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51. Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia

Author

Gorman, Kathleen M., primary, Meyer, Esther, additional, Grozeva, Detelina, additional, Spinelli, Egidio, additional, McTague, Amy, additional, Sanchis-Juan, Alba, additional, Carss, Keren J., additional, Bryant, Emily, additional, Reich, Adi, additional, Schneider, Amy L., additional, Pressler, Ronit M., additional, Simpson, Michael A., additional, Debelle, Geoff D., additional, Wassmer, Evangeline, additional, Morton, Jenny, additional, Sieciechowicz, Diana, additional, Jan-Kamsteeg, Eric, additional, Paciorkowski, Alex R., additional, King, Mary D., additional, Cross, J. Helen, additional, Poduri, Annapurna, additional, Mefford, Heather C., additional, Scheffer, Ingrid E., additional, Haack, Tobias B., additional, McCullagh, Gary, additional, Millichap, John J., additional, Carvill, Gemma L., additional, Clayton-Smith, Jill, additional, Maher, Eamonn R., additional, Raymond, F. Lucy, additional, Kurian, Manju A., additional, McRae, Jeremy F., additional, Clayton, Stephen, additional, Fitzgerald, Tomas W., additional, Kaplanis, Joanna, additional, Prigmore, Elena, additional, Rajan, Diana, additional, Sifrim, Alejandro, additional, Aitken, Stuart, additional, Akawi, Nadia, additional, Alvi, Mohsan, additional, Ambridge, Kirsty, additional, Barrett, Daniel M., additional, Bayzetinova, Tanya, additional, Jones, Philip, additional, Jones, Wendy D., additional, King, Daniel, additional, Krishnappa, Netravathi, additional, Mason, Laura E., additional, Singh, Tarjinder, additional, Tivey, Adrian R., additional, Ahmed, Munaza, additional, Anjum, Uruj, additional, Archer, Hayley, additional, Armstrong, Ruth, additional, Awada, Jana, additional, Balasubramanian, Meena, additional, Banka, Siddharth, additional, Baralle, Diana, additional, Barnicoat, Angela, additional, Batstone, Paul, additional, Baty, David, additional, Bennett, Chris, additional, Berg, Jonathan, additional, Bernhard, Birgitta, additional, Bevan, A. Paul, additional, Bitner-Glindzicz, Maria, additional, Blair, Edward, additional, Blyth, Moira, additional, Bohanna, David, additional, Bourdon, Louise, additional, Bourn, David, additional, Bradley, Lisa, additional, Brady, Angela, additional, Brent, Simon, additional, Brewer, Carole, additional, Brunstrom, Kate, additional, Bunyan, David J., additional, Burn, John, additional, Canham, Natalie, additional, Castle, Bruce, additional, Chandler, Kate, additional, Chatzimichali, Elena, additional, Cilliers, Deirdre, additional, Clarke, Angus, additional, Clasper, Susan, additional, Clowes, Virginia, additional, Coates, Andrea, additional, Cole, Trevor, additional, Colgiu, Irina, additional, Collins, Amanda, additional, Collinson, Morag N., additional, Connell, Fiona, additional, Cooper, Nicola, additional, Cox, Helen, additional, Cresswell, Lara, additional, Cross, Gareth, additional, Crow, Yanick, additional, D’Alessandro, Mariella, additional, Dabir, Tabib, additional, Davidson, Rosemarie, additional, Davies, Sally, additional, de Vries, Dylan, additional, Dean, John, additional, Deshpande, Charu, additional, Devlin, Gemma, additional, Dixit, Abhijit, additional, Dobbie, Angus, additional, Donaldson, Alan, additional, Donnai, Dian, additional, Donnelly, Deirdre, additional, Donnelly, Carina, additional, Douglas, Angela, additional, Douzgou, Sofia, additional, Duncan, Alexis, additional, Eason, Jacqueline, additional, Ellard, Sian, additional, Ellis, Ian, additional, Elmslie, Frances, additional, Evans, Karenza, additional, Everest, Sarah, additional, Fendick, Tina, additional, Fisher, Richard, additional, Flinter, Frances, additional, Foulds, Nicola, additional, Fry, Andrew, additional, Fryer, Alan, additional, Gardiner, Carol, additional, Gaunt, Lorraine, additional, Ghali, Neeti, additional, Gibbons, Richard, additional, Gill, Harinder, additional, Goodship, Judith, additional, Goudie, David, additional, Gray, Emma, additional, Green, Andrew, additional, Greene, Philip, additional, Greenhalgh, Lynn, additional, Gribble, Susan, additional, Harrison, Rachel, additional, Harrison, Lucy, additional, Harrison, Victoria, additional, Hawkins, Rose, additional, He, Liu, additional, Hellens, Stephen, additional, Henderson, Alex, additional, Hewitt, Sarah, additional, Hildyard, Lucy, additional, Hobson, Emma, additional, Holden, Simon, additional, Holder, Muriel, additional, Holder, Susan, additional, Hollingsworth, Georgina, additional, Homfray, Tessa, additional, Humphreys, Mervyn, additional, Hurst, Jane, additional, Hutton, Ben, additional, Ingram, Stuart, additional, Irving, Melita, additional, Islam, Lily, additional, Jackson, Andrew, additional, Jarvis, Joanna, additional, Jenkins, Lucy, additional, Johnson, Diana, additional, Jones, Elizabeth, additional, Josifova, Dragana, additional, Joss, Shelagh, additional, Kaemba, Beckie, additional, Kazembe, Sandra, additional, Kelsell, Rosemary, additional, Kerr, Bronwyn, additional, Kingston, Helen, additional, Kini, Usha, additional, Kinning, Esther, additional, Kirby, Gail, additional, Kirk, Claire, additional, Kivuva, Emma, additional, Kraus, Alison, additional, Kumar, Dhavendra, additional, Kumar, V. K. Ajith, additional, Lachlan, Katherine, additional, Lam, Wayne, additional, Lampe, Anne, additional, Langman, Caroline, additional, Lees, Melissa, additional, Lim, Derek, additional, Longman, Cheryl, additional, Lowther, Gordon, additional, Lynch, Sally A., additional, Magee, Alex, additional, Maher, Eddy, additional, Male, Alison, additional, Mansour, Sahar, additional, Marks, Karen, additional, Martin, Katherine, additional, Maye, Una, additional, McCann, Emma, additional, McConnell, Vivienne, additional, McEntagart, Meriel, additional, McGowan, Ruth, additional, McKay, Kirsten, additional, McKee, Shane, additional, McMullan, Dominic J., additional, McNerlan, Susan, additional, McWilliam, Catherine, additional, Mehta, Sarju, additional, Metcalfe, Kay, additional, Middleton, Anna, additional, Miedzybrodzka, Zosia, additional, Miles, Emma, additional, Mohammed, Shehla, additional, Montgomery, Tara, additional, Moore, David, additional, Morgan, Sian, additional, Mugalaasi, Hood, additional, Murday, Victoria, additional, Murphy, Helen, additional, Naik, Swati, additional, Nemeth, Andrea, additional, Nevitt, Louise, additional, Newbury-Ecob, Ruth, additional, Norman, Andrew, additional, O’Shea, Rosie, additional, Ogilvie, Caroline, additional, Ong, Kai-Ren, additional, Park, Soo-Mi, additional, Parker, Michael J., additional, Patel, Chirag, additional, Paterson, Joan, additional, Payne, Stewart, additional, Perrett, Daniel, additional, Phipps, Julie, additional, Pilz, Daniela T., additional, Pollard, Martin, additional, Pottinger, Caroline, additional, Poulton, Joanna, additional, Pratt, Norman, additional, Prescott, Katrina, additional, Price, Sue, additional, Pridham, Abigail, additional, Procter, Annie, additional, Purnell, Hellen, additional, Quarrell, Oliver, additional, Ragge, Nicola, additional, Rahbari, Raheleh, additional, Randall, Josh, additional, Rankin, Julia, additional, Raymond, Lucy, additional, Rice, Debbie, additional, Robert, Leema, additional, Roberts, Eileen, additional, Roberts, Jonathan, additional, Roberts, Paul, additional, Roberts, Gillian, additional, Ross, Alison, additional, Rosser, Elisabeth, additional, Saggar, Anand, additional, Samant, Shalaka, additional, Sampson, Julian, additional, Sandford, Richard, additional, Sarkar, Ajoy, additional, Schweiger, Susann, additional, Scott, Richard, additional, Scurr, Ingrid, additional, Selby, Ann, additional, Seller, Anneke, additional, Sequeira, Cheryl, additional, Shannon, Nora, additional, Sharif, Saba, additional, Shaw-Smith, Charles, additional, Shearing, Emma, additional, Shears, Debbie, additional, Sheridan, Eamonn, additional, Simonic, Ingrid, additional, Singzon, Roldan, additional, Skitt, Zara, additional, Smith, Audrey, additional, Smith, Kath, additional, Smithson, Sarah, additional, Sneddon, Linda, additional, Splitt, Miranda, additional, Squires, Miranda, additional, Stewart, Fiona, additional, Stewart, Helen, additional, Straub, Volker, additional, Suri, Mohnish, additional, Sutton, Vivienne, additional, Swaminathan, Ganesh Jawahar, additional, Sweeney, Elizabeth, additional, Tatton-Brown, Kate, additional, Taylor, Cat, additional, Taylor, Rohan, additional, Tein, Mark, additional, Temple, I. Karen, additional, Thomson, Jenny, additional, Tischkowitz, Marc, additional, Tomkins, Susan, additional, Torokwa, Audrey, additional, Treacy, Becky, additional, Turner, Claire, additional, Turnpenny, Peter, additional, Tysoe, Carolyn, additional, Vandersteen, Anthony, additional, Varghese, Vinod, additional, Vasudevan, Pradeep, additional, Vijayarangakannan, Parthiban, additional, Vogt, Julie, additional, Wakeling, Emma, additional, Wallwark, Sarah, additional, Waters, Jonathon, additional, Weber, Astrid, additional, Wellesley, Diana, additional, Whiteford, Margo, additional, Widaa, Sara, additional, Wilcox, Sarah, additional, Wilkinson, Emily, additional, Williams, Denise, additional, Williams, Nicola, additional, Wilson, Louise, additional, Woods, Geoff, additional, Wragg, Christopher, additional, Wright, Michael, additional, Yates, Laura, additional, Yau, Michael, additional, Nellåker, Chris, additional, Parker, Michael, additional, Firth, Helen V., additional, Wright, Caroline F., additional, FitzPatrick, David R., additional, Barrett, Jeffrey C., additional, Hurles, Matthew E., additional, Al Turki, Saeed, additional, Anderson, Carl, additional, Anney, Richard, additional, Antony, Dinu, additional, Artigas, Maria Soler, additional, Ayub, Muhammad, additional, Balasubramaniam, Senduran, additional, Barroso, Inês, additional, Beales, Phil, additional, Bentham, Jamie, additional, Bhattacharya, Shoumo, additional, Birney, Ewan, additional, Blackwood, Douglas, additional, Bobrow, Martin, additional, Bochukova, Elena, additional, Bolton, Patrick, additional, Bounds, Rebecca, additional, Boustred, Chris, additional, Breen, Gerome, additional, Calissano, Mattia, additional, Carss, Keren, additional, Chatterjee, Krishna, additional, Chen, Lu, additional, Ciampi, Antonio, additional, Cirak, Sebhattin, additional, Clapham, Peter, additional, Clement, Gail, additional, Coates, Guy, additional, Collier, David, additional, Cosgrove, Catherine, additional, Cox, Tony, additional, Craddock, Nick, additional, Crooks, Lucy, additional, Curran, Sarah, additional, Curtis, David, additional, Daly, Allan, additional, Day-Williams, Aaron, additional, Day, Ian N.M., additional, Down, Thomas, additional, Du, Yuanping, additional, Dunham, Ian, additional, Edkins, Sarah, additional, Ellis, Peter, additional, Evans, David, additional, Faroogi, Sadaf, additional, Fatemifar, Ghazaleh, additional, Fitzpatrick, David R., additional, Flicek, Paul, additional, Flyod, James, additional, Foley, A. Reghan, additional, Franklin, Christopher S., additional, Futema, Marta, additional, Gallagher, Louise, additional, Geihs, Matthias, additional, Geschwind, Daniel, additional, Griffin, Heather, additional, Guo, Xueqin, additional, Guo, Xiaosen, additional, Gurling, Hugh, additional, Hart, Deborah, additional, Hendricks, Audrey, additional, Holmans, Peter, additional, Howie, Bryan, additional, Huang, Liren, additional, Hubbard, Tim, additional, Humphries, Steve E., additional, Hysi, Pirro, additional, Jackson, David K., additional, Jamshidi, Yalda, additional, Jing, Tian, additional, Joyce, Chris, additional, Kaye, Jane, additional, Keane, Thomas, additional, Keogh, Julia, additional, Kemp, John, additional, Kennedy, Karen, additional, Kolb-Kokocinski, Anja, additional, Lachance, Genevieve, additional, Langford, Cordelia, additional, Lawson, Daniel, additional, Lee, Irene, additional, Lek, Monkol, additional, Liang, Jieqin, additional, Lin, Hong, additional, Li, Rui, additional, Li, Yingrui, additional, Liu, Ryan, additional, Lönnqvist, Jouko, additional, Lopes, Margarida, additional, Iotchkova, Valentina, additional, MacArthur, Daniel, additional, Marchini, Jonathan, additional, Maslen, John, additional, Massimo, Mangino, additional, Mathieson, Iain, additional, Marenne, Gaëlle, additional, McGuffin, Peter, additional, McIntosh, Andrew, additional, McKechanie, Andrew G., additional, McQuillin, Andrew, additional, Metrustry, Sarah, additional, Mitchison, Hannah, additional, Moayyeri, Alireza, additional, Morris, James, additional, Muntoni, Francesco, additional, Northstone, Kate, additional, O'Donnovan, Michael, additional, Onoufriadis, Alexandros, additional, O'Rahilly, Stephen, additional, Oualkacha, Karim, additional, Owen, Michael J., additional, Palotie, Aarno, additional, Panoutsopoulou, Kalliope, additional, Parker, Victoria, additional, Parr, Jeremy R., additional, Paternoster, Lavinia, additional, Paunio, Tiina, additional, Payne, Felicity, additional, Pietilainen, Olli, additional, Plagnol, Vincent, additional, Quaye, Lydia, additional, Quail, Michael A., additional, Rehnström, Karola, additional, Ring, Susan, additional, Ritchie, Graham R.S., additional, Roberts, Nicola, additional, Savage, David B., additional, Scambler, Peter, additional, Schiffels, Stephen, additional, Schmidts, Miriam, additional, Schoenmakers, Nadia, additional, Semple, Robert K., additional, Serra, Eva, additional, Sharp, Sally I., additional, Shin, So-Youn, additional, Skuse, David, additional, Small, Kerrin, additional, Southam, Lorraine, additional, Spasic-Boskovic, Olivera, additional, St Clair, David, additional, Stalker, Jim, additional, Stevens, Elizabeth, additional, St Pourcian, Beate, additional, Sun, Jianping, additional, Suvisaari, Jaana, additional, Tachmazidou, Ionna, additional, Tobin, Martin D., additional, Valdes, Ana, additional, Van Kogelenberg, Margriet, additional, Visscher, Peter M., additional, Wain, Louise V., additional, Walters, James T.R., additional, Wang, Guangbiao, additional, Wang, Jun, additional, Wang, Yu, additional, Ward, Kirsten, additional, Wheeler, Elanor, additional, Whyte, Tamieka, additional, Williams, Hywel, additional, Williamson, Kathleen A., additional, Wilson, Crispian, additional, Wong, Kim, additional, Xu, ChangJiang, additional, Yang, Jian, additional, Zhang, Fend, additional, Zhang, Pingbo, additional, Aitman, Timothy, additional, Alachkar, Hana, additional, Ali, Sonia, additional, Allen, Louise, additional, Allsup, David, additional, Ambegaonkar, Gautum, additional, Anderson, Julie, additional, Antrobus, Richard, additional, Arno, Gavin, additional, Arumugakani, Gururaj, additional, Ashford, Sofie, additional, Astle, William, additional, Attwood, Antony, additional, Austin, Steve, additional, Bacchelli, Chiara, additional, Bakchoul, Tamam, additional, Bariana, Tadbir K., additional, Baxendale, Helen, additional, Bennett, David, additional, Bethune, Claire, additional, Bibi, Shahnaz, additional, Bleda, Marta, additional, Boggard, Harm, additional, Bolton-Maggs, Paula, additional, Booth, Claire, additional, Bradley, John R., additional, Brady, Angie, additional, Brown, Matthew, additional, Browning, Michael, additional, Bryson, Christine, additional, Burns, Siobhan, additional, Calleja, Paul, additional, Carmichael, Jenny, additional, Caulfield, Mark, additional, Chalmers, Elizabeth, additional, Chandra, Anita, additional, Chinnery, Patrick, additional, Chitre, Manali, additional, Church, Colin, additional, Clement, Emma, additional, Clements-Brod, Naomi, additional, Coghlan, Gerry, additional, Collins, Peter, additional, Cooper, Nichola, additional, Creaser-Myers, Amanda, additional, DaCosta, Rosa, additional, Daugherty, Louise, additional, Davies, Sophie, additional, Davis, John, additional, De Vries, Minka, additional, Deegan, Patrick, additional, Deevi, Sri V.V., additional, Devlin, Lisa, additional, Dewhurst, Eleanor, additional, Doffinger, Rainer, additional, Dormand, Natalie, additional, Drewe, Elizabeth, additional, Edgar, David, additional, Egner, William, additional, Erber, Wendy N., additional, Erwood, Marie, additional, Everington, Tamara, additional, Favier, Remi, additional, Firth, Helen, additional, Fletcher, Debra, additional, Fox, James C., additional, Frary, Amy, additional, Freson, Kathleen, additional, Furie, Bruce, additional, Furnell, Abigail, additional, Gale, Daniel, additional, Gardham, Alice, additional, Gattens, Michael, additional, Ghataorhe, Pavandeep K., additional, Ghurye, Rohit, additional, Gibbs, Simon, additional, Gilmour, Kimberley, additional, Gissen, Paul, additional, Goddard, Sarah, additional, Gomez, Keith, additional, Gordins, Pavel, additional, Gräf, Stefan, additional, Greene, Daniel, additional, Greenhalgh, Alan, additional, Greinacher, Andreas, additional, Grigoriadou, Sofia, additional, Hackett, Scott, additional, Hadinnapola, Charaka, additional, Hague, Rosie, additional, Haimel, Matthias, additional, Halmagyi, Csaba, additional, Hammerton, Tracey, additional, Hart, Daniel, additional, Hayman, Grant, additional, Heemskerk, Johan W.M., additional, Henderson, Robert, additional, Hensiek, Anke, additional, Henskens, Yvonne, additional, Herwadkar, Archana, additional, Hu, Fengyuan, additional, Huissoon, Aarnoud, additional, Humbert, Marc, additional, James, Roger, additional, Jolles, Stephen, additional, Kazmi, Rashid, additional, Keeling, David, additional, Kelleher, Peter, additional, Kelly, Anne M., additional, Kennedy, Fiona, additional, Kiely, David, additional, Kingston, Nathalie, additional, Koziell, Ania, additional, Krishnakumar, Deepa, additional, Kuijpers, Taco W., additional, Kumararatne, Dinakantha, additional, Kurian, Manju, additional, Laffan, Michael A., additional, Lambert, Michele P., additional, Allen, Hana Lango, additional, Lawrie, Allan, additional, Lear, Sara, additional, Lentaigne, Claire, additional, Liesner, Ri, additional, Linger, Rachel, additional, Longhurst, Hilary, additional, Lorenzo, Lorena, additional, Machado, Rajiv, additional, Mackenzie, Rob, additional, MacLaren, Robert, additional, Maher, Eamonn, additional, Maimaris, Jesmeen, additional, Mangles, Sarah, additional, Manson, Ania, additional, Mapeta, Rutendo, additional, Markus, Hugh S., additional, Martin, Jennifer, additional, Masati, Larahmie, additional, Mathias, Mary, additional, Matser, Vera, additional, Maw, Anna, additional, McDermott, Elizabeth, additional, McJannet, Coleen, additional, Meacham, Stuart, additional, Meehan, Sharon, additional, Megy, Karyn, additional, Michaelides, Michel, additional, Millar, Carolyn M., additional, Moledina, Shahin, additional, Moore, Anthony, additional, Morrell, Nicholas, additional, Mumford, Andrew, additional, Murng, Sai, additional, Murphy, Elaine, additional, Nejentsev, Sergey, additional, Noorani, Sadia, additional, Nurden, Paquita, additional, Oksenhendler, Eric, additional, Ouwehand, Willem H., additional, Papadia, Sofia, additional, Parker, Alasdair, additional, Pasi, John, additional, Patch, Chris, additional, Payne, Jeanette, additional, Peacock, Andrew, additional, Peerlinck, Kathelijne, additional, Penkett, Christopher J., additional, Pepke-Zaba, Joanna, additional, Perry, David J., additional, Pollock, Val, additional, Polwarth, Gary, additional, Ponsford, Mark, additional, Qasim, Waseem, additional, Quinti, Isabella, additional, Rankin, Stuart, additional, Rehnstrom, Karola, additional, Reid, Evan, additional, Rhodes, Christopher J., additional, Richards, Michael, additional, Richardson, Sylvia, additional, Richter, Alex, additional, Roberts, Irene, additional, Rondina, Matthew, additional, Roughley, Catherine, additional, Rue-Albrecht, Kevin, additional, Samarghitean, Crina, additional, Santra, Saikat, additional, Sargur, Ravishankar, additional, Savic, Sinisa, additional, Schulman, Sol, additional, Schulze, Harald, additional, Scully, Marie, additional, Seneviratne, Suranjith, additional, Sewell, Carrock, additional, Shamardina, Olga, additional, Shipley, Debbie, additional, Simeoni, Ilenia, additional, Sivapalaratnam, Suthesh, additional, Smith, Kenneth, additional, Sohal, Aman, additional, Southgate, Laura, additional, Staines, Simon, additional, Staples, Emily, additional, Stauss, Hans, additional, Stein, Penelope, additional, Stephens, Jonathan, additional, Stirrups, Kathleen, additional, Stock, Sophie, additional, Suntharalingam, Jay, additional, Tait, R. Campbell, additional, Talks, Kate, additional, Tan, Yvonne, additional, Thachil, Jecko, additional, Thaventhiran, James, additional, Thomas, Ellen, additional, Thomas, Moira, additional, Thompson, Dorothy, additional, Thrasher, Adrian, additional, Titterton, Catherine, additional, Toh, Cheng-Hock, additional, Toshner, Mark, additional, Treacy, Carmen, additional, Trembath, Richard, additional, Tuna, Salih, additional, Turek, Wojciech, additional, Turro, Ernest, additional, Van Geet, Chris, additional, Veltman, Marijke, additional, von Ziegenweldt, Julie, additional, Vonk Noordegraaf, Anton, additional, Wanjiku, Ivy, additional, Warner, Timothy Q., additional, Watkins, Hugh, additional, Webster, Andrew, additional, Welch, Steve, additional, Westbury, Sarah, additional, Wharton, John, additional, Whitehorn, Deborah, additional, Wilkins, Martin, additional, Willcocks, Lisa, additional, Williamson, Catherine, additional, Woods, Geoffrey, additional, Wort, John, additional, Yeatman, Nigel, additional, Yong, Patrick, additional, Young, Tim, additional, and Yu, Ping, additional

Published
2019
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52. Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus

Author

Ponting Chris P, MacArthur Katie, Campbell Jennifer, Liu Yu-Ning, Tompson Stuart, Blair Helen J, Ruiz-Perez Victor L, and Goodship Judith A

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Background Evc is essential for Indian Hedgehog (Hh) signalling in the cartilage growth plate. The gene encoding Evc2 is in close proximity in divergent orientation to Evc and mutations in both human genes lead to the chondrodysplasia Ellis-van Creveld syndrome. Results Bioinformatic analysis reveals that the Evc and Evc2 genes arose through a duplication event early in metazoan evolution and were subsequently lost in arthropods and nematodes. Here we demonstrate that Evc2 is essential for Hh pathway activation in response to the Smo agonist purmorphamine. A yeast two-hybrid screen using Evc as bait identified Evc2 as an Evc binding partner and we confirmed the interaction by immunoprecipitation. We developed anti-Evc2 antibodies and show that Evc2 and Evc co-localize at the basal body and also on primary cilia. In transfected cells, basal body and cilia localization is observed when Evc and Evc2 constructs are co-transfected but not when either construct is transfected individually. We show that Evc and Evc2 are cilia transmembrane proteins, the C-terminus for both being intracellular and Evc2, but not Evc, having an extracellular portion. Furthermore, Evc is absent at the basal body in Evc2 null cells. Using Western blots of cytoplasmic and nuclear protein, we also demonstrate that full length Evc2 but not Evc, is located in the nucleus. Conclusions We demonstrate for the first time that Evc2 is a positive regulator of the Hh signalling pathway and that it is located at the basal body of primary cilia. We show that the presence of Evc and Evc2 at the basal body and cilia membrane is co-dependent. In addition, Evc2, but not Evc, is present in the cell nucleus suggesting movement of Evc2 between the cilium and nucleus.

Published
2011
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59. Mutational analysis of the PITX2 coding region revealed no common cause for transposition of the great arteries (dTGA)

Author

Goldmuntz Elizabeth, Rüdiger Heinz-Juergen, Schön Karin, Roeth Ralph, Niesler Beate, Muncke Nadja, Goodship Judith, and Rappold Gudrun

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background PITX2 is a bicoid-related homeodomain transcription factor that plays an important role in asymmetric cardiogenesis. Loss of function experiments in mice cause severe heart malformations, including transposition of the great arteries (TGA). TGA accounts for 5–7% of all congenital heart diseases affecting 0.2 per 1000 live births, thereby representing the most frequent cyanotic heart defect diagnosed in the neonatal period. Methods To address whether altered PITX2 function could also contribute to the formation of dTGA in humans, we screened 96 patients with dTGA by means of dHPLC and direct sequencing for mutations within the PITX2 gene. Results Several SNPs could be detected, but no stop or frame shift mutation. In particular, we found seven intronic and UTR variants, two silent mutations and two polymorphisms within the coding region. Conclusion As most sequence variants were also found in controls we conclude that mutations in PITX2 are not a common cause of dTGA.

Published
2005
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61. Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot

Author

Cordell, Heather J., Töpf, Ana, Mamasoula, Chrysovalanto, Postma, Alex V., Bentham, Jamie, Zelenika, Diana, Heath, Simon, Blue, Gillian, Cosgrove, Catherine, Granados Riveron, Javier, Darlay, Rebecca, Soemedi, Rachel, Wilson, Ian J., Ayers, Kristin L., Rahman, Thahira J., Hall, Darroch, Mulder, Barbara J.M., Zwinderman, Aelko H., van Engelen, Klaartje, Brook, J. David, Setchfield, Kerry, Bu'Lock, Frances A., Thornborough, Chris, O'Sullivan, John, Stuart, A. Graham, Parsons, Jonathan, Bhattacharya, Shoumo, Winlaw, David, Mital, Seema, Gewillig, Marc, Breckpot, Jeroen, Devriendt, Koen, Moorman, Antoon F.M., Rauch, Anita, Lathrop, G. Mark, Keavney, Bernard D., and Goodship, Judith A.

Abstract

We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10−7) and replicated convincingly (P = 3.9 × 10−5) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10−11 in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10−7) and replicated convincingly (P = 1.2 × 10−5) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10−11 in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF

Published
2017

63. Distinct genetic architectures for syndromic and nonsyndromic congenital heart defects identified by exome sequencing

Author

Sifrim, Alejandro, Hitz, Marc-Phillip, Wilsdon, Anna, Breckpot, Jeroen, Turki, Saeed H Al, Thienpont, Bernard, McRae, Jeremy, Fitzgerald, Tomas W, Singh, Tarjinder, Swaminathan, Ganesh Jawahar, Prigmore, Elena, Rajan, Diana, Abdul-Khaliq, Hashim, Banka, Siddharth, Bauer, Ulrike MM, Bentham, Jamie, Berger, Felix, Bhattacharya, Shoumo, Bu'Lock, Frances, Canham, Natalie, Colgiu, Irina-Gabriela, Cosgrove, Catherine, Cox, Helen, Daehnert, Ingo, Daly, Allan, Danesh, John, Fryer, Alan, Gewillig, Marc, Hobson, Emma, Hoff, Kirstin, Homfray, Tessa, INTERVAL Study, Kahlert, Anne-Karin, Ketley, Ami, Kramer, Hans-Heiner, Lachlan, Katherine, Lampe, Anne Katrin, Louw, Jacoba J, Manickara, Ashok Kumar, Manase, Dorin, McCarthy, Karen P, Metcalfe, Kay, Moore, Carmel, Newbury-Ecob, Ruth, Omer, Seham Osman, Ouwehand, Willem H, Park, Soo-Mi, Parker, Michael J, Pickardt, Thomas, Pollard, Martin O, Robert, Leema, Roberts, David J, Sambrook, Jennifer, Setchfield, Kerry, Stiller, Brigitte, Thornborough, Chris, Toka, Okan, Watkins, Hugh, Williams, Denise, Wright, Michael, Mital, Seema, Daubeney, Piers EF, Keavney, Bernard, Goodship, Judith, UK10K Consortium, Abu-Sulaiman, Riyadh Mahdi, Klaassen, Sabine, Wright, Caroline F, Firth, Helen V, Barrett, Jeffrey C, Devriendt, Koenraad, FitzPatrick, David R, Brook, J David, Deciphering Developmental Disorders Study, Hurles, Matthew E, Sifrim, Alejandro [0000-0001-8247-4020], Thienpont, Bernard [0000-0002-8772-6845], Banka, Siddharth [0000-0002-8527-2210], Pollard, Martin O [0000-0001-8738-0920], Mital, Seema [0000-0002-7643-4484], Keavney, Bernard [0000-0001-9573-0812], Barrett, Jeffrey C [0000-0002-1152-370X], and Apollo - University of Cambridge Repository

Subjects
Heart Defects, Congenital, Male, Protein Conformation, Syndrome, Autoantigens, CDC2 Protein Kinase, Mutation, Humans, Exome, Female, cardiovascular diseases, Protein Kinase C, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Sequence Deletion
Abstract

Congenital heart defects (CHDs) have a neonatal incidence of 0.8-1% (refs. 1,2). Despite abundant examples of monogenic CHD in humans and mice, CHD has a low absolute sibling recurrence risk (∼2.7%), suggesting a considerable role for de novo mutations (DNMs) and/or incomplete penetrance. De novo protein-truncating variants (PTVs) have been shown to be enriched among the 10% of 'syndromic' patients with extra-cardiac manifestations. We exome sequenced 1,891 probands, including both syndromic CHD (S-CHD, n = 610) and nonsyndromic CHD (NS-CHD, n = 1,281). In S-CHD, we confirmed a significant enrichment of de novo PTVs but not inherited PTVs in known CHD-associated genes, consistent with recent findings. Conversely, in NS-CHD we observed significant enrichment of PTVs inherited from unaffected parents in CHD-associated genes. We identified three genome-wide significant S-CHD disorders caused by DNMs in CHD4, CDK13 and PRKD1. Our study finds evidence for distinct genetic architectures underlying the low sibling recurrence risk in S-CHD and NS-CHD.

Published
2016

65. Histone Lysine Methylases and Demethylases in the Landscape of Human Developmental Disorders

Author

Faundes, Víctor, primary, Newman, William G., additional, Bernardini, Laura, additional, Canham, Natalie, additional, Clayton-Smith, Jill, additional, Dallapiccola, Bruno, additional, Davies, Sally J., additional, Demos, Michelle K., additional, Goldman, Amy, additional, Gill, Harinder, additional, Horton, Rachel, additional, Kerr, Bronwyn, additional, Kumar, Dhavendra, additional, Lehman, Anna, additional, McKee, Shane, additional, Morton, Jenny, additional, Parker, Michael J., additional, Rankin, Julia, additional, Robertson, Lisa, additional, Temple, I. Karen, additional, Banka, Siddharth, additional, Adam, Shelin, additional, du Souich, Christèle, additional, Elliott, Alison M., additional, Mwenifumbo, Jill, additional, Nelson, Tanya N., additional, van Karnebeek, Clara, additional, Friedman, Jan M., additional, McRae, Jeremy F., additional, Clayton, Stephen, additional, Fitzgerald, Tomas W., additional, Kaplanis, Joanna, additional, Prigmore, Elena, additional, Rajan, Diana, additional, Sifrim, Alejandro, additional, Aitken, Stuart, additional, Akawi, Nadia, additional, Alvi, Mohsan, additional, Ambridge, Kirsty, additional, Barrett, Daniel M., additional, Bayzetinova, Tanya, additional, Jones, Philip, additional, Jones, Wendy D., additional, King, Daniel, additional, Krishnappa, Netravathi, additional, Mason, Laura E., additional, Singh, Tarjinder, additional, Tivey, Adrian R., additional, Ahmed, Munaza, additional, Anjum, Uruj, additional, Archer, Hayley, additional, Armstrong, Ruth, additional, Awada, Jana, additional, Balasubramanian, Meena, additional, Baralle, Diana, additional, Barnicoat, Angela, additional, Batstone, Paul, additional, Baty, David, additional, Bennett, Chris, additional, Berg, Jonathan, additional, Bernhard, Birgitta, additional, Bevan, A. Paul, additional, Bitner-Glindzicz, Maria, additional, Blair, Edward, additional, Blyth, Moira, additional, Bohanna, David, additional, Bourdon, Louise, additional, Bourn, David, additional, Bradley, Lisa, additional, Brady, Angela, additional, Brent, Simon, additional, Brewer, Carole, additional, Brunstrom, Kate, additional, Bunyan, David J., additional, Burn, John, additional, Castle, Bruce, additional, Chandler, Kate, additional, Chatzimichali, Elena, additional, Cilliers, Deirdre, additional, Clarke, Angus, additional, Clasper, Susan, additional, Clowes, Virginia, additional, Coates, Andrea, additional, Cole, Trevor, additional, Colgiu, Irina, additional, Collins, Amanda, additional, Collinson, Morag N., additional, Connell, Fiona, additional, Cooper, Nicola, additional, Cox, Helen, additional, Cresswell, Lara, additional, Cross, Gareth, additional, Crow, Yanick, additional, D’Alessandro, Mariella, additional, Dabir, Tabib, additional, Davidson, Rosemarie, additional, Davies, Sally, additional, de Vries, Dylan, additional, Dean, John, additional, Deshpande, Charu, additional, Devlin, Gemma, additional, Dixit, Abhijit, additional, Dobbie, Angus, additional, Donaldson, Alan, additional, Donnai, Dian, additional, Donnelly, Deirdre, additional, Donnelly, Carina, additional, Douglas, Angela, additional, Douzgou, Sofia, additional, Duncan, Alexis, additional, Eason, Jacqueline, additional, Ellard, Sian, additional, Ellis, Ian, additional, Elmslie, Frances, additional, Evans, Karenza, additional, Everest, Sarah, additional, Fendick, Tina, additional, Fisher, Richard, additional, Flinter, Frances, additional, Foulds, Nicola, additional, Fry, Andrew, additional, Fryer, Alan, additional, Gardiner, Carol, additional, Gaunt, Lorraine, additional, Ghali, Neeti, additional, Gibbons, Richard, additional, Goodship, Judith, additional, Goudie, David, additional, Gray, Emma, additional, Green, Andrew, additional, Greene, Philip, additional, Greenhalgh, Lynn, additional, Gribble, Susan, additional, Harrison, Rachel, additional, Harrison, Lucy, additional, Harrison, Victoria, additional, Hawkins, Rose, additional, He, Liu, additional, Hellens, Stephen, additional, Henderson, Alex, additional, Hewitt, Sarah, additional, Hildyard, Lucy, additional, Hobson, Emma, additional, Holden, Simon, additional, Holder, Muriel, additional, Holder, Susan, additional, Hollingsworth, Georgina, additional, Homfray, Tessa, additional, Humphreys, Mervyn, additional, Hurst, Jane, additional, Hutton, Ben, additional, Ingram, Stuart, additional, Irving, Melita, additional, Islam, Lily, additional, Jackson, Andrew, additional, Jarvis, Joanna, additional, Jenkins, Lucy, additional, Johnson, Diana, additional, Jones, Elizabeth, additional, Josifova, Dragana, additional, Joss, Shelagh, additional, Kaemba, Beckie, additional, Kazembe, Sandra, additional, Kelsell, Rosemary, additional, Kingston, Helen, additional, Kini, Usha, additional, Kinning, Esther, additional, Kirby, Gail, additional, Kirk, Claire, additional, Kivuva, Emma, additional, Kraus, Alison, additional, Kumar, V.K. Ajith, additional, Lachlan, Katherine, additional, Lam, Wayne, additional, Lampe, Anne, additional, Langman, Caroline, additional, Lees, Melissa, additional, Lim, Derek, additional, Longman, Cheryl, additional, Lowther, Gordon, additional, Lynch, Sally A., additional, Magee, Alex, additional, Maher, Eddy, additional, Male, Alison, additional, Mansour, Sahar, additional, Marks, Karen, additional, Martin, Katherine, additional, Maye, Una, additional, McCann, Emma, additional, McConnell, Vivienne, additional, McEntagart, Meriel, additional, McGowan, Ruth, additional, McKay, Kirsten, additional, McMullan, Dominic J., additional, McNerlan, Susan, additional, McWilliam, Catherine, additional, Mehta, Sarju, additional, Metcalfe, Kay, additional, Middleton, Anna, additional, Miedzybrodzka, Zosia, additional, Miles, Emma, additional, Mohammed, Shehla, additional, Montgomery, Tara, additional, Moore, David, additional, Morgan, Sian, additional, Mugalaasi, Hood, additional, Murday, Victoria, additional, Murphy, Helen, additional, Naik, Swati, additional, Nemeth, Andrea, additional, Nevitt, Louise, additional, Newbury-Ecob, Ruth, additional, Norman, Andrew, additional, O’Shea, Rosie, additional, Ogilvie, Caroline, additional, Ong, Kai-Ren, additional, Park, Soo-Mi, additional, Patel, Chirag, additional, Paterson, Joan, additional, Payne, Stewart, additional, Perrett, Daniel, additional, Phipps, Julie, additional, Pilz, Daniela T., additional, Pollard, Martin, additional, Pottinger, Caroline, additional, Poulton, Joanna, additional, Pratt, Norman, additional, Prescott, Katrina, additional, Price, Sue, additional, Pridham, Abigail, additional, Procter, Annie, additional, Purnell, Hellen, additional, Quarrell, Oliver, additional, Ragge, Nicola, additional, Rahbari, Raheleh, additional, Randall, Josh, additional, Raymond, Lucy, additional, Rice, Debbie, additional, Robert, Leema, additional, Roberts, Eileen, additional, Roberts, Jonathan, additional, Roberts, Paul, additional, Roberts, Gillian, additional, Ross, Alison, additional, Rosser, Elisabeth, additional, Saggar, Anand, additional, Samant, Shalaka, additional, Sampson, Julian, additional, Sandford, Richard, additional, Sarkar, Ajoy, additional, Schweiger, Susann, additional, Scott, Richard, additional, Scurr, Ingrid, additional, Selby, Ann, additional, Seller, Anneke, additional, Sequeira, Cheryl, additional, Shannon, Nora, additional, Sharif, Saba, additional, Shaw-Smith, Charles, additional, Shearing, Emma, additional, Shears, Debbie, additional, Sheridan, Eamonn, additional, Simonic, Ingrid, additional, Singzon, Roldan, additional, Skitt, Zara, additional, Smith, Audrey, additional, Smith, Kath, additional, Smithson, Sarah, additional, Sneddon, Linda, additional, Splitt, Miranda, additional, Squires, Miranda, additional, Stewart, Fiona, additional, Stewart, Helen, additional, Straub, Volker, additional, Suri, Mohnish, additional, Sutton, Vivienne, additional, Swaminathan, Ganesh Jawahar, additional, Sweeney, Elizabeth, additional, Tatton-Brown, Kate, additional, Taylor, Cat, additional, Taylor, Rohan, additional, Tein, Mark, additional, Thomson, Jenny, additional, Tischkowitz, Marc, additional, Tomkins, Susan, additional, Torokwa, Audrey, additional, Treacy, Becky, additional, Turner, Claire, additional, Turnpenny, Peter, additional, Tysoe, Carolyn, additional, Vandersteen, Anthony, additional, Varghese, Vinod, additional, Vasudevan, Pradeep, additional, Vijayarangakannan, Parthiban, additional, Vogt, Julie, additional, Wakeling, Emma, additional, Wallwark, Sarah, additional, Waters, Jonathon, additional, Weber, Astrid, additional, Wellesley, Diana, additional, Whiteford, Margo, additional, Widaa, Sara, additional, Wilcox, Sarah, additional, Wilkinson, Emily, additional, Williams, Denise, additional, Williams, Nicola, additional, Wilson, Louise, additional, Woods, Geoff, additional, Wragg, Christopher, additional, Wright, Michael, additional, Yates, Laura, additional, Yau, Michael, additional, Nellåker, Chris, additional, Parker, Michael, additional, Firth, Helen V., additional, Wright, Caroline F., additional, FitzPatrick, David R., additional, Barrett, Jeffrey C., additional, and . Hurles, Matthew E., additional

Published
2018
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66. Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve

Author

Yang, Bo, primary, Zhou, Wei, additional, Jiao, Jiao, additional, Nielsen, Jonas B., additional, Mathis, Michael R., additional, Heydarpour, Mahyar, additional, Lettre, Guillaume, additional, Folkersen, Lasse, additional, Prakash, Siddharth, additional, Schurmann, Claudia, additional, Fritsche, Lars, additional, Farnum, Gregory A., additional, Lin, Maoxuan, additional, Othman, Mohammad, additional, Hornsby, Whitney, additional, Driscoll, Anisa, additional, Levasseur, Alexandra, additional, Thomas, Marc, additional, Farhat, Linda, additional, Dubé, Marie-Pierre, additional, Isselbacher, Eric M., additional, Franco-Cereceda, Anders, additional, Guo, Dong-chuan, additional, Bottinger, Erwin P., additional, Deeb, G. Michael, additional, Booher, Anna, additional, Kheterpal, Sachin, additional, Chen, Y. Eugene, additional, Kang, Hyun Min, additional, Kitzman, Jacob, additional, Cordell, Heather J., additional, Keavney, Bernard D., additional, Goodship, Judith A., additional, Ganesh, Santhi K., additional, Abecasis, Gonçalo, additional, Eagle, Kim A., additional, Boyle, Alan P., additional, Loos, Ruth J. F., additional, Eriksson, Per, additional, Tardif, Jean-Claude, additional, Brummett, Chad M., additional, Milewicz, Dianna M., additional, Body, Simon C., additional, and Willer, Cristen J., additional

Published
2017
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68. Discovery of four recessive developmental disorders using probabilistic genotype and phenotype matching among 4,125 families

Author

Akawi, Nadia, McRae, Jeremy, Ansari, Morad, Balasubramanian, Meena, Blyth, Moira, Brady, Angela F, Clayton, Stephen, Cole, Trevor, Deshpande, Charu, Fitzgerald, Tomas W, Foulds, Nicola, Francis, Richard, Gabriel, George, Gerety, Sebastian S, Goodship, Judith, Hobson, Emma, Jones, Wendy D, Joss, Shelagh, King, Daniel, Klena, Nikolai, Kumar, Ajith, Lees, Melissa, Lelliott, Chris, Lord, Jenny, McMullan, Dominic, O'Regan, Mary, Osio, Deborah, Piombo, Virginia, Prigmore, Elena, Rajan, Diana, Rosser, Elisabeth, Sifrim, Alejandro, Smith, Audrey, Swaminathan, Ganesh J, Turnpenny, Peter, Whitworth, James, Wright, Caroline F, Firth, Helen V, Barrett, Jeffrey C, Lo, Cecilia W, FitzPatrick, David R, Hurles, Matthew E, DDD Study, Kumar, Ajith [0000-0003-3878-2856], Lelliott, Chris [0000-0001-8087-4530], Barrett, Jeffrey C [0000-0002-1152-370X], and Apollo - University of Cambridge Repository

Subjects
Family Health, Male, Protein-Arginine N-Methyltransferases, Genotype, Developmental Disabilities, Ubiquitin-Protein Ligases, Genetic Variation, Cell Cycle Proteins, Genes, Recessive, Sequence Analysis, DNA, United Kingdom, Pedigree, Phenotype, Matrix Metalloproteinases, Secreted, Humans, Exome, Female, Genetic Predisposition to Disease, human activities, Genetic Association Studies
Abstract

Discovery of most autosomal recessive disease-associated genes has involved analysis of large, often consanguineous multiplex families or small cohorts of unrelated individuals with a well-defined clinical condition. Discovery of new dominant causes of rare, genetically heterogeneous developmental disorders has been revolutionized by exome analysis of large cohorts of phenotypically diverse parent-offspring trios1,2. Here we analyzed 4,125 families with diverse, rare and genetically heterogeneous developmental disorders and identified four new autosomal recessive disorders. These four disorders were identified by integrating Mendelian filtering (selecting probands with rare, biallelic and putatively damaging variants in the same gene) with statistical assessments of (i) the likelihood of sampling the observed genotypes from the general population and (ii) the phenotypic similarity of patients with recessive variants in the same candidate gene. This new paradigm promises to catalyze the discovery of novel recessive disorders, especially those with less consistent or nonspecific clinical presentations and those caused predominantly by compound heterozygous genotypes.

Published
2015

69. Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls

Author

Soemedi, Rachel, Topf, Ana, Wilson, Ian J., Darlay, Rebecca, Rahman, Thahira, Glen, Elise, Hall, Darroch, Huang, Ni, Bentham, Jamie, Bhattacharya, Shoumo, Cosgrove, Catherine, Brook, J. David, Granados-Riveron, Javier, Setchfield, Kerry, Bu'Lock, Frances, Thornborough, Chris, Devriendt, Koenraad, Breckpot, Jeroen, Hofbeck, Michael, Lathrop, Mark, Rauch, Anita, Blue, Gillian M., Winlaw, David S., Hurles, Matthew, Santibanez-Koref, Mauro, Cordell, Heather J., Goodship, Judith A., Keavney, Bernard D., Soemedi, Rachel, Topf, Ana, Wilson, Ian J., Darlay, Rebecca, Rahman, Thahira, Glen, Elise, Hall, Darroch, Huang, Ni, Bentham, Jamie, Bhattacharya, Shoumo, Cosgrove, Catherine, Brook, J. David, Granados-Riveron, Javier, Setchfield, Kerry, Bu'Lock, Frances, Thornborough, Chris, Devriendt, Koenraad, Breckpot, Jeroen, Hofbeck, Michael, Lathrop, Mark, Rauch, Anita, Blue, Gillian M., Winlaw, David S., Hurles, Matthew, Santibanez-Koref, Mauro, Cordell, Heather J., Goodship, Judith A., and Keavney, Bernard D.

Abstract

Recurrent rearrangements of chromosome 1q21.1 that occur via non-allelic homologous recombination have been associated with variable phenotypes exhibiting incomplete penetrance, including congenital heart disease (CHD). However, the gene or genes within the ∼1 Mb critical region responsible for each of the associated phenotypes remains unknown. We examined the 1q21.1 locus in 948 patients with tetralogy of Fallot (TOF), 1488 patients with other forms of CHD and 6760 ethnically matched controls using single nucleotide polymorphism genotyping arrays (Illumina 660W and Affymetrix 6.0) and multiplex ligation-dependent probe amplification. We found that duplication of 1q21.1 was more common in cases of TOF than in controls [odds ratio (OR) 30.9, 95% confidence interval (CI) 8.9-107.6); P = 2.2 × 10−7], but deletion was not. In contrast, deletion of 1q21.1 was more common in cases of non-TOF CHD than in controls [OR 5.5 (95% CI 1.4-22.0); P = 0.04] while duplication was not. We also detected rare (n = 3) 100-200 kb duplications within the critical region of 1q21.1 in cases of TOF. These small duplications encompassed a single gene in common, GJA5, and were enriched in cases of TOF in comparison to controls [OR = 10.7 (95% CI 1.8-64.3), P = 0.01]. These findings show that duplication and deletion at chromosome 1q21.1 exhibit a degree of phenotypic specificity in CHD, and implicate GJA5 as the gene responsible for the CHD phenotypes observed with copy number imbalances at this locus

Published
2017

70. Protein-altering and regulatory genetic variants near GATA4 implicated in bicuspid aortic valve

Author

Yang, Bo, Zhou, Wei-Wu, Jiao, Jiao, Nielsen, Jonas B., Mathis, Michael R., Heydarpour, Mahyar, Lettre, Guillaume, Folkersen, Lasse Westergaard, Prakash, Siddharth, Schurmann, Claudia, Fritsche, Lars, Farnum, Gregory A., Lin, Maoxuan, Othman, Mohammad, Hornsby, Whitney, Driscoll, Anisa, Levasseur, Alexandra, Thomas, Marc, Farhat, Linda, Dube, Marie-Pierre, Isselbacher, Eric M., Franco-Cereceda, Anders, Guo, Dong-Chuan, Bottinger, Erwin P., Deeb, G. Michael, Booher, Anna, Kheterpal, Sachin, Chen, Y. Eugene, Kang, Hyun Min, Kitzman, Jacob, Cordell, Heather J., Keavney, Bernard D., Goodship, Judith A., Ganesh, Santhi K., Abecasis, Goncalo, Eagle, Kim A., Boyle, Alan P., Loos, Ruth J. F., Eriksson, Per, Tardif, Jean-Claude, Brummett, Chad M., Milewicz, Dianna M., Body, Simon C., Willer, Cristen J., Yang, Bo, Zhou, Wei-Wu, Jiao, Jiao, Nielsen, Jonas B., Mathis, Michael R., Heydarpour, Mahyar, Lettre, Guillaume, Folkersen, Lasse Westergaard, Prakash, Siddharth, Schurmann, Claudia, Fritsche, Lars, Farnum, Gregory A., Lin, Maoxuan, Othman, Mohammad, Hornsby, Whitney, Driscoll, Anisa, Levasseur, Alexandra, Thomas, Marc, Farhat, Linda, Dube, Marie-Pierre, Isselbacher, Eric M., Franco-Cereceda, Anders, Guo, Dong-Chuan, Bottinger, Erwin P., Deeb, G. Michael, Booher, Anna, Kheterpal, Sachin, Chen, Y. Eugene, Kang, Hyun Min, Kitzman, Jacob, Cordell, Heather J., Keavney, Bernard D., Goodship, Judith A., Ganesh, Santhi K., Abecasis, Goncalo, Eagle, Kim A., Boyle, Alan P., Loos, Ruth J. F., Eriksson, Per, Tardif, Jean-Claude, Brummett, Chad M., Milewicz, Dianna M., Body, Simon C., and Willer, Cristen J.

Abstract

Bicuspid aortic valve (BAV) is a heritable congenital heart defect and an important risk factor for valvulopathy and aortopathy. Here we report a genome-wide association scan of 466 BAV cases and 4,660 age, sex and ethnicity-matched controls with replication in up to 1,326 cases and 8,103 controls. We identify association with a noncoding variant 151 kb from the gene encoding the cardiac-specific transcription factor, GATA4, and near-significance for p.Ser377Gly in GATA4. GATA4 was interrupted by CRISPR-Cas9 in induced pluripotent stem cells from healthy donors. The disruption of GATA4 significantly impaired the transition from endothelial cells into mesenchymal cells, a critical step in heart valve development.

Published
2017

73. Primary, Nonsyndromic Vesicoureteric Reflux and Its Nephropathy Is Genetically Heterogeneous, with a Locus on Chromosome 1

Author

Feather, Sally A., Malcolm, Sue, Woolf, Adrian S., Wright, Victoria, Blaydon, Diana, Reid, Christopher J. D., Flinter, Frances A., Proesmans, Willem, Devriendt, Koen, Carter, Joan, Warwicker, Paul, Goodship, Timothy H. J., and Goodship, Judith A.

Subjects
Human genetics -- Research, Genetic research -- Analysis, Kidney diseases -- Genetic aspects, Genetic disorders -- Research, Ureters -- Diseases, Biological sciences
Published
2000

74. Prevalence, phenotype and architecture of developmental disorders caused by de novo mutation: The Deciphering Developmental Disorders Study

Author

McRae, Jeremy F, primary, Clayton, Stephen, additional, Fitzgerald, Tomas W, additional, Kaplanis, Joanna, additional, Prigmore, Elena, additional, Rajan, Diana, additional, Sifrim, AlejandroW, additional, Aitken, Stuart, additional, Akawi, Nadia, additional, Alvi, Mohsan, additional, Ambridge, Kirsty, additional, Barrett, Daniel M, additional, Bayzetinova, Tanya, additional, Jones, Philip, additional, Jones, Wendy D, additional, King, Daniel, additional, Krishnappa, Netravathi, additional, Mason, Laura E, additional, Singh, Tarjinder, additional, Tivey, Adrian R, additional, Ahmed, Munaza, additional, Anjum, Uruj, additional, Archer, Hayley, additional, Armstrong, Ruth, additional, Awada, Jana, additional, Balasubramanian, Meena, additional, Banka, Siddharth, additional, Baralle, Diana, additional, Barnicoat, Angela, additional, Batstone, Paul, additional, Baty, David, additional, Bennett, Chris, additional, Berg, Jonathan, additional, Bernhard, Birgitta, additional, Bevan, A Paul, additional, Bitner-Glindzicz, Maria, additional, Blair, Edward, additional, Blyth, Moira, additional, Bohanna, David, additional, Bourdon, Louise, additional, Bourn, David, additional, Bradley, Lisa, additional, Brady, Angela, additional, Brent, Simon, additional, Brewer, Carole, additional, Brunstrom, Kate, additional, Bunyan, David J, additional, Burn, John, additional, Canham, Natalie, additional, Castle, Bruce, additional, Chandler, Kate, additional, Chatzimichali, Elena, additional, Cilliers, Deirdre, additional, Clarke, Angus, additional, Clasper, Susan, additional, Clayton-Smith, Jill, additional, Clowes, Virginia, additional, Coates, Andrea, additional, Cole, Trevor, additional, Colgiu, Irina, additional, Collins, Amanda, additional, Collinson, Morag N, additional, Connell, Fiona, additional, Cooper, Nicola, additional, Cox, Helen, additional, Cresswell, Lara, additional, Cross, Gareth, additional, Crow, Yanick, additional, D'Alessandro, Mariella, additional, Dabir, Tabib, additional, Davidson, Rosemarie, additional, Davies, Sally, additional, de Vries, Dylan, additional, Dean, John, additional, Deshpande, Charu, additional, Devlin, Gemma, additional, Dixit, Abhijit, additional, Dobbie, Angus, additional, Donaldson, Alan, additional, Donnai, Dian, additional, Donnelly, Deirdre, additional, Donnelly, Carina, additional, Douglas, Angela, additional, Douzgou, Sofia, additional, Duncan, Alexis, additional, Eason, Jacqueline, additional, Ellard, Sian, additional, Ellis, Ian, additional, Elmslie, Frances, additional, Evans, Karenza, additional, Everest, Sarah, additional, Fendick, Tina, additional, Fisher, Richard, additional, Flinter, Frances, additional, Foulds, Nicola, additional, Fry, AndrewW, additional, Fryer, Alan, additional, Gardiner, Carol, additional, Gaunt, Lorraine, additional, Ghali, Neeti, additional, Gibbons, Richard, additional, Gill, Harinder, additional, Goodship, Judith, additional, Goudie, David, additional, Gray, Emma, additional, Green, Andrew, additional, Greene, Philip, additional, Greenhalgh, Lynn, additional, Gribble, Susan, additional, Harrison, Lucy, additional, Harrison, Victoria, additional, Hawkins, Rose, additional, He, Liu, additional, Hellens, Stephen, additional, Henderson, Alex, additional, Hewitt, Sarah, additional, Hildyard, Lucy, additional, Hobson, Emma, additional, Holden, Simon, additional, Holder, Muriel, additional, Holder, Susan, additional, Hollingsworth, Georgina, additional, Homfray, Tessa, additional, Humphreys, Mervyn, additional, Hurst, Jane, additional, Hutton, Ben, additional, Ingram, Stuart, additional, Irving, Melita, additional, Islam, Lily, additional, Jackson, Andrew, additional, Jarvis, Joanna, additional, Jenkins, Lucy, additional, Johnson, Diana, additional, Jones, Elizabeth, additional, Josifova, Dragana, additional, Joss, Shelagh, additional, Kaemba, Beckie, additional, Kazembe, Sandra, additional, Kelsell, Rosemary, additional, Kerr, Bronwyn, additional, Kingston, Helen, additional, Kini, Usha, additional, Kinning, Esther, additional, Kirby, Gail, additional, Kirk, Claire, additional, Kivuva, Emma, additional, Kraus, Alison, additional, Kumar, Dhavendra, additional, Kumar, V.K Ajith, additional, Lachlan, Katherine, additional, Lam, Wayne, additional, Lampe, Anne, additional, Langman, Caroline, additional, Lees, Melissa, additional, Lim, Derek, additional, Longman, Cheryl, additional, Lowther, Gordon, additional, Lynch, Sally A, additional, Magee, Alex, additional, Maher, Eddy, additional, Male, Alison, additional, Mansour, Sahar, additional, Marks, Karen, additional, Martin, Katherine, additional, Maye, Una, additional, McCann, Emma, additional, McConnell, Vivienne, additional, McEntagart, Meriel, additional, McGowan, Ruth, additional, McKay, Kirsten, additional, McKee, Shane, additional, McMullan, Dominic J, additional, McNerlan, Susan, additional, McWilliam, Catherine, additional, Mehta, Sarju, additional, Metcalfe, Kay, additional, Middleton, Anna, additional, Miedzybrodzka, Zosia, additional, Miles, Emma, additional, Mohammed, Shehla, additional, Montgomery, Tara, additional, Moore, David, additional, Morgan, Sian, additional, Morton, Jenny, additional, Mugalaasi, Hood, additional, Murday, Victoria, additional, Murphy, Helen, additional, Naik, Swati, additional, Nemeth, Andrea, additional, Nevitt, Louise, additional, Newbury-Ecob, Ruth, additional, Norman, Andrew, additional, O'Shea, Rosie, additional, Ogilvie, Caroline, additional, Ong, Kai-Ren, additional, Park, Soo-Mi, additional, Parker, Michael J, additional, Patel, Chirag, additional, Paterson, Joan, additional, Payne, Stewart, additional, Perrett, Daniel, additional, Phipps, Julie, additional, Pilz, Daniela T, additional, Pollard, Martin, additional, Pottinger, Caroline, additional, Poulton, Joanna, additional, Pratt, Norman, additional, Prescott, Katrina, additional, Price, Sue, additional, Pridham, Abigail, additional, Procter, Annie, additional, Purnell, Hellen, additional, Quarrell, Oliver, additional, Ragge, Nicola, additional, Rahbari, Raheleh, additional, Randall, Josh, additional, Rankin, Julia, additional, Raymond, Lucy, additional, Rice, Debbie, additional, Robert, Leema, additional, Roberts, Eileen, additional, Roberts, Jonathan, additional, Roberts, Paul, additional, Roberts, Gillian, additional, Ross, Alison, additional, Rosser, Elisabeth, additional, Saggar, Anand, additional, Samant, Shalaka, additional, Sampson, Julian, additional, Sandford, Richard, additional, Sarkar, Ajoy, additional, Schweiger, Susann, additional, Scott, Richard, additional, Scurr, Ingrid, additional, Selby, Ann, additional, Seller, Anneke, additional, Sequeira, Cheryl, additional, Shannon, Nora, additional, Sharif, Saba, additional, Shaw-Smith, Charles, additional, Shearing, Emma, additional, Shears, Debbie, additional, Sheridan, Eamonn, additional, Simonic, Ingrid, additional, Singzon, Roldan, additional, Skitt, Zara, additional, Smith, Audrey, additional, Smith, Kath, additional, Smithson, Sarah, additional, Sneddon, Linda, additional, Splitt, Miranda, additional, Squires, Miranda, additional, Stewart, Fiona, additional, Stewart, Helen, additional, Straub, Volker, additional, Suri, Mohnish, additional, Sutton, Vivienne, additional, Swaminathan, Ganesh Jawahar, additional, Sweeney, Elizabeth, additional, Tatton-Brown, Kate, additional, Taylor, Cat, additional, Taylor, Rohan, additional, Tein, Mark, additional, Temple, I Karen, additional, Thomson, Jenny, additional, Tischkowitz, Marc, additional, Tomkins, Susan, additional, Torokwa, Audrey, additional, Treacy, Becky, additional, Turner, Claire, additional, Turnpenny, Peter, additional, Tysoe, Carolyn, additional, Vandersteen, Anthony, additional, Varghese, Vinod, additional, Vasudevan, Pradeep, additional, Vijayarangakannan, Parthiban, additional, Vogt, Julie, additional, Wakeling, Emma, additional, Wallwark, Sarah, additional, Waters, Jonathon, additional, Weber, Astrid, additional, Wellesley, Diana, additional, Whiteford, Margo, additional, Widaa, Sara, additional, Wilcox, Sarah, additional, Wilkinson, Emily, additional, Williams, Denise, additional, Williams, Nicola, additional, Wilson, Louise, additional, Woods, Geoff, additional, Wragg, Christopher, additional, Wright, Michael, additional, Yates, Laura, additional, Yau, Michael, additional, Nellaker, Chris, additional, Firth, Helen V, additional, Wright, Caroline F, additional, FitzPatrick, David R, additional, Barrett, Jeffrey C, additional, and Hurles, Matthew E, additional

Published
2016
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75. A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20

Author

Hanchard, Neil A., primary, Swaminathan, Shanker, additional, Bucasas, Kristine, additional, Furthner, Dieter, additional, Fernbach, Susan, additional, Azamian, Mahshid S., additional, Wang, Xueqing, additional, Lewin, Mark, additional, Towbin, Jeffrey A., additional, D'Alessandro, Lisa C.A., additional, Morris, Shaine A., additional, Dreyer, William, additional, Denfield, Susan, additional, Ayres, Nancy A., additional, Franklin, Wayne J., additional, Justino, Henri, additional, Lantin-Hermoso, M. Regina, additional, Ocampo, Elena C., additional, Santos, Alexia B., additional, Parekh, Dhaval, additional, Moodie, Douglas, additional, Jeewa, Aamir, additional, Lawrence, Emily, additional, Allen, Hugh D., additional, Penny, Daniel J., additional, Fraser, Charles D., additional, Lupski, James R., additional, Popoola, Mojisola, additional, Wadhwa, Lalita, additional, Brook, J. David, additional, Bu'Lock, Frances A., additional, Bhattacharya, Shoumo, additional, Lalani, Seema R., additional, Zender, Gloria A., additional, Fitzgerald-Butt, Sara M., additional, Bowman, Jessica, additional, Corsmeier, Don, additional, White, Peter, additional, Lecerf, Kelsey, additional, Zapata, Gladys, additional, Hernandez, Patricia, additional, Goodship, Judith A., additional, Garg, Vidu, additional, Keavney, Bernard D., additional, Leal, Suzanne M., additional, Cordell, Heather J., additional, Belmont, John W., additional, and McBride, Kim L., additional

Published
2016
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76. A nonsense mutation in the IKBKG gene in mares with incontinentia pigmenti

Author

Mantovani, Roberto, Towers, Rachel E., Murgiano, Leonardo, Millar, David S., Glen, Elise, Topf, Ana, Jagannathan, Vidhya, Drögemüller, Cord, Goodship, Judith A., Clarke, Angus J., and Leeb, Tosso

Subjects
Male, Candidate gene, Pathology, medicine.medical_specialty, media_common.quotation_subject, Science, Nonsense, Nonsense mutation, Molecular Sequence Data, Biology, Loss of heterozygosity, IKBKG, Homologous chromosome, medicine, Animals, Humans, Horses, Incontinentia Pigmenti, RNA, Messenger, X chromosome, media_common, Multidisciplinary, Genome, 630 Agriculture, Base Sequence, Incontinentia pigmenti, Exons, Sequence Analysis, DNA, medicine.disease, I-kappa B Kinase, Pedigree, Phenotype, Codon, Nonsense, 590 Animals (Zoology), Medicine, Female, Research Article
Abstract

Ectodermal dysplasias (EDs) are a large and heterogeneous group of hereditary disorders characterized by abnormalities in structures of ectodermal origin. Incontinentia pigmenti (IP) is an ED characterized by skin lesions evolving over time, as well as dental, nail, and ocular abnormalities. Due to X-linked dominant inheritance IP symptoms can only be seen in female individuals while affected males die during development in utero. We observed a family of horses, in which several mares developed signs of a skin disorder reminiscent of human IP. Cutaneous manifestations in affected horses included the development of pruritic, exudative lesions soon after birth. These developed into wart-like lesions and areas of alopecia with occasional wooly hair re-growth. Affected horses also had streaks of darker and lighter coat coloration from birth. The observation that only females were affected together with a high number of spontaneous abortions suggested an X-linked dominant mechanism of transmission. Using next generation sequencing we sequenced the whole genome of one affected mare. We analyzed the sequence data for non-synonymous variants in candidate genes and found a heterozygous nonsense variant in the X-chromosomal IKBKG gene (c.184C>T; p.Arg62*). Mutations in IKBKG were previously reported to cause IP in humans and the homologous p.Arg62* variant has already been observed in a human IP patient. The comparative data thus strongly suggest that this is also the causative variant for the observed IP in horses. To our knowledge this is the first large animal model for IP.

Published
2013
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78. Genome-wide association study identifies loci on 12q24 and 13q32 associated with tetralogy of Fallot

Author

Cordell, Heather J, Töpf, Ana, Mamasoula, Chrysovalanto, Postma, Alex V, Bentham, Jamie, Zelenika, Diana, Heath, Simon, Blue, Gillian, Cosgrove, Catherine, Granados Riveron, Javier, Darlay, Rebecca, Soemedi, Rachel, Wilson, Ian J, Ayers, Kristin L, Rahman, Thahira J, Hall, Darroch, Mulder, Barbara J M, Zwinderman, Aelko H, van Engelen, Klaartje, Brook, J David, Setchfield, Kerry, Bu'Lock, Frances A, Thornborough, Chris, O'Sullivan, John, Stuart, A Graham, Parsons, Jonathan, Bhattacharya, Shoumo, Winlaw, David, Mital, Seema, Gewillig, Marc, Breckpot, Jeroen, Devriendt, Koen, Moorman, Antoon F M, Rauch, Anita, Lathrop, G Mark, Keavney, Bernard D, Goodship, Judith A, University of Zurich, and Keavney, Bernard D

Subjects
2716 Genetics (clinical), 1311 Genetics, 10039 Institute of Medical Genetics, 1312 Molecular Biology, 570 Life sciences, biology, 610 Medicine & health
Published
2013
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79. Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16.: Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16

Author

Cordell, Heather J, Bentham, Jamie, Topf, Ana, Zelenika, Diana, Heath, Simon, Mamasoula, Chrysovalanto, Cosgrove, Catherine, Blue, Gillian, Granados-Riveron, Javier, Setchfield, Kerry, Thornborough, Chris, Breckpot, Jeroen, Soemedi, Rachel, Martin, Ruairidh, Rahman, Thahira J, Hall, Darroch, van Engelen, Klaartje, Moorman, Antoon F, Zwinderman, Aelko H, Barnett, Phil, Koopmann, Tamara T, Adriaens, Michiel E, Varro, Andras, George, Alfred L, dos Remedios, Christobal, Bishopric, Nanette H, Bezzina, Connie R, O'Sullivan, John, Gewillig, Marc, Bu'Lock, Frances A, Winlaw, David, Bhattacharya, Shoumo, Devriendt, Koen, Brook, JD, Mulder, Barbara J, Mital, Seema, Postma, Alex V, Lathrop, GM, Farrall, Martin, Goodship, Judith A, Keavney, Bernard D, and RS: FSE MaCSBio

Subjects
cardiovascular diseases
Abstract

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10⁻⁷) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10⁻⁵; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19-1.65; combined P = 2.6 × 10⁻¹⁰). Genotype accounted for ~9% of the population-attributable risk of ASD.

Published
2013

81. 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

Ministero della Salute, Ministerio de Economía y Competitividad (España), Caparrós-Martín, José A., Aglan, Mona, Temtamy, Samia, Valencia, María, Vázquez, Laura, Nevado, Julian, Goodship, Judith A., Ruiz-Pérez, Victor L., Ministero della Salute, Ministerio de Economía y Competitividad (España), Caparrós-Martín, José A., Aglan, Mona, Temtamy, Samia, Valencia, María, Vázquez, Laura, Nevado, Julian, Goodship, Judith A., and Ruiz-Pérez, Victor L.

Abstract

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

82. Association analysis identifies new risk loci for congenital heart disease in Chinese populations

Author

Lin, Yuan, primary, Guo, Xuejiang, additional, Zhao, Bijun, additional, Liu, Juanjuan, additional, Da, Min, additional, Wen, Yang, additional, Hu, Yuanli, additional, Ni, Bixian, additional, Zhang, Kai, additional, Yang, Shiwei, additional, Xu, Jing, additional, Dai, Juncheng, additional, Wang, Xiaowei, additional, Xia, Yankai, additional, Ma, Hongxia, additional, Jin, Guangfu, additional, Yu, Shiqiang, additional, Liu, Jiayin, additional, Keavney, Bernard D., additional, Goodship, Judith A., additional, Cordell, Heather J., additional, Wang, Xinru, additional, Shen, Hongbing, additional, Sha, Jiahao, additional, Zhou, Zuomin, additional, Chen, Yijiang, additional, Mo, Xuming, additional, Luo, Lingfei, additional, and Hu, Zhibin, additional

Published
2015
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84. Urinary Tract Effects of HPSE2 Mutations

Author

Stuart, Helen M., primary, Roberts, Neil A., additional, Hilton, Emma N., additional, McKenzie, Edward A., additional, Daly, Sarah B., additional, Hadfield, Kristen D., additional, Rahal, Jeffery S., additional, Gardiner, Natalie J., additional, Tanley, Simon W., additional, Lewis, Malcolm A., additional, Sites, Emily, additional, Angle, Brad, additional, Alves, Cláudia, additional, Lourenço, Teresa, additional, Rodrigues, Márcia, additional, Calado, Angelina, additional, Amado, Marta, additional, Guerreiro, Nancy, additional, Serras, Inês, additional, Beetz, Christian, additional, Varga, Rita-Eva, additional, Silay, Mesrur Selcuk, additional, Darlow, John M., additional, Dobson, Mark G., additional, Barton, David E., additional, Hunziker, Manuela, additional, Puri, Prem, additional, Feather, Sally A., additional, Goodship, Judith A., additional, Goodship, Timothy H.J., additional, Lambert, Heather J., additional, Cordell, Heather J., additional, Saggar, Anand, additional, Kinali, Maria, additional, Lorenz, Christian, additional, Moeller, Kristina, additional, Schaefer, Franz, additional, Bayazit, Aysun K., additional, Weber, Stefanie, additional, Newman, William G., additional, and Woolf, Adrian S., additional

Published
2015
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85. 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, Helen R., Töpf, Ana, Glen, Elise, Zweier, Christiane, Stuart, A. Graham, Parsons, Jonathan, Peart, Ian, Deanfield, John, O'Sullivan, John, Rauch, Anita, Scambler, Peter, Burn, John, Cordell, Heather J., Keavney, Bernard, Goodship, Judith A., and University of Zurich

Subjects
stomatognathic system, Medizinische Fakultät, 10039 Institute of Medical Genetics, 570 Life sciences, biology, 610 Medicine & health, ddc:610, 2705 Cardiology and Cardiovascular Medicine
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
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86. Positional mapping ofPRKD1,NRP1andPRDM1as novel candidate disease genes in truncus arteriosus

Author

Shaheen, Ranad, primary, Al Hashem, Amal, additional, Alghamdi, Mohammed H, additional, Seidahmad, Mohammed Zain, additional, Wakil, Salma M, additional, Dagriri, Khalid, additional, Keavney, Bernard, additional, Goodship, Judith, additional, Alyousif, Saad, additional, Al-Habshan, Fahad M, additional, Alhussein, Khalid, additional, Almoisheer, Agaadir, additional, Ibrahim, Niema, additional, and Alkuraya, Fowzan S, additional

Published
2015
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87. Functionally significant, rare transcription factor variants in tetralogy of Fallot

Author

Töpf, Ana, Griffin, Helen R, Glen, Elise, Soemedi, Rachel, Brown, Danielle L, Hall, Darroch, Rahman, Thahira J, Eloranta, Jyrki J, Jüngst, Christoph, Stuart, A Graham, O'Sullivan, John, Keavney, Bernard D, Goodship, Judith A, Töpf, Ana, Griffin, Helen R, Glen, Elise, Soemedi, Rachel, Brown, Danielle L, Hall, Darroch, Rahman, Thahira J, Eloranta, Jyrki J, Jüngst, Christoph, Stuart, A Graham, O'Sullivan, John, Keavney, Bernard D, and Goodship, Judith A

Abstract

OBJECTIVE: Rare variants in certain transcription factors involved in cardiac development cause Mendelian forms of congenital heart disease. The purpose of this study was to systematically assess the frequency of rare transcription factor variants in sporadic patients with the cardiac outflow tract malformation tetralogy of Fallot (TOF). METHODS AND RESULTS: We sequenced the coding, 5'UTR, and 3'UTR regions of twelve transcription factor genes implicated in cardiac outflow tract development (NKX2.5, GATA4, ISL1, TBX20, MEF2C, BOP/SMYD1, HAND2, FOXC1, FOXC2, FOXH, FOXA2 and TBX1) in 93 non-syndromic, non-Mendelian TOF cases. We also analysed Illumina Human 660W-Quad SNP Array data for copy number variants in these genes; none were detected. Four of the rare variants detected have previously been shown to affect transactivation in in vitro reporter assays: FOXC1 p.P297S, FOXC2 p.Q444R, FOXH1 p.S113T and TBX1 p.P43_G61del PPPPRYDPCAAAAPGAPGP. Two further rare variants, HAND2 p.A25_A26insAA and FOXC1 p.G378_G380delGGG, A488_491delAAAA, affected transactivation in in vitro reporter assays. Each of these six functionally significant variants was present in a single patient in the heterozygous state; each of the four for which parental samples were available were maternally inherited. Thus in the 93 TOF cases we identified six functionally significant mutations in the secondary heart field transcriptional network. SIGNIFICANCE: This study indicates that rare genetic variants in the secondary heart field transcriptional network with functional effects on protein function occur in 3-13% of patients with TOF. This is the first report of a functionally significant HAND2 mutation in a patient with congenital heart disease.

Published
2014

89. Functionally Significant, Rare Transcription Factor Variants in Tetralogy of Fallot

Author

Töpf, Ana, primary, Griffin, Helen R., additional, Glen, Elise, additional, Soemedi, Rachel, additional, Brown, Danielle L., additional, Hall, Darroch, additional, Rahman, Thahira J., additional, Eloranta, Jyrki J., additional, Jüngst, Christoph, additional, Stuart, A. Graham, additional, O'Sullivan, John, additional, Keavney, Bernard D., additional, and Goodship, Judith A., additional

Published
2014
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90. Chromosomal Imbalances in Patients with Congenital Cardiac Defects: A Meta-analysis Reveals Novel Potential Critical Regions Involved in Heart Development

Author

Thorsson, Thor, primary, Russell, William W., additional, El-Kashlan, Nour, additional, Soemedi, Rachel, additional, Levine, Jonathan, additional, Geisler, Sarah B., additional, Ackley, Todd, additional, Tomita-Mitchell, Aoy, additional, Rosenfeld, Jill A., additional, Töpf, Ana, additional, Tayeh, Marwan, additional, Goodship, Judith, additional, Innis, Jeffrey W., additional, Keavney, Bernard, additional, and Russell, Mark W., additional

Published
2014
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92. Inversin/Nephrocystin-2 is required for fibroblast polarity and directional cell migration

Author

Veland, Iben Rønn, Montjean, Rodrick, Eley, Lorraine, Pedersen, Lotte Bang, Schwab, Albrecht, Goodship, Judith, Kristiansen, Karsten, Pedersen, Stine Helene Falsig, Saunier, Sophie, Christensen, Søren Tvorup, Veland, Iben Rønn, Montjean, Rodrick, Eley, Lorraine, Pedersen, Lotte Bang, Schwab, Albrecht, Goodship, Judith, Kristiansen, Karsten, Pedersen, Stine Helene Falsig, Saunier, Sophie, and Christensen, Søren Tvorup

Published
2013

93. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

Author

UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Banka, Siddharth, Veeramachaneni, Ratna, Reardon, William, Howard, Emma, Bunstone, Sancha, Ragge, Nicola, Parker, Michael J, Crow, Yanick J, Kerr, Bronwyn, Kingston, Helen, Metcalfe, Kay, Chandler, Kate, Magee, Alex, Stewart, Fiona, McConnell, Vivienne P M, Donnelly, Deirdre E, Berland, Siren, Houge, Gunnar, Morton, Jenny E, Oley, Christine, Revencu, Nicole, Park, Soo-Mi, Davies, Sally J, Fry, Andrew E, Lynch, Sally Ann, Gill, Harinder, Schweiger, Susann, Lam, Wayne W K, Tolmie, John, Mohammed, Shehla N, Hobson, Emma, Smith, Audrey, Blyth, Moira, Bennett, Christopher, Vasudevan, Pradeep C, García-Miñaúr, Sixto, Henderson, Alex, Goodship, Judith, Wright, Michael J, Fisher, Richard, Gibbons, Richard, Price, Susan M, C de Silva, Deepthi, Temple, I Karen, Collins, Amanda L, Lachlan, Katherine, Elmslie, Frances, McEntagart, Meriel, Castle, Bruce, Clayton-Smith, Jill, Black, Graeme C, Donnai, Dian, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, UCL - (SLuc) Centre de génétique médicale UCL, Banka, Siddharth, Veeramachaneni, Ratna, Reardon, William, Howard, Emma, Bunstone, Sancha, Ragge, Nicola, Parker, Michael J, Crow, Yanick J, Kerr, Bronwyn, Kingston, Helen, Metcalfe, Kay, Chandler, Kate, Magee, Alex, Stewart, Fiona, McConnell, Vivienne P M, Donnelly, Deirdre E, Berland, Siren, Houge, Gunnar, Morton, Jenny E, Oley, Christine, Revencu, Nicole, Park, Soo-Mi, Davies, Sally J, Fry, Andrew E, Lynch, Sally Ann, Gill, Harinder, Schweiger, Susann, Lam, Wayne W K, Tolmie, John, Mohammed, Shehla N, Hobson, Emma, Smith, Audrey, Blyth, Moira, Bennett, Christopher, Vasudevan, Pradeep C, García-Miñaúr, Sixto, Henderson, Alex, Goodship, Judith, Wright, Michael J, Fisher, Richard, Gibbons, Richard, Price, Susan M, C de Silva, Deepthi, Temple, I Karen, Collins, Amanda L, Lachlan, Katherine, Elmslie, Frances, McEntagart, Meriel, Castle, Bruce, Clayton-Smith, Jill, Black, Graeme C, and Donnai, Dian

Abstract

MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients.

Published
2012

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

Author

Hoischen, Alexander, van Bon, Bregje W M, Rodríguez-Santiago, Benjamín, Gilissen, Christian, Vissers, Lisenka E L M, de Vries, Petra, Janssen, Irene, van Lier, Bart, Hastings, Rob, Smithson, Sarah F, Newbury-Ecob, Ruth, Kjærgaard, Susanne, Goodship, Judith, McGowan, Ruth, Bartholdi, Deborah, Rauch, Anita, Peippo, Maarit, Cobben, Jan M, Wieczorek, Dagmar, Gillessen-Kaesbach, Gabriele, Veltman, Joris A, Brunner, Han G, de Vries, Bert B B A, Hoischen, Alexander, van Bon, Bregje W M, Rodríguez-Santiago, Benjamín, Gilissen, Christian, Vissers, Lisenka E L M, de Vries, Petra, Janssen, Irene, van Lier, Bart, Hastings, Rob, Smithson, Sarah F, Newbury-Ecob, Ruth, Kjærgaard, Susanne, Goodship, Judith, McGowan, Ruth, Bartholdi, Deborah, Rauch, Anita, Peippo, Maarit, Cobben, Jan M, Wieczorek, Dagmar, Gillessen-Kaesbach, Gabriele, Veltman, Joris A, Brunner, Han G, and de Vries, Bert B B A

Abstract

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

96. Bohring-Opitz (Oberklaid-Danks) syndrome: clinical study, review of the literature, and discussion of possible pathogenesis

Author

Hastings, Rob, Cobben, Jan-Maarten, Gillessen-Kaesbach, Gabriele, Goodship, Judith, Hove, Hanne Buciek, Kjærgaard, Susanne, Kemp, Helena, Kingston, Helen, Lunt, Peter, Mansour, Sahar, McGowan, Ruth, Metcalfe, Kay, Murdoch-Davis, Catherine, Ray, Mary, Rio, Marlène, Smithson, Sarah, Tolmie, John, Turnpenny, Peter, van Bon, Bregje, Wieczorek, Dagmar, Newbury-Ecob, Ruth, Hastings, Rob, Cobben, Jan-Maarten, Gillessen-Kaesbach, Gabriele, Goodship, Judith, Hove, Hanne Buciek, Kjærgaard, Susanne, Kemp, Helena, Kingston, Helen, Lunt, Peter, Mansour, Sahar, McGowan, Ruth, Metcalfe, Kay, Murdoch-Davis, Catherine, Ray, Mary, Rio, Marlène, Smithson, Sarah, Tolmie, John, Turnpenny, Peter, van Bon, Bregje, Wieczorek, Dagmar, and Newbury-Ecob, Ruth

Abstract

Bohring-Opitz syndrome (BOS) is a rare congenital disorder of unknown etiology diagnosed on the basis of distinctive clinical features. We suggest diagnostic criteria for this condition, describe ten previously unreported patients, and update the natural history of four previously reported patients. This is the largest series reported to date, providing a unique opportunity to document the key clinical features and course through childhood. Investigations undertaken to try and elucidate the underlying pathogenesis of BOS using array comparative genomic hybridization and tandem mass spectrometry of cholesterol precursors did not show any pathogenic changes responsible.

Published
2011

97. Evc2 is a positive modulator of Hedgehog signalling that interacts with Evc at the cilia membrane and is also found in the nucleus

Author

Ruiz-Pérez, Victor L., Goodship, Judith A., Ruiz-Pérez, Victor L., and Goodship, Judith A.

Abstract

[Background]: Evc is essential for Indian Hedgehog (Hh) signalling in the cartilage growth plate. The gene encoding Evc2 is in close proximity in divergent orientation to Evc and mutations in both human genes lead to the chondrodysplasia Ellis-van Creveld syndrome. [Results]: Bioinformatic analysis reveals that the Evc and Evc2 genes arose through a duplication event early in metazoan evolution and were subsequently lost in arthropods and nematodes. Here we demonstrate that Evc2 is essential for Hh pathway activation in response to the Smo agonist purmorphamine. A yeast two-hybrid screen using Evc as bait identified Evc2 as an Evc binding partner and we confirmed the interaction by immunoprecipitation. We developed anti-Evc2 antibodies and show that Evc2 and Evc co-localize at the basal body and also on primary cilia. In transfected cells, basal body and cilia localization is observed when Evc and Evc2 constructs are co-transfected but not when either construct is transfected individually. We show that Evc and Evc2 are cilia transmembrane proteins, the C-terminus for both being intracellular and Evc2, but not Evc, having an extracellular portion. Furthermore, Evc is absent at the basal body in Evc2 null cells. Using Western blots of cytoplasmic and nuclear protein, we also demonstrate that full length Evc2 but not Evc, is located in the nucleus. [Conclusions]: We demonstrate for the first time that Evc2 is a positive regulator of the Hh signalling pathway and that it is located at the basal body of primary cilia. We show that the presence of Evc and Evc2 at the basal body and cilia membrane is co-dependent. In addition, Evc2, but not Evc, is present in the cell nucleus suggesting movement of Evc2 between the cilium and nucleus.

Published
2011

98. Ellis-van Creveld syndrome and Weyers acrodental dysostosis are caused by cilia-mediated diminished response to Hedgehog ligands

Author

Ruiz-Pérez, Victor L., Goodship, Judith A., Ruiz-Pérez, Victor L., and Goodship, Judith A.

Abstract

Ellis-van Creveld syndrome (EvC; OMIM 225500) is a recessive disorder comprising chondrodysplasia, polydactyly, nail dysplasia, orofacial abnormalities and, in a proportion of patients, cardiovascular malformations. Weyers acrodental dysostosis (Weyers;OMIM 193530) is an allelic dominant disorder comprising polydactyly, nail dysplasia, and orofacial abnormalities. EvC results from loss-of-function mutations in EVC or EVC2, the phenotype associated with the mutations in these two genes being indistinguishable. Three convincing causative mutations have been identified in patients with Weyers acrodental dysostosis, which are clustered in the last coding exon of EVC2 and lead to production of a truncated protein lacking the final 43 amino acids. Localization and function of EVC and EVC2 are inferred from studying the murine orthologs. Both Evc and Evc2 proteins localize to the basal bodies of primary cilia and analysis of an Ellis-van Creveld mouse model, which includes the limb shortening and tooth abnormalities of EvC patients, has demonstrated Hedgehog signaling defects in the absence of Evc. The loss of Evc2 has not been studied directly, but Hedgehog signaling is impaired when a mutant murine Evc2 Weyer variant is expressed in vitro. We conclude that the phenotypic abnormalities in EvC and Weyers syndrome result from tissue specific disruption of the response to Hh ligands. © 2009 Wiley-Liss, Inc.

Published
2009

100. Association Between C677T Polymorphism of Methylene Tetrahydrofolate Reductase and Congenital Heart Disease

Author

Mamasoula, Chrysovalanto, primary, Prentice, R. Reid, additional, Pierscionek, Tomasz, additional, Pangilinan, Faith, additional, Mills, James L., additional, Druschel, Charlotte, additional, Pass, Kenneth, additional, Russell, Mark W., additional, Hall, Darroch, additional, Töpf, Ana, additional, Brown, Danielle L., additional, Zelenika, Diana, additional, Bentham, Jamie, additional, Cosgrove, Catherine, additional, Bhattacharya, Shoumo, additional, Riveron, Javier Granados, additional, Setchfield, Kerry, additional, Brook, J. David, additional, Bu’Lock, Frances A., additional, Thornborough, Chris, additional, Rahman, Thahira J., additional, Doza, Julian Palomino, additional, Tan, Huay L., additional, O’Sullivan, John, additional, Stuart, A. Graham, additional, Blue, Gillian, additional, Winlaw, David, additional, Postma, Alex V., additional, Mulder, Barbara J.M., additional, Zwinderman, Aelko H., additional, van Engelen, Klaartje, additional, Moorman, Antoon F.M., additional, Rauch, Anita, additional, Gewillig, Marc, additional, Breckpot, Jeroen, additional, Devriendt, Koen, additional, Lathrop, G. Mark, additional, Farrall, Martin, additional, Goodship, Judith A., additional, Cordell, Heather J., additional, Brody, Lawrence C., additional, and Keavney, Bernard D., additional

Published
2013
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