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4. Genetic counselling legislation and practice in cancer in EU Member States

Author

McCrary, J. Matt, Van Valckenborgh, Els, Poirel, Hélène A., de Putter, Robin, van Rooij, Jeroen, Horgan, Denis, Dierks, Marie Luise, Antonova, Olga, Brunet, Joan, Chirita-Emandi, Adela, Colas, Chrystelle, Dalmas, Miriam, Ehrencrona, Hans, Grima, Claire, Janavičius, Ramūnas, Klink, Barbara, Koczok, Katalin, Krajc, Mateja, Lace, Baiba, Leitsalu, Liis, Mistrik, Martin, Paneque, Milena, Primorac, Dragan, Roetzer, Katharina M., Ronez, Joelle, Slámová, Lucie, Spanou, Elena, Stamatopoulos, Kostas, Stoklosa, Tomasz, Strang-Karlsson, Sonja, Szakszon, Katalin, Szczałuba, Krzysztof, Turner, Jacqueline, van Dooren, Marieke F., van Zelst-Stams, Wendy A.G., Vassallo, Loredana Maria, Wadt, Karin A.W., Žigman, Tamara, Ripperger, Tim, Genuardi, Maurizio, Van den Bulcke, Marc, Bergmann, Anke Katharina, McCrary, J. Matt, Van Valckenborgh, Els, Poirel, Hélène A., de Putter, Robin, van Rooij, Jeroen, Horgan, Denis, Dierks, Marie Luise, Antonova, Olga, Brunet, Joan, Chirita-Emandi, Adela, Colas, Chrystelle, Dalmas, Miriam, Ehrencrona, Hans, Grima, Claire, Janavičius, Ramūnas, Klink, Barbara, Koczok, Katalin, Krajc, Mateja, Lace, Baiba, Leitsalu, Liis, Mistrik, Martin, Paneque, Milena, Primorac, Dragan, Roetzer, Katharina M., Ronez, Joelle, Slámová, Lucie, Spanou, Elena, Stamatopoulos, Kostas, Stoklosa, Tomasz, Strang-Karlsson, Sonja, Szakszon, Katalin, Szczałuba, Krzysztof, Turner, Jacqueline, van Dooren, Marieke F., van Zelst-Stams, Wendy A.G., Vassallo, Loredana Maria, Wadt, Karin A.W., Žigman, Tamara, Ripperger, Tim, Genuardi, Maurizio, Van den Bulcke, Marc, and Bergmann, Anke Katharina

Abstract

Background: Somatic and germline genetic alterations are significant drivers of cancer. Increasing integration of new technologies which profile these alterations requires timely, equitable and high-quality genetic counselling to facilitate accurate diagnoses and informed decision-making by patients and their families in preventive and clinical settings. This article aims to provide an overview of genetic counselling legislation and practice across European Union (EU) Member States to serve as a foundation for future European recommendations and action. Methods: National legislative databases of all 27 Member States were searched using terms relevant to genetic counselling, translated as appropriate. Interviews with relevant experts from each Member State were conducted to validate legislative search results and provide detailed insights into genetic counselling practice in each country. Results: Genetic counselling is included in national legislative documents of 22 of 27 Member States, with substantial variation in legal mechanisms and prescribed details (i.e. the ‘who, what, when and where’ of counselling). Practice is similarly varied. Workforce capacity (25 of 27 Member States) and genetic literacy (all Member States) were common reported barriers. Recognition and/or better integration of genetic counsellors and updated legislation and were most commonly noted as the ‘most important change’ which would improve practice. Conclusions: This review highlights substantial variability in genetic counselling across EU Member States, as well as common barriers notwithstanding this variation. Future recommendations and action should focus on addressing literacy and capacity challenges through legislative, regulatory and/or strategic approaches at EU, national, regional and/or local levels.

Published
2024

5. CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

Author

Windpassinger, Christian, Piard, Juliette, Bonnard, Carine, Alfadhel, Majid, Lim, Shuhui, Bisteau, Xavier, Blouin, Stéphane, Ali, Nur’Ain B., Ng, Alvin Yu Jin, Lu, Hao, Tohari, Sumanty, Talib, S. Zakiah A., van Hul, Noémi, Caldez, Matias J., Van Maldergem, Lionel, Yigit, Gökhan, Kayserili, Hülya, Youssef, Sameh A., Coppola, Vincenzo, de Bruin, Alain, Tessarollo, Lino, Choi, Hyungwon, Rupp, Verena, Roetzer, Katharina, Roschger, Paul, Klaushofer, Klaus, Altmüller, Janine, Roy, Sudipto, Venkatesh, Byrappa, Ganger, Rudolf, Grill, Franz, Ben Chehida, Farid, Wollnik, Bernd, Altunoglu, Umut, Al Kaissi, Ali, Reversade, Bruno, and Kaldis, Philipp

Published
2017
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6. Identifying adult hypophosphatasia in the rheumatology unit

Author

Hadzimuratovic, Benjamin, additional, Feurstein, Julia, additional, Behanova, Martina, additional, Haschka, Judith, additional, Roetzer, Katharina, additional, Uyanik, Gökhan, additional, Witsch-Baumgartner, Martina, additional, Schett, Georg, additional, Zwerina, Jochen, additional, and Kocijan, Roland, additional

Published
2022
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8. Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for autism, schizophrenia and seizures

Author

Lionel, Anath C., Vaags, Andrea K., Sato, Daisuke, Gazzellone, Matthew J., Mitchell, Elyse B., Chen, Hong Yang, Costain, Gregory, Walker, Susan, Egger, Gerald, Thiruvahindrapuram, Bhooma, Merico, Daniele, Prasad, Aparna, Anagnostou, Evdokia, Fombonne, Eric, Zwaigenbaum, Lonnie, Roberts, Wendy, Szatmari, Peter, Fernandez, Bridget A., Georgieva, Lyudmila, Brzustowicz, Linda M., Roetzer, Katharina, Kaschnitz, Wolfgang, Vincent, John B., Windpassinger, Christian, Marshall, Christian R., Trifiletti, Rosario R., Kirmani, Salman, Kirov, George, Petek, Erwin, Hodge, Jennelle C., Bassett, Anne S., and Scherer, Stephen W.

Published
2013
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9. 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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11. A patient with Melorheostosis manifesting with features similar to tricho-dento-osseous syndrome: a case report

Author

Al Kaissi Ali, Skoumal Martin, Roetzer Katharina, Grill Franz, and Klaushofer Klaus

Subjects
Medicine
Abstract

Abstract Introduction A case of melorheostosis in association with tricho-dento-osseous (TDO) syndrome has been encountered. Case presentation The clinical and the radiographic manifestations of melorheostosis have been encountered in a 41-year-old man. Mutations in the 13 exons and flanking intronic regions of the LEMD3-gene have not been detected. His phenotypic features were consistent but not completely diagnostic for tricho-dento-osseous syndrome (TDO). We report what might be a novel syndromic association. Conclusion Melorheostosis has not previously been reported to be a part of TDO and an extensive review of the literature suggests that the constellation of hair, tooth and bone abnormalities found in our patient either represents an unusual variant of tricho-dento-osseous syndrome or a new syndrome.

Published
2008
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12. Vertebral hyperostosis, ankylosed vertebral fracture and atlantoaxial rotatory subluxation in an elderly patient with a history of infantile idiopathic scoliosis; a case report

Author

Al Kaissi Ali, Zwettler Elisabeth, Roetzer Katharina M, Haller Joerg, Varga Franz, Klaushofer Klaus, and Grill Franz

Subjects
Medicine
Abstract

Abstract This is a case report of a 48-year-old-woman with scoliosis since early childhood. Recent radiographic spinal assessment revealed the presence of distinctive spinal abnormalities. To the best of our knowledge this is the first clinical report describing a constellation of unusual changes in an elderly woman with a history of infantile idiopathic scoliosis.

Published
2007
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13. CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

Author

Regenerative Medicine, Stem Cells & Cancer, Windpassinger, Christian, Piard, Juliette, Bonnard, Carine, Alfadhel, Majid, Lim, Shuhui, Bisteau, Xavier, Blouin, Stéphane, Ali, Nur'Ain B, Ng, Alvin Yu Jin, Lu, Hao, Tohari, Sumanty, Talib, S Zakiah A, van Hul, Noémi, Caldez, Matias J, Van Maldergem, Lionel, Yigit, Gökhan, Kayserili, Hülya, Youssef, Sameh A, Coppola, Vincenzo, de Bruin, Alain, Tessarollo, Lino, Choi, Hyungwon, Rupp, Verena, Roetzer, Katharina, Roschger, Paul, Klaushofer, Klaus, Altmüller, Janine, Roy, Sudipto, Venkatesh, Byrappa, Ganger, Rudolf, Grill, Franz, Ben Chehida, Farid, Wollnik, Bernd, Altunoglu, Umut, Al Kaissi, Ali, Reversade, Bruno, Kaldis, Philipp, Regenerative Medicine, Stem Cells & Cancer, Windpassinger, Christian, Piard, Juliette, Bonnard, Carine, Alfadhel, Majid, Lim, Shuhui, Bisteau, Xavier, Blouin, Stéphane, Ali, Nur'Ain B, Ng, Alvin Yu Jin, Lu, Hao, Tohari, Sumanty, Talib, S Zakiah A, van Hul, Noémi, Caldez, Matias J, Van Maldergem, Lionel, Yigit, Gökhan, Kayserili, Hülya, Youssef, Sameh A, Coppola, Vincenzo, de Bruin, Alain, Tessarollo, Lino, Choi, Hyungwon, Rupp, Verena, Roetzer, Katharina, Roschger, Paul, Klaushofer, Klaus, Altmüller, Janine, Roy, Sudipto, Venkatesh, Byrappa, Ganger, Rudolf, Grill, Franz, Ben Chehida, Farid, Wollnik, Bernd, Altunoglu, Umut, Al Kaissi, Ali, Reversade, Bruno, and Kaldis, Philipp

Published
2017

14. CDK10 mutations in humans and mice cause severe growth retardation, spine malformations, and developmental delays

Author

Karabey, Hülya Kayserili; Wollnik, Bernd; Kaldis, Philipp, Windpassinger, Christian; Piard, Juliette; Bonnard, Carine; Alfadhel, Majid; Lim, Shuhui; Bisteau, Xavier; Blouin, Stéphane; Ali, Nur'Ain B.; Ng, Alvin Yu Jin; Lu, Hao; Tohari, Sumanty; Talib, S. Zakiah A.; van Hul, Noémi; Caldez, Matias J.; Van Maldergem, Lionel; Yiğit, Gökhan; Youssef, Sameh A.; Coppola, Vincenzo; de Bruin, Alain; Tessarollo, Lino; Choi, Hyungwon; Rupp, Verena; Roetzer, Katharina; Roschger, Paul; Klaushofer, Klaus; Altmüller, Janine; Roy, Sudipto; Venkatesh, Byrappa; Ganger, Rudolf; Grill, Franz; Ben Chehida, Farid; Altunoglu, Umut; Al Kaissi, Ali; Reversade, Bruno, School of Medicine, Department of Medical Genetics, Karabey, Hülya Kayserili; Wollnik, Bernd; Kaldis, Philipp, Windpassinger, Christian; Piard, Juliette; Bonnard, Carine; Alfadhel, Majid; Lim, Shuhui; Bisteau, Xavier; Blouin, Stéphane; Ali, Nur'Ain B.; Ng, Alvin Yu Jin; Lu, Hao; Tohari, Sumanty; Talib, S. Zakiah A.; van Hul, Noémi; Caldez, Matias J.; Van Maldergem, Lionel; Yiğit, Gökhan; Youssef, Sameh A.; Coppola, Vincenzo; de Bruin, Alain; Tessarollo, Lino; Choi, Hyungwon; Rupp, Verena; Roetzer, Katharina; Roschger, Paul; Klaushofer, Klaus; Altmüller, Janine; Roy, Sudipto; Venkatesh, Byrappa; Ganger, Rudolf; Grill, Franz; Ben Chehida, Farid; Altunoglu, Umut; Al Kaissi, Ali; Reversade, Bruno, School of Medicine, and Department of Medical Genetics

Abstract

In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development., NIH, the National Cancer Institute; Center for Cancer Research; Strategic Positioning Fund for the Genetic Orphan Diseases program; Industry Alignment Fund for the Singapore Childhood Undiagnosed Diseases program from the A*STAR (Agency for Science, Technology, and Research) Biomedical Research Council; A*STAR Biomedical Research Council

Published
2017

15. Re‐alignment‐procedures for Skeletal Dysplasia in Three Patients with Genetically Diverse Syndromes

Author

Al Kaissi, Ali, Ganger, Rudolf, Roetzer, Katharina M., Schwarzbraun, Thomas, Klaushofer, Klaus, and Grill, Franz

Subjects
Joint Instability, Male, Hyaline Membrane Disease, Ossification, Heterotopic, Collagen Diseases, Dwarfism, Osteochondrodysplasias, Cleft Palate, Craniofacial Abnormalities, Genu Valgum, Polydactyly, Diabetes Mellitus, Type 1, Treatment Outcome, Lower Extremity, Child, Preschool, Face, Clinical Articles, Humans, Orthopedic Procedures, Child, Epiphyses
Abstract

OBJECTIVE: Disruption to endochondral ossification leads to delayed and irregular bone formation and can result in a heterogeneous group of genetic disorders known as osteochondrodysplasias. These genetic disorders arise through disturbances in the complex processes of skeletal growth causing development of unsightly skeletal deformities. METHODS : Each syndrome was diagnosed on the basis of detailed clinical and radiographic assessment. Lower limb deformities were the prime presenting feature. RESULTS: Here are presented three patients with diverse genetic syndromes, namely Wolcott–Rallison syndrome (WRS), Kniest dysplasia (KD) and Desbuquois dysplasia (DS). Genetic testing was performed in the patients with WRS and DS. The diagnosis of KD was made purely on a clinical and radiographic basis. Variable orthopaedic interventions to realign these patients' lower limbs were implemented with the aim of improving their balance and gait. CONCLUSIONS: The aim of this paper is twofold. The first part is to outline the importance of diagnosing the causes of various skeletal abnormalities in patients with osteochondrodysplasias by phenotypic and genotypic characterization. The second part is to demonstrate our techniques for surgical corrections in patients with joint laxity and malalignment and show how far techniques for growth modulation, re‐alignment and ligament reconstruction have advanced.

Published
2013

22. Chromosomal contacts connect loci associated with autism, BMI and head circumference phenotypes

Author

Loviglio, M N, Leleu, M, Männik, K, Passeggeri, M, Giannuzzi, G, Van Der Werf, I, Waszak, S M, Zazhytska, M, Roberts-Caldeira, I, Gheldof, N, Migliavacca, E, Alfaiz, A A, Hippolyte, L, Maillard, A M, Loviglio, Maria Nicla, Männik, Katrin, Van Der Werf, Ilse, Giannuzzi, Giuliana, Zazhytska, Marianna, Gheldof, Nele, Migliavacca, Eugenia, Alfaiz, Ali A, Roberts-Caldeira, Inês, Hippolyte, Loyse, Maillard, Anne M, Ferrarini, Alessandra, Butschi, Florence Niel, Conrad, Bernard, Addor, Marie-Claude, Belfiore, Marco, Roetzer, Katharina, Dijck, Anke Van, Blaumeiser, Bettina, Kooy, Frank, Roelens, Filip, Dheedene, Annelies, Chiaie, Barbara Delle, Menten, Björn, Oostra, Ann, Caberg, Jean-Hubert, Carter, Melissa, Kellam, Barbara, Stavropoulos, Dimitri J, Marshall, Christian, Scherer, Stephen W, Weksberg, Rosanna, Cytrynbaum, Cheryl, Bassett, Anne, Lowther, Chelsea, Gillis, Jane, Mackay, Sara, Bache, Iben, Ousager, Lilian B, Smerdel, Maja Patricia, Graakjaer, Jesper, Kjaergaard, Susanne, Metspalu, Andres, Mathieu, Michele, Bonneau, Dominique, Guichet, Agnes, Parent, Philippe, Férec, Claude, Gerard, Marion, Plessis, Ghislaine, Lespinasse, James, Masurel, Alice, Marle, Nathalie, Faivre, Laurence, Callier, Patrick, Layet, Valerie, Meur, Nathalie Le, Le Goff, Céline, Duban-Bedu, Bénédicte, Sukno, Sylvie, Boute, Odile, Andrieux, Joris, Blanchet, Patricia, Geneviève, David, Puechberty, Jacques, Schneider, Anouck, Leheup, Bruno, Jonveaux, Philippe, Mercier, Sandra, David, Albert, Le Caignec, Cédric, De Pontual, Loic, Pipiras, Eva, Jacquette, Aurelia, Keren, Boris, Gilbert-Dussardier, Brigitte, Bilan, Frederic, Goldenberg, Alice, Chambon, Pascal, Toutain, Annick, Till, Marianne, Sanlaville, Damien, Leube, Barbara, Royer-Pokora, Brigitte, Grabe, Hans Jörgen, Schmidt, Carsten Oliver, Schurmann, Claudia, Homuth, Georg, Thorleifsson, Gudmar, Thorsteinsdottir, Unnur, Bernardini, Laura, Novelli, Antonio, Micale, Lucia, Merla, Giuseppe, Zollino, Marcella, Mari, Francesca, Rizzo, Caterina Lo, Renieri, Alessandra, Silengo, Margherita, Vulto-Van Silfhout, Anneke T, Schouten, Meyke, Pfundt, Rolph, De Leeuw, Nicole, Vansenne, Fleur, Maas, Saskia M, Barge-Schaapveld, Daniela Qcm, Knegt, Alida C, Stadheim, Barbro, Rodningen, Olaug, Houge, Gunnar, Price, Sue, Hawkes, Lara, Campbell, Carolyn, Kini, Usha, Vogt, Julie, Walters, Robin, Blakemore, Alexandra, Gusella, James F, Shen, Yiping, Scott, Daryl, Bacino, Carlos A, Tsuchiya, Karen, Ladda, Roger, Sell, Susan, Asamoah, Alexander, Hamati, Aline I, Rosenfeld, Jill A, Shaffer, Lisa G, Mitchell, Elyse, Hodge, Jennelle C, Beckmann, Jacques S, Jacquemont, Sébastien, Reymond, Alexandre, Ewans, Lisa J, Mowat, David, Walker, Jan, Amor, David J, Esch, Hilde Van, Leroy, Patricia, Bamforth, John-Steven, Babu, Deepti, Isidor, Bertrand, Didonato, Nataliya, Hackmann, Karl, Passeggeri, Marzia, Haeringen, Arie Van, Smith, Rosemarie, Ellingwood, Sara, Farber, Darren M, Puri, Vinay, Zadeh, Neda, Weaver, David D, Miller, Mandy, Wilks, Timothy, Jorgez, Carolina J, Lafayette, Deedee, Van Dijck, A, Kooy, R F, Sanlaville, D, Rosenfeld, J A, Shaffer, L G, Andrieux, J, Marshall, C, Scherer, S W, Shen, Y, Gusella, J F, Thorsteinsdottir, U, Thorleifsson, G, Dermitzakis, E T, Deplancke, B, Beckmann, J S, Rougemont, J, Jacquemont, S, Reymond, A, 2p15 Consortium, and 16p11 2 Consortium

Abstract

Copy number variants (CNVs) are major contributors to genomic imbalance disorders. Phenotyping of 137 unrelated deletion and reciprocal duplication carriers of the distal 16p11.2 220 kb BP2-BP3 interval showed that these rearrangements are associated with autism spectrum disorders and mirror phenotypes of obesity/underweight and macrocephaly/microcephaly. Such phenotypes were previously associated with rearrangements of the non-overlapping proximal 16p11.2 600 kb BP4-BP5 interval. These two CNV-prone regions at 16p11.2 are reciprocally engaged in complex chromatin looping, as successfully confirmed by 4C-seq, fluorescence in situ hybridization and Hi-C, as well as coordinated expression and regulation of encompassed genes. We observed that genes differentially expressed in 16p11.2 BP4-BP5 CNV carriers are concomitantly modified in their chromatin interactions, suggesting that disruption of chromatin interplays could participate in the observed phenotypes. We also identified cis- and trans-acting chromatin contacts to other genomic regions previously associated with analogous phenotypes. For example, we uncovered that individuals with reciprocal rearrangements of the trans-contacted 2p15 locus similarly display mirror phenotypes on head circumference and weight. Our results indicate that chromosomal contacts’ maps could uncover functionally and clinically related genes.

23. CDK10 Mutations in Humans and Mice Cause Severe Growth Retardation, Spine Malformations, and Developmental Delays

Author

Sudipto Roy, Noémi van Hul, Janine Altmüller, Hyungwon Choi, Nur'Ain Binte Ali, Xavier Bisteau, Shuhui Lim, Christian Windpassinger, Stéphane Blouin, Verena Rupp, Carine Bonnard, Franz Grill, Byrappa Venkatesh, Bruno Reversade, Rudolf Ganger, Vincenzo Coppola, S. Zakiah A. Talib, Klaus Klaushofer, Majid Alfadhel, Gökhan Yigit, Farid Ben Chehida, Paul Roschger, Ali Al Kaissi, Matias J. Caldez, Umut Altunoglu, Bernd Wollnik, Hülya Kayserili, Lionel Van Maldergem, Alvin Yu Jin Ng, Sameh A. Youssef, Lino Tessarollo, Katharina M. Roetzer, Hao Lu, Philipp Kaldis, Juliette Piard, Alain de Bruin, Sumanty Tohari, Karabey, Hülya Kayserili, Wollnik, Bernd, Kaldis, Philipp, Windpassinger, Christian, Piard, Juliette, Bonnard, Carine, Alfadhel, Majid, Lim, Shuhui, Bisteau, Xavier, Blouin, Stéphane, Ali, Nur'Ain B., Ng, Alvin Yu Jin, Lu, Hao, Tohari, Sumanty, Talib, S. Zakiah A., van Hul, Noémi, Caldez, Matias J., Van Maldergem, Lionel, Yiğit, Gökhan, Youssef, Sameh A., Coppola, Vincenzo, de Bruin, Alain, Tessarollo, Lino, Choi, Hyungwon, Rupp, Verena, Roetzer, Katharina, Roschger, Paul, Klaushofer, Klaus, Altmüller, Janine, Roy, Sudipto, Venkatesh, Byrappa, Ganger, Rudolf, Grill, Franz, Ben Chehida, Farid, Altunoglu, Umut, Al Kaissi, Ali, Reversade, Bruno, School of Medicine, Department of Medical Genetics, Regenerative Medicine, Stem Cells & Cancer, Amsterdam Cardiovascular Sciences, Amsterdam Reproduction & Development (AR&D), Center for Reproductive Medicine, ACS - Heart failure & arrhythmias, and ACS - Diabetes & metabolism

Subjects
0301 basic medicine, Male, Developmental Disabilities, medicine.disease_cause, Mice, 0302 clinical medicine, Phosphorylation, Child, Genetics (clinical), Exome sequencing, Cells, Cultured, Growth Disorders, Mice, Knockout, Mutation, Cultured, Cilium, Cell Cycle, Disease gene identification, Phenotype, Cyclin-Dependent Kinases, Pedigree, Embryo, 030220 oncology & carcinogenesis, Child, Preschool, Female, Signal Transduction, medicine.medical_specialty, Cells, Knockout, Biology, Article, 03 medical and health sciences, Germline mutation, Internal medicine, Ciliogenesis, Journal Article, Genetics, medicine, Animals, Humans, Star syndrome, Genome browser, Protein-kinase, Cdk10/Cyclin M, Family, Gene, Pisslre, DNA, Melanoma, Member, Cilia, Preschool, Cell Proliferation, Medicine, Genetics and heredity, Mammalian, Infant, Fibroblasts, medicine.disease, Embryo, Mammalian, Spine, 030104 developmental biology, Endocrinology, Congenital disorder, Al Kaissi syndrome knockout mice, CDK10, ETS2, cilia, congenital disorder, growth retardation, metabolism, spine malformation
Abstract

In five separate families, we identified nine individuals affected by a previously unidentified syndrome characterized by growth retardation, spine malformation, facial dysmorphisms, and developmental delays. Using homozygosity mapping, array CGH, and exome sequencing, we uncovered bi-allelic loss-of-function CDK10 mutations segregating with this disease. CDK10 is a protein kinase that partners with cyclin M to phosphorylate substrates such as ETS2 and PKN2 in order to modulate cellular growth. To validate and model the pathogenicity of these CDK10 germline mutations, we generated conditional-knockout mice. Homozygous Cdk10-knockout mice died postnatally with severe growth retardation, skeletal defects, and kidney and lung abnormalities, symptoms that partly resemble the disease's effect in humans. Fibroblasts derived from affected individuals and Cdk10-knockout mouse embryonic fibroblasts (MEFs) proliferated normally; however, Cdk10-knockout MEFs developed longer cilia. Comparative transcriptomic analysis of mutant and wild-type mouse organs revealed lipid metabolic changes consistent with growth impairment and altered ciliogenesis in the absence of CDK10. Our results document the CDK10 loss-of-function phenotype and point to a function for CDK10 in transducing signals received at the primary cilia to sustain embryonic and postnatal development., NIH, the National Cancer Institute; Center for Cancer Research; Strategic Positioning Fund for the Genetic Orphan Diseases program; Industry Alignment Fund for the Singapore Childhood Undiagnosed Diseases program from the A*STAR (Agency for Science, Technology, and Research) Biomedical Research Council; A*STAR Biomedical Research Council

Published
2017
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24. Genetic counselling legislation and practice in cancer in EU Member States.

Author

McCrary JM, Van Valckenborgh E, Poirel HA, de Putter R, van Rooij J, Horgan D, Dierks ML, Antonova O, Brunet J, Chirita-Emandi A, Colas C, Dalmas M, Ehrencrona H, Grima C, Janavičius R, Klink B, Koczok K, Krajc M, Lace B, Leitsalu L, Mistrik M, Paneque M, Primorac D, Roetzer KM, Ronez J, Slámová L, Spanou E, Stamatopoulos K, Stoklosa T, Strang-Karlsson S, Szakszon K, Szczałuba K, Turner J, van Dooren MF, van Zelst-Stams WAG, Vassallo LM, Wadt KAW, Žigman T, Ripperger T, Genuardi M, Van den Bulcke M, and Bergmann AK

Subjects
Humans, Genetic Testing legislation & jurisprudence, European Union, Genetic Counseling legislation & jurisprudence, Neoplasms genetics
Abstract

Background: Somatic and germline genetic alterations are significant drivers of cancer. Increasing integration of new technologies which profile these alterations requires timely, equitable and high-quality genetic counselling to facilitate accurate diagnoses and informed decision-making by patients and their families in preventive and clinical settings. This article aims to provide an overview of genetic counselling legislation and practice across European Union (EU) Member States to serve as a foundation for future European recommendations and action., Methods: National legislative databases of all 27 Member States were searched using terms relevant to genetic counselling, translated as appropriate. Interviews with relevant experts from each Member State were conducted to validate legislative search results and provide detailed insights into genetic counselling practice in each country., Results: Genetic counselling is included in national legislative documents of 22 of 27 Member States, with substantial variation in legal mechanisms and prescribed details (i.e. the 'who, what, when and where' of counselling). Practice is similarly varied. Workforce capacity (25 of 27 Member States) and genetic literacy (all Member States) were common reported barriers. Recognition and/or better integration of genetic counsellors and updated legislation and were most commonly noted as the 'most important change' which would improve practice., Conclusions: This review highlights substantial variability in genetic counselling across EU Member States, as well as common barriers notwithstanding this variation. Future recommendations and action should focus on addressing literacy and capacity challenges through legislative, regulatory and/or strategic approaches at EU, national, regional and/or local levels., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Public Health Association.)

Published
2024
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25. Extra phenotypic features in a girl with Miller syndrome.

Author

Al Kaissi A, Roetzer KM, Ulz P, Heitzer E, Klaushofer K, and Grill F

Subjects
Child, Preschool, Dihydroorotate Dehydrogenase, Female, Finger Phalanges abnormalities, Heterozygote, Humans, Leg Bones abnormalities, Mutation, Missense, Oxidoreductases Acting on CH-CH Group Donors genetics, Phenotype, Spine abnormalities, Toe Phalanges abnormalities, Abnormalities, Multiple diagnosis, Limb Deformities, Congenital diagnosis, Mandibulofacial Dysostosis diagnosis, Micrognathism diagnosis
Abstract

A 4-year-old girl, the child of nonconsanguineous parents was referred for clinical assessment because of postaxial limb defects associated with mild facial dysmorphism. The overall phenotypic features were compatible with the Miller syndrome. The proband manifested distinctive bone defects, consisting of triangular-shaped terminal phalanges and cone-shaped epiphyses of the middle phalanges of the feet. Using the sequence analysis of the DHODH gene we identified compound heterozygous mutations in the proband. Furthermore, both the parents were found to be heterozygous carriers of one of the two mutations found in the proband. Interestingly, the father had a history of postaxial polydactyly. We speculated that the postaxial polydactyly in the father was either a heterozygote manifestation or is unrelated.

Published
2011
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