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2. Gain and loss of function variants in EZH1 disrupt neurogenesis and cause dominant and recessive neurodevelopmental disorders

Author

Gracia-Diaz, Carolina, Zhou, Yijing, Yang, Qian, Maroofian, Reza, Espana-Bonilla, Paula, Lee, Chul-Hwan, Zhang, Shuo, Padilla, Natàlia, Fueyo, Raquel, Waxman, Elisa A., Lei, Sunyimeng, Otrimski, Garrett, Li, Dong, Sheppard, Sarah E., Mark, Paul, Harr, Margaret H., Hakonarson, Hakon, Rodan, Lance, Jackson, Adam, Vasudevan, Pradeep, Powel, Corrina, Mohammed, Shehla, Maddirevula, Sateesh, Alzaidan, Hamad, Faqeih, Eissa A., Efthymiou, Stephanie, Turchetti, Valentina, Rahman, Fatima, Maqbool, Shazia, Salpietro, Vincenzo, Ibrahim, Shahnaz H., di Rosa, Gabriella, Houlden, Henry, Alharbi, Maha Nasser, Al-Sannaa, Nouriya Abbas, Bauer, Peter, Zifarelli, Giovanni, Estaras, Conchi, Hurst, Anna C. E., Thompson, Michelle L., Chassevent, Anna, Smith-Hicks, Constance L., de la Cruz, Xavier, Holtz, Alexander M., Elloumi, Houda Zghal, Hajianpour, M J, Rieubland, Claudine, Braun, Dominique, Banka, Siddharth, French, Deborah L., Heller, Elizabeth A., Saade, Murielle, Song, Hongjun, Ming, Guo-li, Alkuraya, Fowzan S., Agrawal, Pankaj B., Reinberg, Danny, Bhoj, Elizabeth J., Martínez-Balbás, Marian A., and Akizu, Naiara

Published
2023
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4. MARK2 variants cause autism spectrum disorder via the downregulation of WNT/β-catenin signaling pathway

Author

Gong, Maolei, primary, Li, Jiayi, additional, Liu, Yijun, additional, Matheus, Vernet Machado Bressan Wilk, additional, Li, Qian, additional, Liu, Haoran, additional, Liang, Chen, additional, Joel A, Morales-Rosado, additional, Cohen, Ana S.A., additional, Hughes, Susan S., additional, Sullivan, Bonnie R, additional, Waddell, Valerie, additional, Henriette van den Boogaard, Marie Jose, additional, van Jaarsveld, Richard H., additional, Binsbergen, Ellen van, additional, van Gassen, Koen L, additional, Wang, Tianyun, additional, Hiatt, Susan M., additional, Amaral, Michelle D., additional, Kelley, Whitley V., additional, Zhao, Jianbo, additional, Feng, Weixing, additional, Ren, Changhong, additional, Yu, Yazhen, additional, Boczek, Nicole J, additional, Ferber, Matthew J., additional, Lahner, Carrie, additional, Elliott, Sherr, additional, Ruan, Yiyan, additional, Mignot, Cyril, additional, Keren, Boris, additional, Xie, Hua, additional, Wang, Xiaoyan, additional, Popp, Bernt, additional, Zweier, Christiane, additional, Piard, Juliette, additional, Coubes, Christine, additional, Tran-Mau-Them, Frederic, additional, Safraou, Hana, additional, Innes, Micheil, additional, Gauthier, Julie, additional, Michaud, Jacques L, additional, Koboldt, Daniel C., additional, Sylvie, ODENT, additional, Willems, Marjolaine, additional, Tan, Wen-Hann, additional, Cogne, Benjamin, additional, Rieubland, Claudine, additional, Braun, Dominique, additional, McLean, Scott Douglas, additional, Platzer, Konrad, additional, Zacher, Pia, additional, Oppermann, Henry, additional, Evenepoel, Lucie, additional, BLANC, Pierre, additional, Khattabi, Laila El, additional, Haque, Neshatul, additional, Dsouza, Nikita R., additional, Zimmermann, Michael T, additional, Urrutia, Raul A, additional, Klee, Eric W, additional, Shen, Yiping, additional, Du, Hong-Zhen, additional, Qin, Zailong, additional, Liu, Chang-Mei, additional, and chen, xiaoli, additional

Published
2024
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5. De novo variants predicting haploinsufficiency for DIP2C are associated with expressive speech delay

Author

Ha, Thoa, primary, Morgan, Angela, additional, Bartos, Meghan N., additional, Beatty, Katelyn, additional, Cogné, Benjamin, additional, Braun, Dominique, additional, Gerber, Céline B., additional, Gaspar, Harald, additional, Kopps, Anna M., additional, Rieubland, Claudine, additional, Hurst, Anna C. E., additional, Amor, David J., additional, Nizon, Mathilde, additional, Pasquier, Laurent, additional, Pfundt, Rolph, additional, Reis, André, additional, Siu, Victoria Mok, additional, Tessarech, Marine, additional, Thompson, Michelle L., additional, Vincent, Marie, additional, de Vries, Bert B. A., additional, Walsh, Matthew B., additional, Wechsler, Stephanie Burns, additional, Zweier, Christiane, additional, Schnur, Rhonda E., additional, Guillen Sacoto, Maria J., additional, Margot, Henri, additional, Masotto, Barbara, additional, Palafoll, Maria Irene Valenzuela, additional, Nawaz, Urwah, additional, Voineagu, Irina, additional, and Slavotinek, Anne, additional

Published
2024
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7. Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2

Author

Faundes, Víctor, Goh, Stephanie, Akilapa, Rhoda, Bezuidenhout, Heidre, Bjornsson, Hans T., Bradley, Lisa, Brady, Angela F., Brischoux-Boucher, Elise, Brunner, Han, Bulk, Saskia, Canham, Natalie, Cody, Declan, Dentici, Maria Lisa, Digilio, Maria Cristina, Elmslie, Frances, Fry, Andrew E., Gill, Harinder, Hurst, Jane, Johnson, Diana, Julia, Sophie, Lachlan, Katherine, Lebel, Robert Roger, Byler, Melissa, Gershon, Eric, Lemire, Edmond, Gnazzo, Maria, Lepri, Francesca Romana, Marchese, Antonia, McEntagart, Meriel, McGaughran, Julie, Mizuno, Seiji, Okamoto, Nobuhiko, Rieubland, Claudine, Rodgers, Jonathan, Sasaki, Erina, Scalais, Emmanuel, Scurr, Ingrid, Suri, Mohnish, van der Burgt, Ineke, Matsumoto, Naomichi, Miyake, Noriko, Benoit, Valérie, Lederer, Damien, and Banka, Siddharth

Published
2021
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9. Expanding Genotype/Phenotype Correlation in 2p11.2-p12 Microdeletion Syndrome.

Author

Ferrario, Alessandra, Aliu, Nijas, Rieubland, Claudine, Vuilleumier, Sébastian, Grabe, Hilary M., and Escher, Pascal

Subjects
COMPARATIVE genomic hybridization, AGENESIS of corpus callosum, PHENOTYPES, PSYCHOMOTOR disorders, ARNOLD-Chiari deformity, GENOTYPES, INNER ear
Abstract

Chromosomal abnormalities on the short arm of chromosome 2 in the region p11.2 have been associated with developmental delay, intellectual disability, facial anomalies, abnormal ears, skeletal and genital malformations. Here we describe a patient with a de novo interstitial heterozygous microdeletion on the short arm of chromosome 2 in the region p11.2-p12. He presents with facial dysmorphism characterized by a broad and low root of the nose and low-set protruding ears. Clinical examinations during follow-up visits revealed congenital pendular nystagmus, decreased visual acuity and psychomotor development disorder including intellectual disability. The heterozygous 5 Mb-microdeletion was characterized by an array CGH (Comparative Genomic Hybridization) analysis. In the past two decades, nine patients with microdeletions in this region have been identified by array CGH analysis and were reported in the literature. All these patients show psychomotor development disorder and outer and/or inner ear anomalies. In addition, most of the patients have mild to severe intellectual disability and show facial malformations. We reviewed the literature on PubMed and OMIM using the gene/loci names as search terms in an attempt to identify correlations between genes located within the heterozygous microdeletion and the clinical phenotype of the patient, in order to define a recognizable phenotype for the 2p11.2p12 microdeletion syndrome. We discuss additional symptoms that are not systematically present in all patients and contribute to a heterogeneous clinical presentation of this microdeletion syndrome. [ABSTRACT FROM AUTHOR]

Published
2023
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11. The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders

Author

Saffari, Afshin, primary, Lau, Tracy, additional, Tajsharghi, Homa, additional, Karimiani, Ehsan Ghayoor, additional, Kariminejad, Ariana, additional, Efthymiou, Stephanie, additional, Zifarelli, Giovanni, additional, Sultan, Tipu, additional, Toosi, Mehran Beiraghi, additional, Sedighzadeh, Sahar, additional, Siu, Victoria Mok, additional, Ortigoza-Escobar, Juan Darío, additional, AlShamsi, Aisha M, additional, Ibrahim, Shahnaz, additional, Al-Sannaa, Nouriya Abbas, additional, Al-Hertani, Walla, additional, Sandra, Whalen, additional, Tarnopolsky, Mark, additional, Alavi, Shahryar, additional, Li, Chumei, additional, Day-Salvatore, Debra-Lynn, additional, Martínez-González, Maria Jesús, additional, Levandoski, Kristin M, additional, Bedoukian, Emma, additional, Madan-Khetarpal, Suneeta, additional, Idleburg, Michaela J, additional, Menezes, Minal Juliet, additional, Siddharth, Aishwarya, additional, Platzer, Konrad, additional, Oppermann, Henry, additional, Smitka, Martin, additional, Collins, Felicity, additional, Lek, Monkol, additional, Shahrooei, Mohmmad, additional, Ghavideldarestani, Maryam, additional, Herman, Isabella, additional, Rendu, John, additional, Faure, Julien, additional, Baker, Janice, additional, Bhambhani, Vikas, additional, Calderwood, Laurel, additional, Akhondian, Javad, additional, Imannezhad, Shima, additional, Mirzadeh, Hanieh Sadat, additional, Hashemi, Narges, additional, Doosti, Mohammad, additional, Safi, Mojtaba, additional, Ahangari, Najmeh, additional, Torbati, Paria Najarzadeh, additional, Abedini, Soheila, additional, Salpietro, Vincenzo, additional, Gulec, Elif Yilmaz, additional, Eshaghian, Safieh, additional, Ghazavi, Mohammadreza, additional, Pascher, Michael T, additional, Vogel, Marina, additional, Abicht, Angela, additional, Moutton, Sébastien, additional, Bruel, Ange-Line, additional, Rieubland, Claudine, additional, Gallati, Sabina, additional, Strom, Tim M, additional, Lochmüller, Hanns, additional, Mohammadi, Mohammad Hasan, additional, Alvi, Javeria Raza, additional, Zackai, Elaine H, additional, Keena, Beth A, additional, Skraban, Cara M, additional, Berger, Seth I, additional, Andrew, Erin H, additional, Rahimian, Elham, additional, Morrow, Michelle M, additional, Wentzensen, Ingrid M, additional, Millan, Francisca, additional, Henderson, Lindsay B, additional, Dafsari, Hormos Salimi, additional, Jungbluth, Heinz, additional, Gomez-Ospina, Natalia, additional, McRae, Anne, additional, Peter, Merlene, additional, Veltra, Danai, additional, Marinakis, Nikolaos M, additional, Sofocleous, Christalena, additional, Ashrafzadeh, Farah, additional, Pehlivan, Davut, additional, Lemke, Johannes R, additional, Melki, Judith, additional, Benezit, Audrey, additional, Bauer, Peter, additional, Weis, Denisa, additional, Lupski, James R, additional, Senderek, Jan, additional, Christodoulou, John, additional, Chung, Wendy K, additional, Goodchild, Rose, additional, Offiah, Amaka C, additional, Moreno-De-Luca, Andres, additional, Suri, Mohnish, additional, Ebrahimi-Fakhari, Darius, additional, Houlden, Henry, additional, and Maroofian, Reza, additional

Published
2023
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12. Phenotype and genotype in 103 patients with tricho-rhino-phalangeal syndrome

Author

Maas, Saskia M., Shaw, Adam C., Bikker, Hennie, Lüdecke, Hermann-Josef, van der Tuin, Karin, Badura-Stronka, Magdalena, Belligni, Elga, Biamino, Elisa, Bonati, Maria Teresa, Carvalho, Daniel R., Cobben, JanMaarten, de Man, Stella A., Den Hollander, Nicolette S., Di Donato, Nataliya, Garavelli, Livia, Grønborg, Sabine, Herkert, Johanna C., Hoogeboom, A. Jeannette M., Jamsheer, Aleksander, Latos-Bielenska, Anna, Maat-Kievit, Anneke, Magnani, Cinzia, Marcelis, Carlo, Mathijssen, Inge B., Nielsen, Maartje, Otten, Ellen, Ousager, Lilian B., Pilch, Jacek, Plomp, Astrid, Poke, Gemma, Poluha, Anna, Posmyk, Renata, Rieubland, Claudine, Silengo, Margharita, Simon, Marleen, Steichen, Elisabeth, Stumpel, Connie, Szakszon, Katalin, Polonkai, Edit, van den Ende, Jenneke, van der Steen, Antony, van Essen, Ton, van Haeringen, Arie, van Hagen, Johanna M., Verheij, Joke B.G.M., Mannens, Marcel M., and Hennekam, Raoul C.

Published
2015
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14. Activating RAC1 variants in the switch II region cause a developmental syndrome and alter neuronal morphology

Author

Banka, Siddharth, primary, Bennington, Abigail, additional, Baker, Martin J, additional, Rijckmans, Ellen, additional, Clemente, Giuliana D, additional, Ansor, Nurhuda Mohamad, additional, Sito, Hilary, additional, Prasad, Pritha, additional, Anyane-Yeboa, Kwame, additional, Badalato, Lauren, additional, Dimitrov, Boyan, additional, Fitzpatrick, David, additional, Hurst, Anna C E, additional, Jansen, Anna C, additional, Kelly, Melissa A, additional, Krantz, Ian, additional, Rieubland, Claudine, additional, Ross, Meredith, additional, Rudy, Natasha L, additional, Sanz, Javier, additional, Stouffs, Katrien, additional, Xu, Zhuo Luan, additional, Malliri, Angeliki, additional, Kazanietz, Marcelo G, additional, and Millard, Tom H, additional

Published
2022
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15. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Author

Reinthaler, Eva M., Lal, Dennis, Lebon, Sebastien, Hildebrand, Michael S., Dahl, Hans-Henrik M., Regan, Brigid M., Feucht, Martha, Steinböck, Hannelore, Neophytou, Birgit, Ronen, Gabriel M., Roche, Laurian, Gruber-Sedlmayr, Ursula, Geldner, Julia, Haberlandt, Edda, Hoffmann, Per, Herms, Stefan, Gieger, Christian, Waldenberger, Melanie, Franke, Andre, Wittig, Michael, Schoch, Susanne, Becker, Albert J., Hahn, Andreas, Männik, Katrin, Toliat, Mohammad R., Winterer, Georg, Lerche, Holger, Nürnberg, Peter, Mefford, Heather, Scheffer, Ingrid E., Berkovic, Samuel F., Beckmann, Jacques S., Sander, Thomas, Jacquemont, Sebastien, Reymond, Alexandre, Zimprich, Fritz, Neubauer, Bernd A., Reinthaler, Eva M., Zimprich, Fritz, Feucht, Martha, Steinböck, Hannelore, Neophytou, Birgit, Geldner, Julia, Gruber-Sedlmayr, Ursula, Haberlandt, Edda, Ronen, Gabriel M., Roche, Laurian, Lal, Dennis, Nürnberg, Peter, Sander, Thomas, Lerche, Holger, Neubauer, Bernd, Zimprich, Fritz, Mörzinger, Martina, Feucht, Martha, Suls, Arvid, Weckhuysen, Sarah, Claes, Lieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Møller, Rikke S, Klitten, Laura L., Hjalgrim, Helle, Møller, Rikke S, Campus, Kiel, Helbig, Ingo, Muhle, Hiltrud, Ostertag, Philipp, von Spiczak, Sarah, Stephani, Ulrich, Nürnberg, Peter, Sander, Thomas, Trucks, Holger, Elger, Christian E., Kleefu-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Gaus, Verena, Janz, Dieter, Sander, Thomas, Schmitz, Bettina, Rosenow, Felix, Klein, Karl Martin, Reif, Philipp S., Oertel, Wolfgang H., Hamer, Hajo M., Becker, Felicitas, Weber, Yvonne, Lerche, Holger, Koeleman, Bobby P.C., de Kovel, Carolien, Lindhout, Dick, Lindhout, Dick, Ameil, Agnès, Andrieux, Joris, Bouquillon, Sonia, Boute, Odile, de Flandre, Jeanne, Cuisset, Jean Marie, Cuvellier, Jean-Christophe, Salengro, Roger, David, Albert, de Vries, Bert, Delrue, Marie-Ange, Doco-Fenzy, Martine, Fernandez, Bridget A., Heron, Delphine, Keren, Boris, Lebel, Robert, Leheup, Bruno, Lewis, Suzanne, Mencarelli, Maria Antonietta, Mignot, Cyril, Minet, Jean-Claude, Moerman, Alexandre, Morice-Picard, Fanny, Mucciolo, Mafalda, Ounap, Katrin, Pasquier, Laurent, Petit, Florence, Ragona, Francesca, Rajcan-Separovic, Evica, Renieri, Alessandra, Rieubland, Claudine, Sanlaville, Damien, Sarrazin, Elisabeth, Shen, Yiping, van Haelst, Mieke, and Silfhout, Anneke Vulto-van

Published
2014
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17. Mirror extreme BMI phenotypes associated with gene dosage at the chromosome 16p11.2 locus

Author

Jacquemont, Sébastien, Reymond, Alexandre, Zufferey, Flore, Harewood, Louise, Walters, Robin G., Kutalik, Zoltán, Martinet, Danielle, Shen, Yiping, Valsesia, Armand, Beckmann, Noam D., Thorleifsson, Gudmar, Belfiore, Marco, Bouquillon, Sonia, Campion, Dominique, de Leeuw, Nicole, de Vries, Bert B. A., Esko, Tõnu, Fernandez, Bridget A., Fernández-Aranda, Fernando, Fernández-Real, José Manuel, Gratacòs, Mònica, Guilmatre, Audrey, Hoyer, Juliane, Jarvelin, Marjo-Riitta, Kooy, Frank R., Kurg, Ants, Le Caignec, Cédric, Männik, Katrin, Platt, Orah S., Sanlaville, Damien, Van Haelst, Mieke M., Gomez, Sergi Villatoro, Walha, Faida, Wu, Bai-lin, Yu, Yongguo, Aboura, Azzedine, Addor, Marie-Claude, Alembik, Yves, Antonarakis, Stylianos E., Arveiler, Benoît, Barth, Magalie, Bednarek, Nathalie, Béna, Frédérique, Bergmann, Sven, Beri, Mylène, Bernardini, Laura, Blaumeiser, Bettina, Bonneau, Dominique, Bottani, Armand, Boute, Odile, Brunner, Han G., Cailley, Dorothée, Callier, Patrick, Chiesa, Jean, Chrast, Jacqueline, Coin, Lachlan, Coutton, Charles, Cuisset, Jean-Marie, Cuvellier, Jean-Christophe, David, Albert, de Freminville, Bénédicte, Delobel, Bruno, Delrue, Marie-Ange, Demeer, Bénédicte, Descamps, Dominique, Didelot, Gérard, Dieterich, Klaus, Disciglio, Vittoria, Doco-Fenzy, Martine, Drunat, Séverine, Duban-Bedu, Bénédicte, Dubourg, Christèle, Moustafa, Julia S. El-Sayed, Elliott, Paul, Faas, Brigitte H. W., Faivre, Laurence, Faudet, Anne, Fellmann, Florence, Ferrarini, Alessandra, Fisher, Richard, Flori, Elisabeth, Forer, Lukas, Gaillard, Dominique, Gerard, Marion, Gieger, Christian, Gimelli, Stefania, Gimelli, Giorgio, Grabe, Hans J., Guichet, Agnès, Guillin, Olivier, Hartikainen, Anna-Liisa, Heron, Délphine, Hippolyte, Loyse, Holder, Muriel, Homuth, Georg, Isidor, Bertrand, Jaillard, Sylvie, Jaros, Zdenek, Jiménez-Murcia, Susana, Helas, Géraldine Joly, Jonveaux, Philippe, Kaksonen, Satu, Keren, Boris, Kloss-Brandstätter, Anita, Knoers, Nine V. A. M., Koolen, David A., Kroisel, Peter M., Kronenberg, Florian, Labalme, Audrey, Landais, Emilie, Lapi, Elisabetta, Layet, Valérie, Legallic, Solenn, Leheup, Bruno, Leube, Barbara, Lewis, Suzanne, Lucas, Josette, MacDermot, Kay D., Magnusson, Pall, Marshall, Christian, Mathieu-Dramard, Michèle, McCarthy, Mark I., Meitinger, Thomas, Mencarelli, Maria Antonietta, Merla, Giuseppe, Moerman, Alexandre, Mooser, Vincent, Morice-Picard, Fanny, Mucciolo, Mafalda, Nauck, Matthias, Ndiaye, Ndeye Coumba, Nordgren, Ann, Pasquier, Laurent, Petit, Florence, Pfundt, Rolph, Plessis, Ghislaine, Rajcan-Separovic, Evica, Ramelli, Gian Paolo, Rauch, Anita, Ravazzolo, Roberto, Reis, Andre, Renieri, Alessandra, Richart, Cristobal, Ried, Janina S., Rieubland, Claudine, Roberts, Wendy, Roetzer, Katharina M., Rooryck, Caroline, Rossi, Massimiliano, Saemundsen, Evald, Satre, Véronique, Schurmann, Claudia, Sigurdsson, Engilbert, Stavropoulos, Dimitri J., Stefansson, Hreinn, Tengström, Carola, Thorsteinsdóttir, Unnur, Tinahones, Francisco J., Touraine, Renaud, Vallée, Louis, van Binsbergen, Ellen, Van der Aa, Nathalie, Vincent-Delorme, Catherine, Visvikis-Siest, Sophie, Vollenweider, Peter, Völzke, Henry, Vulto-van Silfhout, Anneke T., Waeber, Gérard, Wallgren-Pettersson, Carina, Witwicki, Robert M., Zwolinksi, Simon, Andrieux, Joris, Estivill, Xavier, Gusella, James F., Gustafsson, Omar, Metspalu, Andres, Scherer, Stephen W., Stefansson, Kari, Blakemore, Alexandra I. F., Beckmann, Jacques S., and Froguel, Philippe

Published
2011
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20. Delineation of phenotypes and genotypes related to cohesin structural protein RAD21

Author

Krab, Lianne C., primary, Marcos-Alcalde, Iñigo, additional, Assaf, Melissa, additional, Balasubramanian, Meena, additional, Andersen, Janne Bayer, additional, Bisgaard, Anne-Marie, additional, Fitzpatrick, David R., additional, Gudmundsson, Sanna, additional, Huisman, Sylvia A., additional, Kalayci, Tugba, additional, Maas, Saskia M., additional, Martinez, Francisco, additional, McKee, Shane, additional, Menke, Leonie A., additional, Mulder, Paul A., additional, Murch, Oliver D., additional, Parker, Michael, additional, Pie, Juan, additional, Ramos, Feliciano J., additional, Rieubland, Claudine, additional, Rosenfeld Mokry, Jill A., additional, Scarano, Emanuela, additional, Shinawi, Marwan, additional, Gómez-Puertas, Paulino, additional, Tümer, Zeynep, additional, and Hennekam, Raoul C., additional

Published
2020
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21. SCN5A mutations in 442 neonates and children: Genotype-phenotype correlation and identification of higher-risk subgroups

Author

Baruteau, Alban-Elouen, primary, Kyndt, Florence, additional, Behr, Elijah, additional, Vink, Arja, additional, Lachaud, Matthias, additional, Joong, Anna, additional, Schott, Jean-Jacques, additional, Horie, Minoru, additional, Denjoy, Isabelle, additional, Crotti, Lia, additional, Shimizu, Wataru, additional, Bos, Johan, additional, Stephenson, Elizabeth, additional, Wong, Leonie, additional, Abrams, Dominic, additional, Davis, Andrew, additional, Winbo, Annika, additional, Dubin, Anne, additional, Sanatani, Shubhayan, additional, Liberman, Leonardo, additional, Kaski, Juan-Pablo, additional, Rudic, Boris, additional, Kwok, Sit Yee, additional, Rieubland, Claudine, additional, Tfelt-Hansen, Jacob, additional, Van Hare, George, additional, Guyomarc’h-Delasalle, Béatrice, additional, Blom, Nico, additional, Wijeyeratne, Yanushi, additional, Gourraud, Jean-Baptiste, additional, Le Marec, Hervé, additional, Ozawa, Junichi, additional, Fressart, Véronique, additional, Lupoglazoff, Jean-Marc, additional, Dagradi, Federica, additional, Spazzolini, Carla, additional, Aiba, Takeshi, additional, Tester, David, additional, Zahavich, Laura, additional, Beauséjour-Ladouceur, Virginie, additional, Jadhav, Mangesh, additional, Skinner, Jonathan, additional, Franciosi, Sonia, additional, Krahn, Andrew, additional, Abdelsayed, Mena, additional, Ruben, Peter, additional, Yung, Tak-Cheung, additional, Ackerman, Michael, additional, Wilde, Arthur, additional, Schwartz, Peter, additional, and Probst, Vincent, additional

Published
2019
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25. Recommendations for genetic testing and counselling after sudden cardiac death: practical aspects for Swiss practice

Author

Medeiros Domingo, Argelia, Bolliger, Stephan, Gräni, Christoph, Rieubland, Claudine, Hersch, Deborah, Asatryan, Babken, Schyma, Christian, Saguner, Ardan Muammer, Wyler, Daniel, Bhuiyan, Zahir, Fellman, Florence, Osculati, Antonio Marco, Ringger, Rebekka, Fokstuen, Siv, Sabatasso, Sara, Wilhelm, Matthias, Michaud, Katarzyna, and Swiss Working Group on Sudden Cardiac Death

Subjects
Age Factors, Autopsy, Death, Sudden, Cardiac/etiology, Family/psychology, Forensic Pathology, Genetic Counseling, Genetic Predisposition to Disease, Genetic Testing, Humans, Switzerland, 360 Social problems & social services, education, 610 Medicine & health
Abstract

There is a need to standardise, within a coordinated Swiss framework, the practical aspects of genetic testing and genetic counselling on possibly inherited cardiovascular disorders in relatives of a sudden cardiac death (SCD) victim. Because of the major advances in genetic investigation techniques and recent publication of international guidelines in the field of cardiology, genetics and pathology, we consider it important to summarise the current evidence and propose an optimal approach to post-mortem genetic investigation for SCD victims and their families in Switzerland. In this article, we discuss important technical, financial and medico-ethical aspects, and provide updated information on specific situations in which forensic pathologists, general practitioners and cardiologists should suspect a genetic origin of the SCD. At present, the principles of benefit, the duty to warn and the impact of genetic information for family members at risk are considered as strong justifications for post-mortem disclosure and prevail over the arguments of respect for a deceased person's privacy and confidentiality. This paper underlines also the need to update and improve the general knowledge concerning the genetic risk of cardiovascular pathologies, the importance to perform an autopsy and post-mortem genetic testing in SCD victims, and to develop standardized post-mortem disclosure policy at national and international levels for SCD cases and relatives.

Published
2018

26. 16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Author

Reinthaler, Eva M., Lal, Dennis, Lebon, Sebastien, Hildebrand, Michael S., Dahl, Hans-Henrik M., Regan, Brigid M., Feucht, Martha, Steinböck, Hannelore, Neophytou, Birgit, Ronen, Gabriel M., Roche, Laurian, Gruber-Sedlmayr, Ursula, Geldner, Julia, Haberlandt, Edda, Hoffmann, Per, Herms, Stefan, Gieger, Christian, Waldenberger, Melanie, Franke, Andre, Wittig, Michael, Schoch, Susanne, Becker, Albert J., Hahn, Andreas, Männik, Katrin, Toliat, Mohammad R., Winterer, Georg, Lerche, Holger, Nürnberg, Peter, Mefford, Heather, Scheffer, Ingrid E., Berkovic, Samuel F., Beckmann, Jacques S., Sander, Thomas, Jacquemont, Sebastien, Reymond, Alexandre, Zimprich, Fritz, Neubauer, Bernd A., Neubauer, Bernd, Mörzinger, Martina, Suls, Arvid, Weckhuysen, Sarah, Claes, Lieve, Deprez, Liesbet, Smets, Katrien, Van Dyck, Tine, Deconinck, Tine, De Jonghe, Peter, Møller, Rikke S., Klitten, Laura L., Hjalgrim, Helle, Campus, Kiel, Helbig, Ingo, Muhle, Hiltrud, Ostertag, Philipp, von Spiczak, Sarah, Stephani, Ulrich, Trucks, Holger, Elger, Christian E., Kleefuß-Lie, Ailing A., Kunz, Wolfram S., Surges, Rainer, Gaus, Verena, Janz, Dieter, Schmitz, Bettina, Rosenow, Felix, Klein, Karl Martin, Reif, Philipp S., Oertel, Wolfgang H., Hamer, Hajo M., Becker, Felicitas, Weber, Yvonne, Koeleman, Bobby P.C., de Kovel, Carolien, Lindhout, Dick, Ameil, Agnès, Andrieux, Joris, Bouquillon, Sonia, Boute, Odile, de Flandre, Jeanne, Cuisset, Jean Marie, Cuvellier, Jean-Christophe, Salengro, Roger, David, Albert, de Vries, Bert, Delrue, Marie-Ange, Doco-Fenzy, Martine, Fernandez, Bridget A., Heron, Delphine, Keren, Boris, Lebel, Robert, Leheup, Bruno, Lewis, Suzanne, Mencarelli, Maria Antonietta, Mignot, Cyril, Minet, Jean-Claude, Moerman, Alexandre, Morice-Picard, Fanny, Mucciolo, Mafalda, Ounap, Katrin, Pasquier, Laurent, Petit, Florence, Ragona, Francesca, Rajcan-Separovic, Evica, Renieri, Alessandra, Rieubland, Claudine, Sanlaville, Damien, Sarrazin, Elisabeth, Shen, Yiping, van Haelst, Mieke, and Silfhout, Anneke Vulto-van

Abstract

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10−6, odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10−4). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical RE

Published
2017

27. Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6Avariants causing X-linked Kabuki syndrome type 2

Author

Faundes, Víctor, Goh, Stephanie, Akilapa, Rhoda, Bezuidenhout, Heidre, Bjornsson, Hans T., Bradley, Lisa, Brady, Angela F., Brischoux-Boucher, Elise, Brunner, Han, Bulk, Saskia, Canham, Natalie, Cody, Declan, Dentici, Maria Lisa, Digilio, Maria Cristina, Elmslie, Frances, Fry, Andrew E., Gill, Harinder, Hurst, Jane, Johnson, Diana, Julia, Sophie, Lachlan, Katherine, Lebel, Robert Roger, Byler, Melissa, Gershon, Eric, Lemire, Edmond, Gnazzo, Maria, Lepri, Francesca Romana, Marchese, Antonia, McEntagart, Meriel, McGaughran, Julie, Mizuno, Seiji, Okamoto, Nobuhiko, Rieubland, Claudine, Rodgers, Jonathan, Sasaki, Erina, Scalais, Emmanuel, Scurr, Ingrid, Suri, Mohnish, van der Burgt, Ineke, Matsumoto, Naomichi, Miyake, Noriko, Benoit, Valérie, Lederer, Damien, and Banka, Siddharth

Abstract

The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood.

Published
2021
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28. SCN5A mutations in 442 neonates and children: genotype–phenotype correlation and identification of higher-risk subgroups

Author

Baruteau, Alban-Elouen, primary, Kyndt, Florence, additional, Behr, Elijah R, additional, Vink, Arja S, additional, Lachaud, Matthias, additional, Joong, Anna, additional, Schott, Jean-Jacques, additional, Horie, Minoru, additional, Denjoy, Isabelle, additional, Crotti, Lia, additional, Shimizu, Wataru, additional, Bos, Johan M, additional, Stephenson, Elizabeth A, additional, Wong, Leonie, additional, Abrams, Dominic J, additional, Davis, Andrew M, additional, Winbo, Annika, additional, Dubin, Anne M, additional, Sanatani, Shubhayan, additional, Liberman, Leonardo, additional, Kaski, Juan Pablo, additional, Rudic, Boris, additional, Kwok, Sit Yee, additional, Rieubland, Claudine, additional, Tfelt-Hansen, Jacob, additional, Van Hare, George F, additional, Guyomarc’h-Delasalle, Béatrice, additional, Blom, Nico A, additional, Wijeyeratne, Yanushi D, additional, Gourraud, Jean-Baptiste, additional, Le Marec, Hervé, additional, Ozawa, Junichi, additional, Fressart, Véronique, additional, Lupoglazoff, Jean-Marc, additional, Dagradi, Federica, additional, Spazzolini, Carla, additional, Aiba, Takeshi, additional, Tester, David J, additional, Zahavich, Laura A, additional, Beauséjour-Ladouceur, Virginie, additional, Jadhav, Mangesh, additional, Skinner, Jonathan R, additional, Franciosi, Sonia, additional, Krahn, Andrew D, additional, Abdelsayed, Mena, additional, Ruben, Peter C, additional, Yung, Tak-Cheung, additional, Ackerman, Michael J, additional, Wilde, Arthur A, additional, Schwartz, Peter J, additional, and Probst, Vincent, additional

Published
2018
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30. Phenotypes and genotypes in individuals with SMC1A variants

Author

Huisman, Sylvia, primary, Mulder, Paul A., additional, Redeker, Egbert, additional, Bader, Ingrid, additional, Bisgaard, Anne‐Marie, additional, Brooks, Alice, additional, Cereda, Anna, additional, Cinca, Constanza, additional, Clark, Dinah, additional, Cormier‐Daire, Valerie, additional, Deardorff, Matthew A., additional, Diderich, Karin, additional, Elting, Mariet, additional, van Essen, Anthonie, additional, FitzPatrick, David, additional, Gervasini, Cristina, additional, Gillessen‐Kaesbach, Gabriele, additional, Girisha, Katta M., additional, Hilhorst‐Hofstee, Yvonne, additional, Hopman, Saskia, additional, Horn, Denise, additional, Isrie, Mala, additional, Jansen, Sandra, additional, Jespersgaard, Cathrine, additional, Kaiser, Frank J., additional, Kaur, Maninder, additional, Kleefstra, Tjitske, additional, Krantz, Ian D., additional, Lakeman, Phillis, additional, Landlust, Annemiek, additional, Lessel, Davor, additional, Michot, Caroline, additional, Moss, Jo, additional, Noon, Sarah E., additional, Oliver, Chris, additional, Parenti, Ilaria, additional, Pie, Juan, additional, Ramos, Feliciano J., additional, Rieubland, Claudine, additional, Russo, Silvia, additional, Selicorni, Angelo, additional, Tümer, Zeynep, additional, Vorstenbosch, Rieneke, additional, Wenger, Tara L., additional, van Balkom, Ingrid, additional, Piening, Sigrid, additional, Wierzba, Jolanta, additional, and Hennekam, Raoul C., additional

Published
2017
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32. 96-77: Phenotypic Spectrum of HCN4 Mutations: Further Evidence of involvement in Left Ventricular Non-Compaction, Sick Sinus Syndrome, and Mood- and Anxiety Disorder

Author

Servatius, Helge, primary, Pless, Stephan A., additional, Schaller, Andre, additional, Lynagh, Timothy, additional, Tanner, Hildegard, additional, Rieubland, Claudine, additional, Roten, Laurent, additional, Seiler, Jens, additional, Noti, Fabian, additional, Tran, V. Nam, additional, Haeberlin, Andreas, additional, Lam, Anna, additional, Gallati, Sabina, additional, Fuhrer, Juerg, additional, and Domingo, Argelia Medeiros, additional

Published
2016
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33. Mutations in the LHX2 gene are not a frequent cause of micro/anophthalmia

Author

Desmaison, Annaïck, Vigouroux, Adeline, Rieubland, Claudine, Peres, Christine, Calvas, Patrick, and Chassaing, Nicolas

Subjects
Homeodomain Proteins, congenital, hereditary, and neonatal diseases and abnormalities, Base Sequence, LIM-Homeodomain Proteins, Molecular Sequence Data, Mutation, Missense, Anophthalmos, eye diseases, Cohort Studies, Amino Acid Sequence, Anophthalmos/genetics, Conserved Sequence/genetics, Homeodomain Proteins/chemistry, Homeodomain Proteins/genetics, Humans, Microphthalmos/genetics, Mutation, Missense/genetics, Transcription Factors/chemistry, Transcription Factors/genetics, embryonic structures, Microphthalmos, Conserved Sequence, Research Article, Transcription Factors
Abstract

Purpose: Microphthalmia and anophthalmia are at the severe end of the spectrum of abnormalities in ocular development. A few genes (orthodenticle homeobox 2 [OTX2], retina and anterior neural fold homeobox [RAX], SRY-box 2 [SOX2], CEH10 homeodomain-containing homolog [CHX10], and growth differentiation factor 6 [GDF6]) have been implicated mainly in isolated micro/anophthalmia but causative mutations of these genes explain less than a quarter of these developmental defects. The essential role of the LIM homeobox 2 (LHX2) transcription factor in early eye development has recently been documented. We postulated that mutations in this gene could lead to micro/anophthalmia, and thus performed molecular screening of its sequence in patients having micro/anophthalmia. Methods: Seventy patients having non-syndromic forms of colobomatous microphthalmia (n=25), isolated microphthalmia (n=18), or anophthalmia (n=17), and syndromic forms of micro/anophthalmia (n=10) were included in this study after negative molecular screening for OTX2, RAX, SOX2, and CHX10 mutations. Mutation screening of LHX2 was performed by direct sequencing of the coding sequences and intron/exon boundaries. Results: Two heterozygous variants of unknown significance (c.128C > G [p.Pro43Arg]; c.776C > A [p.Pro259Gln]) were identified in LHX2 among the 70 patients. These variations were not identified in a panel of 100 control patients of mixed origins. The variation c.776C > A (p.Pro259Gln) was considered as non pathogenic by in silico analysis, while the variation c.128C > G (p.Pro43Arg) considered as deleterious by in silico analysis and was inherited from the asymptomatic father. Conclusions: Mutations in LHX2 do not represent a frequent cause of micro/anophthalmia.

Published
2010

35. Metopic and sagittal synostosis in Greig cephalopolysyndactyly syndrome: five cases with intragenic mutations or complete deletions of GLI3

Author

Hurst, Jane A, primary, Jenkins, Dagan, additional, Vasudevan, Pradeep C, additional, Kirchhoff, Maria, additional, Skovby, Flemming, additional, Rieubland, Claudine, additional, Gallati, Sabina, additional, Rittinger, Olaf, additional, Kroisel, Peter M, additional, Johnson, David, additional, Biesecker, Leslie G, additional, and Wilkie, Andrew OM, additional

Published
2011
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39. Functional characterization of a novel SCN5A variant associated with long QT syndrome and sudden cardiac death

Author

Neubauer, Jacqueline, Wang, Zizun, Rougier, Jean-Sébastien, Abriel, Hugues, Rieubland, Claudine, Bartholdi, Deborah, Haas, Cordula, and Medeiros-Domingo, Argelia

Subjects
570 Life sciences, biology, 610 Medicine & health, 3. Good health
Abstract

Sudden arrhythmic death syndrome (SADS) in young individuals is a devastating and tragic event often caused by an undiagnosed inherited cardiac disease. Although post-mortem genetic testing represents a promising tool to elucidate potential disease-causing mechanisms in such autopsy-negative death cases, a variant interpretation is still challenging, and functional consequences of identified sequence alterations often remain unclear. Recently, we have identified a novel heterozygous missense variant (N1774H) in the Nav1.5 channel-encoding gene SCN5A in a 19-year-old female SADS victim. The aim of this study was to perform a co-segregation analysis in family members of the index case and to evaluate the functional consequences of this SCN5A variant. Functional characterization of the SCN5A N1774H variant was performed using patch-clamp techniques in TsA-201 cell line transiently expressing either wild-type or variant Nav1.5 channels. Electrophysiological analyses revealed that variant Nav1.5 channels show a loss-of-function in the peak current densities, but an increased late current compared to the wild-type channels, which could lead to both, loss- and gain-of-function respectively. Furthermore, clinical assessment and genetic testing of the relatives of the index case showed that all N1774H mutation carriers have prolonged QT intervals. The identification of several genotype and phenotype positive family members and the functional implication of the SCN5A N1774H variant support the evidence of the in silico predicted pathogenicity of the here reported sequence alteration.

40. Recommendations for genetic testing and counselling after sudden cardiac death: practical aspects for Swiss practice.

Author

Medeiros Domingo A, Bolliger S, Gräni C, Rieubland C, Hersch D, Asatryan B, Schyma C, Saguner A, Wyler D, Bhuiyan Z, Fellman F, Osculati AM, Ringger R, Fokstuen S, Sabatasso S, Wilhelm M, and Michaud K

Subjects
Age Factors, Autopsy, Forensic Pathology, Humans, Switzerland, Death, Sudden, Cardiac etiology, Family psychology, Genetic Counseling, Genetic Predisposition to Disease, Genetic Testing
Abstract

There is a need to standardise, within a coordinated Swiss framework, the practical aspects of genetic testing and genetic counselling on possibly inherited cardiovascular disorders in relatives of a sudden cardiac death (SCD) victim. Because of the major advances in genetic investigation techniques and recent publication of international guidelines in the field of cardiology, genetics and pathology, we consider it important to summarise the current evidence and propose an optimal approach to post-mortem genetic investigation for SCD victims and their families in Switzerland. In this article, we discuss important technical, financial and medico-ethical aspects, and provide updated information on specific situations in which forensic pathologists, general practitioners and cardiologists should suspect a genetic origin of the SCD. At present, the principles of benefit, the duty to warn and the impact of genetic information for family members at risk are considered as strong justifications for post-mortem disclosure and prevail over the arguments of respect for a deceased person's privacy and confidentiality. This paper underlines also the need to update and improve the general knowledge concerning the genetic risk of cardiovascular pathologies, the importance to perform an autopsy and post-mortem genetic testing in SCD victims, and to develop standardized post-mortem disclosure policy at national and international levels for SCD cases and relatives.

Published
2018
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41. Sudden cardiac death in forensic medicine – Swiss recommendations for a multidisciplinary approach.

Author

Wilhelm M, Bolliger SA, Bartsch C, Fokstuen S, Gräni C, Martos V, Medeiros Domingo A, Osculati A, Rieubland C, Sabatasso S, Saguner AM, Schyma C, Tschui J, Wyler D, Bhuiyan ZA, Fellmann F, and Michaud K

Subjects
Age Factors, Cause of Death, Communication, Genetic Predisposition to Disease, Humans, Switzerland, Autopsy methods, Death, Sudden, Cardiac etiology, Family, Forensic Pathology methods, Genetic Testing methods
Abstract

Sudden cardiac death (SCD) is by definition unexpected and cardiac in nature. The investigation is almost invariably performed by a forensic pathologist. Under these circumstances the role of the forensic pathologist is twofold: (1.) to determine rapidly and efficiently the cause and manner of death and (2.) to initiate a multidisciplinary process in order to prevent further deaths in existing family members. If the death is determined to be due to "natural" causes the district attorney in charge often refuses further examinations. However, additional examinations, i.e. extensive histopathological investigations and/or molecular genetic analyses, are necessary in many cases to clarify the cause of death. The Swiss Society of Legal Medicine created a multidisciplinary working group together with clinical and molecular geneticists and cardiologists in the hope of harmonising the approach to investigate SCD. The aim of this paper is to close the gap between the Swiss recommendations for routine forensic post-mortem cardiac examination and clinical recommendations for genetic testing of inherited cardiac diseases; this is in order to optimise the diagnostic procedures and preventive measures for living family members. The key points of the recommendations are (1.) the forensic autopsy procedure for all SCD victims under 40 years of age, (2.) the collection and storage of adequate samples for genetic testing, (3.) communication with the families, and (4.) a multidisciplinary approach including cardiogenetic counselling.

Published
2015
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42. Mutations in the LHX2 gene are not a frequent cause of micro/anophthalmia.

Author

Desmaison A, Vigouroux A, Rieubland C, Peres C, Calvas P, and Chassaing N

Subjects
Amino Acid Sequence, Base Sequence, Cohort Studies, Conserved Sequence genetics, Homeodomain Proteins chemistry, Humans, LIM-Homeodomain Proteins, Molecular Sequence Data, Transcription Factors chemistry, Anophthalmos genetics, Homeodomain Proteins genetics, Microphthalmos genetics, Mutation, Missense genetics, Transcription Factors genetics
Abstract

Purpose: Microphthalmia and anophthalmia are at the severe end of the spectrum of abnormalities in ocular development. A few genes (orthodenticle homeobox 2 [OTX2], retina and anterior neural fold homeobox [RAX], SRY-box 2 [SOX2], CEH10 homeodomain-containing homolog [CHX10], and growth differentiation factor 6 [GDF6]) have been implicated mainly in isolated micro/anophthalmia but causative mutations of these genes explain less than a quarter of these developmental defects. The essential role of the LIM homeobox 2 (LHX2) transcription factor in early eye development has recently been documented. We postulated that mutations in this gene could lead to micro/anophthalmia, and thus performed molecular screening of its sequence in patients having micro/anophthalmia., Methods: Seventy patients having non-syndromic forms of colobomatous microphthalmia (n=25), isolated microphthalmia (n=18), or anophthalmia (n=17), and syndromic forms of micro/anophthalmia (n=10) were included in this study after negative molecular screening for OTX2, RAX, SOX2, and CHX10 mutations. Mutation screening of LHX2 was performed by direct sequencing of the coding sequences and intron/exon boundaries., Results: Two heterozygous variants of unknown significance (c.128C>G [p.Pro43Arg]; c.776C>A [p.Pro259Gln]) were identified in LHX2 among the 70 patients. These variations were not identified in a panel of 100 control patients of mixed origins. The variation c.776C>A (p.Pro259Gln) was considered as non pathogenic by in silico analysis, while the variation c.128C>G (p.Pro43Arg) considered as deleterious by in silico analysis and was inherited from the asymptomatic father., Conclusions: Mutations in LHX2 do not represent a frequent cause of micro/anophthalmia.

Published
2010

43. Mutations in the SDHB gene are associated with extra-adrenal and/or malignant phaeochromocytomas.

Author

Gimenez-Roqueplo AP, Favier J, Rustin P, Rieubland C, Crespin M, Nau V, Khau Van Kien P, Corvol P, Plouin PF, and Jeunemaitre X

Subjects
Adrenal Gland Neoplasms blood supply, Adrenal Gland Neoplasms enzymology, Adult, DNA, Neoplasm genetics, Female, Germ-Line Mutation, Humans, Iron-Sulfur Proteins, Loss of Heterozygosity, Male, Middle Aged, Pheochromocytoma blood supply, Pheochromocytoma enzymology, Urinary Bladder Neoplasms blood supply, Urinary Bladder Neoplasms enzymology, Urinary Bladder Neoplasms genetics, Adrenal Gland Neoplasms genetics, Pheochromocytoma genetics, Protein Subunits genetics, Succinate Dehydrogenase genetics
Abstract

Germ-line mutations in the genes encoding succinate dehydrogenase complex subunits B (SDHB) and D (SDHD) have been reported in familial paragangliomas and apparently sporadic phaeochromocytomas (ASP), but the genotype-phenotype relationships of these mutations are unknown. Eighty-four patients (all but 2 followed up for 8.8 +/- 5.7 years) with ASP (57 with adrenal tumors, 27 with extra-adrenal, multiple, malignant, or recurrent tumors) were screened for the major susceptibility genes for phaeochromocytoma (RET, VHL, SDHD, and SDHB). Thirty-three tumors were available for molecular analysis, enzyme assays, and immunohistochemistry. No (0%) RET and 2 (2.4%) VHL mutations were detected. Only two coding single nucleotide polymorphisms in the SDHD gene (G12S and H50R) were found in 6 patients (7%). Conversely, six deleterious mutations in the SDHB gene were identified in 8 patients (9.5%). Ectopic site and recurrence or malignancy were strongly associated with SDHB mutations (7 of 8, 87%, versus 20 of 76, 26%; P = 0.001). Somatic DNA analysis indicated a loss of heterozygosity at chromosome 1p36 (SDHB locus) in 16 of 33 cases (48%). A loss of heterozygosity at the SDHB locus was found in all tumors with SDHB mutation, and assays of respiratory chain enzymes showed a complete loss of complex II catalytic activity. The vascular architecture of tumors with SDHB mutations displayed features typical of malignancy. These data strongly suggest that SDHB gene is a tumor suppressor gene and that the identification of germ-line mutations in SDHB gene in patients with ASPs should be considered as a high-risk factor for malignancy or recurrence.

Published
2003

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