, Rodriguez-Santiago, B., Gilissen, C.F.H.A., Vissers, L.E.L.M., Vries, P.F. de, Janssen, I.M., Lier, B. van, Hastings, R., Smithson, S.F., Newbury-Ecob, R., Kjaergaard, S., Goodship, J., McGowan, R., Bartholdi, D., Rauch, A., Peippo, M., Cobben, J.M., Wieczorek, D., Gillessen-Kaesbach, G., Veltman, J.A., Brunner, H.G., and Vries, L.B.A. de

Abstract

Item does not contain fulltext, Bohring-Opitz syndrome is characterized by severe intellectual disability, distinctive facial features and multiple congenital malformations. We sequenced the exomes of three individuals with Bohring-Opitz syndrome and in each identified heterozygous de novo nonsense mutations in ASXL1, which is required for maintenance of both activation and silencing of Hox genes. In total, 7 out of 13 subjects with a Bohring-Opitz phenotype had de novo ASXL1 mutations, suggesting that the syndrome is genetically heterogeneous.

Published
2011

36. Systematic survey of variants in TBX1 in non-syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that reduces transcriptional activity but finds no evidence for association with common variants

Author

Griffin, H R, Töpf, A, Glen, E, Zweier, C, Stuart, A G, Parsons, J, Peart, I, Deanfield, J, O'Sullivan, J, Rauch, A, Scambler, P, Burn, J, Cordell, H J, Keavney, B, Goodship, J A, Griffin, H R, Töpf, A, Glen, E, Zweier, C, Stuart, A G, Parsons, J, Peart, I, Deanfield, J, O'Sullivan, J, Rauch, A, Scambler, P, Burn, J, Cordell, H J, Keavney, B, and Goodship, J A

Abstract

BACKGROUND: Tetralogy of Fallot (TOF) is common in individuals with hemizygous deletions of chromosome 22q11.2 that remove the cardiac transcription factor TBX1. OBJECTIVE: To assess the contribution of common and rare TBX1 genetic variants to TOF. DESIGN: Rare TBX1 variants were sought by resequencing coding exons and splice-site boundaries. Common TBX1 variants were investigated by genotyping 20 haplotype-tagging SNPs capturing all the common variations present at the locus. Association analysis was performed using the program UNPHASED. PATIENTS: TBX1 exons were sequenced in 93 patients with non-syndromic TOF. Single nucleotide polymorphism analysis was performed in 356 patients with TOF, their parents and healthy controls. RESULTS: Three novel variants not present in 1000 chromosomes from healthy ethnically matched controls were identified. One of these variants, an in-frame 57 base-pair deletion in the third exon which removed 19 evolutionarily conserved residues, decreased transcriptional activity by 40% in a dual luciferase assay (p=0.008). Protein expression studies demonstrated that this mutation affected TBX1 protein stability. After correction for multiple comparisons, no significant associations between common genetic variants and TOF susceptibility were found. CONCLUSION: This study demonstrates that rare TBX1 variants with functional consequences are present in a small proportion of non-syndromic TOF.

Published
2010

38. Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot

Author

Cordell, H. J., primary, Topf, A., additional, Mamasoula, C., additional, Postma, A. V., additional, Bentham, J., additional, Zelenika, D., additional, Heath, S., additional, Blue, G., additional, Cosgrove, C., additional, Granados Riveron, J., additional, Darlay, R., additional, Soemedi, R., additional, Wilson, I. J., additional, Ayers, K. L., additional, Rahman, T. J., additional, Hall, D., additional, Mulder, B. J. M., additional, Zwinderman, A. H., additional, van Engelen, K., additional, Brook, J. D., additional, Setchfield, K., additional, Bu'Lock, F. A., additional, Thornborough, C., additional, O'Sullivan, J., additional, Stuart, A. G., additional, Parsons, J., additional, Bhattacharya, S., additional, Winlaw, D., additional, Mital, S., additional, Gewillig, M., additional, Breckpot, J., additional, Devriendt, K., additional, Moorman, A. F. M., additional, Rauch, A., additional, Lathrop, G. M., additional, Keavney, B. D., additional, and Goodship, J. A., additional

Published
2013
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39. Identification of a novel transcript disrupted by a balanced translocation associated with DiGeorge syndrome

Author

Sutherland, H. F., Wadey, R., Mckie, J. M., Taylor, C., Atif, U., Johnstone, K. A., Halford, S., Kim, U. -J, Goodship, J., Antonio Baldini, Scambler, P. J., H. F., Sutherland, R., Wadey, J. M., Mckie, C., Taylor, U., Atif, K. A., Johnstone, S., Halford, U. J., Kim, J., Goodship, Baldini, Antonio, and P. J., Scambler

Abstract

Most cases of DiGeorge syndrome (DGS) and related abnormalities are associated with deletions within 22q11. Shortest region of deletion overlap (SRO) mapping previously identified a critical region (the DGCR) of 500 kb, which was presumed to contain a gene or genes of major effect in the haploinsufficiency syndromes. The DGCR also contains sequences disrupted by a balanced translocation that is associated with DGS--the ADU breakpoint. We have cloned sequences at the breakpoint and screened for novel genes in its vicinity. A series of alternatively spliced transcripts expressed during human and murine embryogenesis, but with no obvious protein encoding potential, were identified. The gene encoding these RNAs has been named DGCR5 and it is disrupted by the patient ADU breakpoint. DGCR5 is distinct from the DGCR3 open reading frame (ORF) previously shown to be interrupted by the ADU translocation, although DGCR3 is embedded within a DGCR5 intron and in the same (predicted) transcriptional orientation. No mutations of DGCR5 have yet been detected. By analogy to other loci encoding conserved, nontranslated RNAs, it is possible that DGCR5 originates from a cis-acting transcriptional control element in the vicinity of the ADU/VDU breakpoint. Disruption of such an element would result in altered transcription of neighboring genes secondary to a position effect, a hypothesis in keeping with recent refinement of the SRO placing the ADU breakpoint outside the DGCR.

Published
1996

40. CATCH-22 - CAN MOLECULAR GENETICS EXPLAIN THE PHENOTYPE

Author

Halford, S, Wadey, R, Roberts, C, Daw, S, Whiting, J, Odonnell, H, Dunham, I, Bentley, D, Lindsay, E, Baldini, A, Francis, F, Lehrach, H, Williamson, R, Wilson, D, Goodship, J, Cross, I, Burn, J, and Scambler, P

Published
1995

41. 132 Non-synonymous SMAD6 mutations impaired inhibition of bmp signalling in patients with congenital cardiovascular malformation

Author

Tan, H. L., primary, Glen, E. A., additional, Topf, A. L., additional, Hall, D. H., additional, O'Sullivan, J. J., additional, Sneddon, L., additional, Wren, C., additional, Avery, P., additional, Lewis, R. J., additional, ten Dijke, P., additional, Arthur, H. M., additional, Goodship, J. A., additional, and Keavney, B. D., additional

Published
2011
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44. Ebstein’s anomaly may be caused by mutations in the sarcomere protein gene MYH7

Author

van Engelen, K., primary, Postma, A. V., additional, van de Meerakker, J. B. A., additional, Roos-Hesselink, J. W., additional, Helderman-van den Enden, A. T. J. M., additional, Vliegen, H. W., additional, Rahman, T., additional, Baars, M. J. H., additional, Sels, J-W, additional, Bauer, U., additional, Pickardt, T., additional, Sperling, S. R., additional, Moorman, A. F. M., additional, Keavney, B., additional, Goodship, J., additional, Klaassen, S., additional, and Mulder, B. J. M., additional

Published
2011
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46. Systematic survey of variants in TBX1 in non-syndromic tetralogy of Fallot identifies a novel 57 base pair deletion that reduces transcriptional activity but finds no evidence for association with common variants

Author

Griffin, H. R., primary, Topf, A., additional, Glen, E., additional, Zweier, C., additional, Stuart, A. G., additional, Parsons, J., additional, Peart, I., additional, Deanfield, J., additional, O'Sullivan, J., additional, Rauch, A., additional, Scambler, P., additional, Burn, J., additional, Cordell, H. J., additional, Keavney, B., additional, and Goodship, J. A., additional

Published
2010
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48. Molecular genetic study of the frequency of monosomy 22q11 in DiGeorge syndrome

Author

Burn J, Ah, Carey, Dumanski J, Goodship J, Halford S, Kelly D, Paul T, Andrew Sharkey, Wadey R, and Wilson D

Subjects
Genomic Library, Monosomy, Chromosomes, Human, Pair 22, DiGeorge Syndrome, Humans, Original Articles, Chromosome Deletion, DNA Probes, In Situ Hybridization, Fluorescence
Abstract

It is well established that DiGeorge syndrome (DGS) may be associated with monosomy of 22q11-pter. More recently, DNA probes have been used to detect hemizygosity for this region in patients with no visible karyotypic abnormality. However, DGS has also been described in cases where the cytogenetic abnormality does not involve 22q11; for instance, four cases of 10p- have been reported. In this study we have prospectively analyzed patients, by using DNA markers from 22q11, to assess the frequency of 22q11 rearrangements in DGS. Twenty-one of 22 cases had demonstrable hemizygosity for 22q11. Cytogenetic analysis had identified interstitial deletion in 6 of 16 cases tested; in 6 other cases no karyotype was available. When these results are combined with those from our previous studies, 33 of 35 DGS patients had chromosome 22q11 deletions detectable by DNA probes.

Published
1992

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