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1. Generation of induced pluripotent stem cell lines from two unrelated patients affected by intellectual disability carrying homozygous variants in SGIP1

Author

Dillen, Lieke, primary, Fatima, Neelam, additional, Hommersom, Marina P., additional, Çepni, Ece, additional, Fatima, Fareeha, additional, van Beusekom, Ellen, additional, Albert, Silvia, additional, van Hagen, Johanna M., additional, de Vries, Bert B.A., additional, Ali Khan, Asma, additional, de Brouwer, Arjan P.M., additional, and van Bokhoven, Hans, additional

Published
2024
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2. Deletions and loss-of-function variants in TP63 associated with orofacial clefting

Author

Khandelwal, Kriti D., van den Boogaard, Marie-José H., Mehrem, Sarah L., Gebel, Jakob, Fagerberg, Christina, van Beusekom, Ellen, van Binsbergen, Ellen, Topaloglu, Ozan, Steehouwer, Marloes, Gilissen, Christian, Ishorst, Nina, van Rooij, Iris A. L. M., Roeleveld, Nel, Christensen, Kaare, Schoenaers, Joseph, Bergé, Stefaan, Murray, Jeffrey C., Hens, Greet, Devriendt, Koen, Ludwig, Kerstin U., Mangold, Elisabeth, Hoischen, Alexander, Zhou, Huiqing, Dötsch, Volker, Carels, Carine E. L., and van Bokhoven, Hans

Published
2019
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3. Variants affecting diverse domains of MEPE are associated with two distinct bone disorders, a craniofacial bone defect and otosclerosis

Author

Schrauwen, Isabelle, Valgaeren, Hanne, Tomas-Roca, Laura, Sommen, Manou, Altunoglu, Umut, Wesdorp, Mieke, Beyens, Matthias, Fransen, Erik, Nasir, Abdul, Vandeweyer, Geert, Schepers, Anne, Rahmoun, Malika, van Beusekom, Ellen, Huentelman, Matt J., Offeciers, Erwin, Dhooghe, Ingeborg, Huber, Alex, Van de Heyning, Paul, Zanetti, Diego, De Leenheer, Els M. R., Gilissen, Christian, Hoischen, Alexander, Cremers, Cor W., Verbist, Berit, de Brouwer, Arjan P. M., Padberg, George W., Pennings, Ronald, Kayserili, Hülya, Kremer, Hannie, Van Camp, Guy, and van Bokhoven, Hans

Published
2019
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4. A complex structural variant near SOX3 causes X-linked split-hand/foot malformation

Author

de Boer, Elke, primary, Marcelis, Carlo, additional, Neveling, Kornelia, additional, van Beusekom, Ellen, additional, Hoischen, Alexander, additional, Klein, Willemijn M., additional, de Leeuw, Nicole, additional, Mantere, Tuomo, additional, Melo, Uirá S., additional, van Reeuwijk, Jeroen, additional, Smeets, Dominique, additional, Spielmann, Malte, additional, Kleefstra, Tjitske, additional, van Bokhoven, Hans, additional, and Vissers, Lisenka E.L.M., additional

Published
2023
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7. Back Cover, Volume 43, Issue 7

Author

Lima, Ariadne R., primary, Ferreira, Barbara M., additional, Zhang, Chaofan, additional, Jolly, Angad, additional, Du, Haowei, additional, White, Janson J., additional, Dawood, Moez, additional, Lins, Tulio C., additional, Chiabai, Marcela A., additional, van Beusekom, Ellen, additional, Cordoba, Mara S., additional, Caldas Rosa, Erica C.C., additional, Kayserili, Hulya, additional, Kimonis, Virginia, additional, Wu, Erica, additional, Mellado, Cecilia, additional, Aggarwal, Vineet, additional, Richieri‐Costa, Antonio, additional, Brunoni, Décio, additional, Canó, Talyta M., additional, Jorge, Alexander A. L., additional, Kim, Chong A., additional, Honjo, Rachel, additional, Bertola, Débora R., additional, Dandalo‐Girardi, Raissa M., additional, Bayram, Yavuz, additional, Gezdirici, Alper, additional, Yilmaz‐Gulec, Elif, additional, Gumus, Evren, additional, Yilmaz, Gülay C., additional, Okamoto, Nobuhiko, additional, Ohashi, Hirofumi, additional, Coban–Akdemir, Zeynep, additional, Mitani, Tadahiro, additional, Jhangiani, Shalini N., additional, Muzny, Donna M., additional, Regattieri, Neysa A.P., additional, Pogue, Robert, additional, Pereira, Rinaldo W., additional, Otto, Paulo A., additional, Gibbs, Richard A., additional, Ali, Bassam R., additional, van Bokhoven, Hans, additional, Brunner, Han G., additional, Sutton, V. Reid, additional, Lupski, James R., additional, Vianna‐Morgante, Angela M., additional, Carvalho, Claudia M. B., additional, and Mazzeu, Juliana F., additional

Published
2022
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8. Phenotypic and mutational spectrum of ROR2 ‐related Robinow syndrome

Author

Lima, Ariadne R., primary, Ferreira, Barbara M., additional, Zhang, Chaofan, additional, Jolly, Angad, additional, Du, Haowei, additional, White, Janson J., additional, Dawood, Moez, additional, Lins, Tulio C., additional, Chiabai, Marcela A., additional, van Beusekom, Ellen, additional, Cordoba, Mara S., additional, Caldas Rosa, Erica C.C., additional, Kayserili, Hulya, additional, Kimonis, Virginia, additional, Wu, Erica, additional, Mellado, Cecilia, additional, Aggarwal, Vineet, additional, Richieri‐Costa, Antonio, additional, Brunoni, Décio, additional, Canó, Talyta M., additional, Jorge, Alexander A. L., additional, Kim, Chong A., additional, Honjo, Rachel, additional, Bertola, Débora R., additional, Dandalo‐Girardi, Raissa M., additional, Bayram, Yavuz, additional, Gezdirici, Alper, additional, Yilmaz‐Gulec, Elif, additional, Gumus, Evren, additional, Yilmaz, Gülay C., additional, Okamoto, Nobuhiko, additional, Ohashi, Hirofumi, additional, Coban–Akdemir, Zeynep, additional, Mitani, Tadahiro, additional, Jhangiani, Shalini N., additional, Muzny, Donna M., additional, Regattieri, Neysa A.P., additional, Pogue, Robert, additional, Pereira, Rinaldo W., additional, Otto, Paulo A., additional, Gibbs, Richard A., additional, Ali, Bassam R., additional, van Bokhoven, Hans, additional, Brunner, Han G., additional, Sutton, V. Reid, additional, Lupski, James R., additional, Vianna‐Morgante, Angela M., additional, Carvalho, Claudia M. B., additional, and Mazzeu, Juliana F., additional

Published
2022
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10. Phenotypic and mutational spectrum of ROR2-related Robinow syndrome.

Author

Lima, Ariadne R, Lima, Ariadne R, Ferreira, Barbara M, Zhang, Chaofan, Jolly, Angad, Du, Haowei, White, Janson J, Dawood, Moez, Lins, Tulio C, Chiabai, Marcela A, van Beusekom, Ellen, Cordoba, Mara S, Caldas Rosa, Erica CC, Kayserili, Hulya, Kimonis, Virginia, Wu, Erica, Mellado, Cecilia, Aggarwal, Vineet, Richieri-Costa, Antonio, Brunoni, Décio, Canó, Talyta M, Jorge, Alexander AL, Kim, Chong A, Honjo, Rachel, Bertola, Débora R, Dandalo-Girardi, Raissa M, Bayram, Yavuz, Gezdirici, Alper, Yilmaz-Gulec, Elif, Gumus, Evren, Yilmaz, Gülay C, Okamoto, Nobuhiko, Ohashi, Hirofumi, Coban-Akdemir, Zeynep, Mitani, Tadahiro, Jhangiani, Shalini N, Muzny, Donna M, Regattieri, Neysa AP, Pogue, Robert, Pereira, Rinaldo W, Otto, Paulo A, Gibbs, Richard A, Ali, Bassam R, van Bokhoven, Hans, Brunner, Han G, Sutton, V Reid, Lupski, James R, Vianna-Morgante, Angela M, Carvalho, Claudia MB, Mazzeu, Juliana F, Lima, Ariadne R, Lima, Ariadne R, Ferreira, Barbara M, Zhang, Chaofan, Jolly, Angad, Du, Haowei, White, Janson J, Dawood, Moez, Lins, Tulio C, Chiabai, Marcela A, van Beusekom, Ellen, Cordoba, Mara S, Caldas Rosa, Erica CC, Kayserili, Hulya, Kimonis, Virginia, Wu, Erica, Mellado, Cecilia, Aggarwal, Vineet, Richieri-Costa, Antonio, Brunoni, Décio, Canó, Talyta M, Jorge, Alexander AL, Kim, Chong A, Honjo, Rachel, Bertola, Débora R, Dandalo-Girardi, Raissa M, Bayram, Yavuz, Gezdirici, Alper, Yilmaz-Gulec, Elif, Gumus, Evren, Yilmaz, Gülay C, Okamoto, Nobuhiko, Ohashi, Hirofumi, Coban-Akdemir, Zeynep, Mitani, Tadahiro, Jhangiani, Shalini N, Muzny, Donna M, Regattieri, Neysa AP, Pogue, Robert, Pereira, Rinaldo W, Otto, Paulo A, Gibbs, Richard A, Ali, Bassam R, van Bokhoven, Hans, Brunner, Han G, Sutton, V Reid, Lupski, James R, Vianna-Morgante, Angela M, Carvalho, Claudia MB, and Mazzeu, Juliana F

Abstract

Robinow syndrome is characterized by a triad of craniofacial dysmorphisms, disproportionate-limb short stature, and genital hypoplasia. A significant degree of phenotypic variability seems to correlate with different genes/loci. Disturbances of the noncanonical WNT-pathway have been identified as the main cause of the syndrome. Biallelic variants in ROR2 cause an autosomal recessive form of the syndrome with distinctive skeletal findings. Twenty-two patients with a clinical diagnosis of autosomal recessive Robinow syndrome were screened for variants in ROR2 using multiple molecular approaches. We identified 25 putatively pathogenic ROR2 variants, 16 novel, including single nucleotide variants and exonic deletions. Detailed phenotypic analyses revealed that all subjects presented with a prominent forehead, hypertelorism, short nose, abnormality of the nasal tip, brachydactyly, mesomelic limb shortening, short stature, and genital hypoplasia in male patients. A total of 19 clinical features were present in more than 75% of the subjects, thus pointing to an overall uniformity of the phenotype. Disease-causing variants in ROR2, contribute to a clinically recognizable autosomal recessive​​​​​ trait phenotype with multiple skeletal defects. A comprehensive quantitative clinical evaluation of this cohort delineated the phenotypic spectrum of ROR2-related Robinow syndrome. The identification of exonic deletion variant alleles further supports the contention of a loss-of-function mechanism in the etiology of the syndrome.

Published
2022

11. Disruption of the podosome adaptor protein TKS4 (SH3PXD2B) causes the skeletal dysplasia, eye and cardiac abnormalities of Frank-Ter Haar syndrome

Author

Iqbal, Zafar, Cejudo-Martin, Pilar, de Brouwer, Arjan, van der Zwaag, Bert, Ruiz-Lozano, Pilar, Scimia, M. Cecilia, Lindsey, James D., Weinreb, Robert, Albrecht, Beate, Megarbane, Andre, Alanay, Yasemin, Ben-Neriah, Ziva, Amenduni, Mariangela, Artuso, Rosangela, Veltman, Joris A., van Beusekom, Ellen, Oudakker, Astrid, Courtneidge, Sara A., van Bokhoven, Hans, Millan, Jose Luis, Hennekam, Raoul, and Hamel, Ben

Subjects
Dysplasia -- Genetic aspects, Dysplasia -- Risk factors, Eye diseases -- Genetic aspects, Eye diseases -- Risk factors, Heart diseases -- Genetic aspects, Heart diseases -- Risk factors, Biological sciences
Abstract

Studies reveal that disruption of the podosome adaptor protein TKS4 causes the skeletal dysplasia, eye and cardiac abnormalities of the autosomal-recessive disorder Frank-Ter Haar syndrome (FTHS). An analysis identifies homozygous mutations of the SH3PXD2B gene which encodes the TKS4 protein as the cause of the disorder.

Published
2010

13. Mutations in the O-mannosyltransferase gene POMT1 give rise to the severe neuronal migration disorder Walker-Warburg syndrome

Author

de Bernabe, Daniel Beltran-Valero, Currier, Sophie, Steinbrecher, Alice, Celli, Jacopo, van Beusekom, Ellen, van der Zwaag, Bert, Kayserili, Hulya, Merlini, Luciano, Chitayat, David, Dobyns, William B., Cormand, Bru, Lehesjoki, Ana-Elina, Cruces, Jesus, Voit, Thomas, Walsh, Christopher A., van Bokhoven, Hans, and Brunner, Han G.

Subjects
Encephalopathy -- Genetic aspects, Gene mutations -- Physiological aspects, Genetic disorders -- Research, Human genetics -- Research, Biological sciences
Published
2002

14. Homozygous Missense Variants in NTNG2, Encoding a Presynaptic Netrin-G2 Adhesion Protein, Lead to a Distinct Neurodevelopmental Disorder

Author

Dias, Caroline M., primary, Punetha, Jaya, additional, Zheng, Céline, additional, Mazaheri, Neda, additional, Rad, Abolfazl, additional, Efthymiou, Stephanie, additional, Petersen, Andrea, additional, Dehghani, Mohammadreza, additional, Pehlivan, Davut, additional, Partlow, Jennifer N., additional, Posey, Jennifer E., additional, Salpietro, Vincenzo, additional, Gezdirici, Alper, additional, Malamiri, Reza Azizi, additional, Al Menabawy, Nihal M., additional, Selim, Laila A., additional, Vahidi Mehrjardi, Mohammad Yahya, additional, Banu, Selina, additional, Polla, Daniel L., additional, Yang, Edward, additional, Rezazadeh Varaghchi, Jamileh, additional, Mitani, Tadahiro, additional, van Beusekom, Ellen, additional, Najafi, Maryam, additional, Sedaghat, Alireza, additional, Keller-Ramey, Jennifer, additional, Durham, Leslie, additional, Coban-Akdemir, Zeynep, additional, Karaca, Ender, additional, Orlova, Valeria, additional, Schaeken, Lieke L.M., additional, Sherafat, Amir, additional, Jhangiani, Shalini N., additional, Stanley, Valentina, additional, Shariati, Gholamreza, additional, Galehdari, Hamid, additional, Gleeson, Joseph G., additional, Walsh, Christopher A., additional, Lupski, James R., additional, Seiradake, Elena, additional, Houlden, Henry, additional, van Bokhoven, Hans, additional, and Maroofian, Reza, additional

Published
2019
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15. Deletions and loss-of-function variants in TP63 associated with orofacial clefting

Author

Genetica, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Khandelwal, Kriti D., van den Boogaard, Marie José H., Mehrem, Sarah L., Gebel, Jakob, Fagerberg, Christina, van Beusekom, Ellen, van Binsbergen, Ellen, Topaloglu, Ozan, Steehouwer, Marloes, Gilissen, Christian, Ishorst, Nina, van Rooij, Iris A.L.M., Roeleveld, Nel, Christensen, Kaare, Schoenaers, Joseph, Bergé, Stefaan, Murray, Jeffrey C., Hens, Greet, Devriendt, Koen, Ludwig, Kerstin U., Mangold, Elisabeth, Hoischen, Alexander, Zhou, Huiqing, Dötsch, Volker, Carels, Carine E.L., van Bokhoven, Hans, Genetica, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Khandelwal, Kriti D., van den Boogaard, Marie José H., Mehrem, Sarah L., Gebel, Jakob, Fagerberg, Christina, van Beusekom, Ellen, van Binsbergen, Ellen, Topaloglu, Ozan, Steehouwer, Marloes, Gilissen, Christian, Ishorst, Nina, van Rooij, Iris A.L.M., Roeleveld, Nel, Christensen, Kaare, Schoenaers, Joseph, Bergé, Stefaan, Murray, Jeffrey C., Hens, Greet, Devriendt, Koen, Ludwig, Kerstin U., Mangold, Elisabeth, Hoischen, Alexander, Zhou, Huiqing, Dötsch, Volker, Carels, Carine E.L., and van Bokhoven, Hans

Published
2019

16. Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-l-Ribitol Pyrophosphorylase A Muscular Dystrophy

Author

van Tol, Walinka, primary, van Scherpenzeel, Monique, additional, Alsady, Mohammad, additional, Riemersma, Moniek, additional, Hermans, Esther, additional, Kragt, Else, additional, Tasca, Giorgio, additional, Kamsteeg, Erik-Jan, additional, Pennings, Maartje, additional, van Beusekom, Ellen, additional, Vermeulen, Jeroen R, additional, van Bokhoven, Hans, additional, Voermans, Nicol C, additional, Willemsen, Michèl A, additional, Ashikov, Angel, additional, and Lefeber, Dirk J, additional

Published
2019
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17. Correction: Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice

Author

Rainger, Joe, primary, van Beusekom, Ellen, additional, Ramsay, Jacqueline K., additional, McKie, Lisa, additional, Al-Gazali, Lihadh, additional, Pallotta, Rosanna, additional, Saponari, Anita, additional, Branney, Peter, additional, Fisher, Malcolm, additional, Morrison, Harris, additional, Bicknell, Louise, additional, Gautier, Philippe, additional, Perry, Paul, additional, Sokhi, Kishan, additional, Sexton, David, additional, Bardakjian, Tanya M., additional, Schneider, Adele S., additional, Elcioglu, Nursel, additional, Ozkinay, Ferda, additional, Koenig, Rainer, additional, Mégarbané, Andre, additional, Semerci, C. Nur, additional, Khan, Ayesha, additional, Zafar, Saemah, additional, Hennekam, Raoul, additional, Sousa, Sérgio B., additional, Ramos, Lina, additional, Garavelli, Livia, additional, Furga, Andrea Superti, additional, Wischmeijer, Anita, additional, Jackson, Ian J., additional, Gillessen-Kaesbach, Gabriele, additional, Brunner, Han G., additional, Wieczorek, Dagmar, additional, van Bokhoven, Hans, additional, and FitzPatrick, David R., additional

Published
2018
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18. Identification of a de novo variant in CHUK in a patient with an EEC/AEC syndrome-like phenotype and hypogammaglobulinemia

Author

Khandelwal, Kriti D., primary, Ockeloen, Charlotte W., additional, Venselaar, Hanka, additional, Boulanger, Cécile, additional, Brichard, Bénédicte, additional, Sokal, Etienne, additional, Pfundt, Rolph, additional, Rinne, Tuula, additional, van Beusekom, Ellen, additional, Bloemen, Marjon, additional, Vriend, Gerrit, additional, Revencu, Nicole, additional, Carels, Carine E. L., additional, van Bokhoven, Hans, additional, and Zhou, Huiqing, additional

Published
2017
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20. Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

Author

Ockeloen, Charlotte W., primary, Khandelwal, Kriti D., additional, Dreesen, Karoline, additional, Ludwig, Kerstin U., additional, Sullivan, Robert, additional, van Rooij, Iris A.L.M., additional, Thonissen, Michelle, additional, Swinnen, Steven, additional, Phan, Milien, additional, Conte, Federica, additional, Ishorst, Nina, additional, Gilissen, Christian, additional, Roa Fuentes, Laury, additional, van de Vorst, Maartje, additional, Henkes, Arjen, additional, Steehouwer, Marloes, additional, van Beusekom, Ellen, additional, Bloemen, Marjon, additional, Vankeirsbilck, Bruno, additional, Bergé, Stefaan, additional, Hens, Greet, additional, Schoenaers, Joseph, additional, Vander Poorten, Vincent, additional, Roosenboom, Jasmien, additional, Verdonck, An, additional, Devriendt, Koen, additional, Roeleveldt, Nel, additional, Jhangiani, Shalini N., additional, Vissers, Lisenka E.L.M., additional, Lupski, James R., additional, de Ligt, Joep, additional, Von den Hoff, Johannes W., additional, Pfundt, Rolph, additional, Brunner, Han G., additional, Zhou, Huiqing, additional, Dixon, Jill, additional, Mangold, Elisabeth, additional, van Bokhoven, Hans, additional, Dixon, Michael J., additional, Kleefstra, Tjitske, additional, Hoischen, Alexander, additional, and Carels, Carine E.L., additional

Published
2016
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21. De Novo Mutations In Plxnd1 And Rev3L Cause Mobius Syndrome

Author

Tomas-Roca, Laura, Tsaalbi-Shtylik, Anastasia, Jansen, Jacob G., Singh, Manvendra K., Epstein, Jonathan A., Altunoglu, Umut, Verzijl, Harriette, Soria, Laura, van Beusekom, Ellen, Roscioli, Tony, Iqbal, Zafar, Gilissen, Christian, Hoischen, Alexander, de Brouwer, Arjan P. M., Erasmus, Corrie, Schubert, Dirk, Brunner, Han, Aytes, Antonio Perez, Marin, Faustino, and Aroca, Pilar

Subjects
animal structures
Abstract

Mobius syndrome (MBS) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies. The aetiology of this syndrome has been enigmatic since the initial descriptions by von Graefe in 1880 and by Mobius in 1888, and it has been debated for decades whether MBS has a genetic or a non-genetic aetiology. Here, we report de novo mutations affecting two genes, PLXND1 and REV3L in MBS patients. PLXND1 and REV3L represent totally unrelated pathways involved in hindbrain development: neural migration and DNA translesion synthesis, essential for the replication of endogenously damaged DNA, respectively. Interestingly, analysis of Plxnd1 and Rev3l mutant mice shows that disruption of these separate pathways converge at the facial branchiomotor nucleus, affecting either motoneuron migration or proliferation. The finding that PLXND1 and REV3L mutations are responsible for a proportion of MBS patients suggests that de novo mutations in other genes might account for other MBS patients.

Published
2015

22. Cytidine Diphosphate-Ribitol Analysis for Diagnostics and Treatment Monitoring of Cytidine Diphosphate-LRibitol Pyrophosphorylase A Muscular Dystrophy.

Author

van Tol, Walinka, van Scherpenzeel, Monique, Alsady, Mohammad, Riemersma, Moniek, Hermans, Esther, Kragt, Else, Tasca, Giorgio, Kamsteeg, Erik-Jan, Pennings, Maartje, van Beusekom, Ellen, Vermeulen, Jeroen R., van Bokhoven, Hans, Voermans, Nicol C., Willemsen, Michèl A., Ashikov, Angel, and Lefeber, Dirk J.

Published
2019
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23. Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

Author

Ockeloen, Charlotte W., Khandelwal, Kriti D., Dreesen, Karoline, Ludwig, Kerstin U., Sullivan, Robert, Van Rooij, Iris A L M, Thonissen, Michelle, Swinnen, Steven, Phan, Milien, Conte, Federica, Ishorst, Nina, Gilissen, Christian, Roa Fuentes, Laury, Van De Vorst, Maartje, Henkes, Arjen, Steehouwer, Marloes, Van Beusekom, Ellen, Bloemen, Marjon, Vankeirsbilck, Bruno, Bergé, Stefaan, Hens, Greet, Schoenaers, Joseph, Vander Poorten, Vincent, Roosenboom, Jasmien, Verdonck, An, Devriendt, Koen, Roeleveldt, Nel, Jhangiani, Shalini N., Vissers, Lisenka E L M, Lupski, James R., De Ligt, Joep, Von Den Hoff, Johannes W., Pfundt, Rolph, Brunner, Han G., Zhou, Huiqing, Dixon, Jill, Mangold, Elisabeth, Van Bokhoven, Hans, Dixon, Michael J., Kleefstra, Tjitske, Hoischen, Alexander, Carels, Carine E L, Ockeloen, Charlotte W., Khandelwal, Kriti D., Dreesen, Karoline, Ludwig, Kerstin U., Sullivan, Robert, Van Rooij, Iris A L M, Thonissen, Michelle, Swinnen, Steven, Phan, Milien, Conte, Federica, Ishorst, Nina, Gilissen, Christian, Roa Fuentes, Laury, Van De Vorst, Maartje, Henkes, Arjen, Steehouwer, Marloes, Van Beusekom, Ellen, Bloemen, Marjon, Vankeirsbilck, Bruno, Bergé, Stefaan, Hens, Greet, Schoenaers, Joseph, Vander Poorten, Vincent, Roosenboom, Jasmien, Verdonck, An, Devriendt, Koen, Roeleveldt, Nel, Jhangiani, Shalini N., Vissers, Lisenka E L M, Lupski, James R., De Ligt, Joep, Von Den Hoff, Johannes W., Pfundt, Rolph, Brunner, Han G., Zhou, Huiqing, Dixon, Jill, Mangold, Elisabeth, Van Bokhoven, Hans, Dixon, Michael J., Kleefstra, Tjitske, Hoischen, Alexander, and Carels, Carine E L

Published
2016

24. Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

Author

Hubrecht Institute with UMC, Ockeloen, Charlotte W., Khandelwal, Kriti D., Dreesen, Karoline, Ludwig, Kerstin U., Sullivan, Robert, Van Rooij, Iris A L M, Thonissen, Michelle, Swinnen, Steven, Phan, Milien, Conte, Federica, Ishorst, Nina, Gilissen, Christian, Roa Fuentes, Laury, Van De Vorst, Maartje, Henkes, Arjen, Steehouwer, Marloes, Van Beusekom, Ellen, Bloemen, Marjon, Vankeirsbilck, Bruno, Bergé, Stefaan, Hens, Greet, Schoenaers, Joseph, Vander Poorten, Vincent, Roosenboom, Jasmien, Verdonck, An, Devriendt, Koen, Roeleveldt, Nel, Jhangiani, Shalini N., Vissers, Lisenka E L M, Lupski, James R., De Ligt, Joep, Von Den Hoff, Johannes W., Pfundt, Rolph, Brunner, Han G., Zhou, Huiqing, Dixon, Jill, Mangold, Elisabeth, Van Bokhoven, Hans, Dixon, Michael J., Kleefstra, Tjitske, Hoischen, Alexander, Carels, Carine E L, Hubrecht Institute with UMC, Ockeloen, Charlotte W., Khandelwal, Kriti D., Dreesen, Karoline, Ludwig, Kerstin U., Sullivan, Robert, Van Rooij, Iris A L M, Thonissen, Michelle, Swinnen, Steven, Phan, Milien, Conte, Federica, Ishorst, Nina, Gilissen, Christian, Roa Fuentes, Laury, Van De Vorst, Maartje, Henkes, Arjen, Steehouwer, Marloes, Van Beusekom, Ellen, Bloemen, Marjon, Vankeirsbilck, Bruno, Bergé, Stefaan, Hens, Greet, Schoenaers, Joseph, Vander Poorten, Vincent, Roosenboom, Jasmien, Verdonck, An, Devriendt, Koen, Roeleveldt, Nel, Jhangiani, Shalini N., Vissers, Lisenka E L M, Lupski, James R., De Ligt, Joep, Von Den Hoff, Johannes W., Pfundt, Rolph, Brunner, Han G., Zhou, Huiqing, Dixon, Jill, Mangold, Elisabeth, Van Bokhoven, Hans, Dixon, Michael J., Kleefstra, Tjitske, Hoischen, Alexander, and Carels, Carine E L

Published
2016

25. p63 Gene Mutations in EEC Syndrome, Limb-Mammary Syndrome, and Isolated Split Hand--Split Foot Malformation Suggest a Genotype-Phenotype Correlation

Author

van Bokhoven, Hans, Hamel, Ben C. J., Bamshad, Mike, Sangiorgi, Eugenio, Gurrieri, Fiorella, Duijf, Pascal H. G., Vanmolkot, Kate R. J., van Beusekom, Ellen, van Beersum, Sylvia E. C., Celli, Jacopo, Merkx, Gerard F. M., Tenconi, Romano, Fryns, Jean Pierre, Verloes, Alain, Newbury-Ecob, Ruth A., Raas-Rotschild, Annick, Majewski, Frank, Beemer, Frits A., Janecke, Andreas, Chitayat, David, Crisponi, Giangiorgio, Kayserili, Hulya, Yates, John R. W., Neri, Giovanni, and Brunner, Han G.

Subjects
Gene mutations -- Analysis, Orthopedics -- Research, Genetic disorders -- Analysis, Genetic epistasis -- Analysis, Biological sciences
Published
2001

26. Familial Syndromic Esophageal Atresia Maps to 2p23-p24

Author

Celli, Jacopo, van Beusekom, Ellen, Hennekam, Raoul C. M., Gallardo, M. Esther, Smeets, Dominique F. C. M., de Cordoba, Santiago Rodriguez, Innis, Jeffrey W., Frydman, Moshe, Konig, Rainer, Kingston, Helen, Tolmie, John, Govaerts, Lutgarde C. P., van van Bokhoven, Hans, and Brunner, Han G.

Subjects
Human genetics -- Research, Esophagus -- Atresia, Birth defects -- Causes of, Genetic disorders -- Analysis, Chromosome mapping -- Research, Biological sciences
Published
2000

27. De novo mutations in Plxnd1 and Rev3l cause mobius syndrome

Author

Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Tomas-Roca, Laura; Tsaalbi-Shtylik, Anastasia; Jansen, Jacob G.; Singh, Manvendra K.; Epstein, Jonathan A.; Altunoglu, Umut; Verzijl, Harriette; Soria, Laura; van Beusekom, Ellen; Roscioli, Tony; Iqbal, Zafar; Gilissen, Christian; Hoischen, Alexander; de Brouwer,Arjan P. M.; Erasmus, Corrie; Schubert, Dirk; Brunner, Han; Aytes, Antonio Perez; Marin, Faustino; Aroca, Pilar; Carta, Arturo; de Wind, Niels; Padberg, George W.; van Bokhoven, Hans, School of Medicine, Department of Medical Genetics, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Tomas-Roca, Laura; Tsaalbi-Shtylik, Anastasia; Jansen, Jacob G.; Singh, Manvendra K.; Epstein, Jonathan A.; Altunoglu, Umut; Verzijl, Harriette; Soria, Laura; van Beusekom, Ellen; Roscioli, Tony; Iqbal, Zafar; Gilissen, Christian; Hoischen, Alexander; de Brouwer,Arjan P. M.; Erasmus, Corrie; Schubert, Dirk; Brunner, Han; Aytes, Antonio Perez; Marin, Faustino; Aroca, Pilar; Carta, Arturo; de Wind, Niels; Padberg, George W.; van Bokhoven, Hans, School of Medicine, and Department of Medical Genetics

Abstract

Mobius syndrome (MBS) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies. The aetiology of this syndrome has been enigmatic since the initial descriptions by von Graefe in 1880 and by Mobius in 1888, and it has been debated for decades whether MBS has a genetic or a non-genetic aetiology. Here, we report de novo mutations affecting two genes, PLXND1 and REV3L in MBS patients. PLXND1 and REV3L represent totally unrelated pathways involved in hindbrain development: neural migration and DNA translesion synthesis, essential for the replication of endogenously damaged DNA, respectively. Interestingly, analysis of Plxnd1 and Rev3l mutant mice shows that disruption of these separate pathways converge at the facial branchiomotor nucleus, affecting either motoneuron migration or proliferation. The finding that PLXND1 and REV3L mutations are responsible for a proportion of MBS patients suggests that de novo mutations in other genes might account for other MBS patients., Fundacion Seneca fellowship; EMBO short-term fellowship; IBRO Project InEurope grants programme; Fundacion Cultural Privada Esteban-Romero; European Union FP7 Large-Scale Integrating Project Genetic and Epigenetic Networks in Cognitive Dysfunction; Scientific and Technological Research Council of Turkey (TÜBİTAK); CRANIRARE consortia of the European Research Area Network (E-RARE); Italian Association of Mobius Syndrome (AISMO); Dutch Cancer Society; Netherlands Organization for Health Research and Development

Published
2015

28. Deletions and loss-of-function variants in TP63associated with orofacial clefting

Author

Khandelwal, Kriti D., van den Boogaard, Marie-José H., Mehrem, Sarah L., Gebel, Jakob, Fagerberg, Christina, van Beusekom, Ellen, van Binsbergen, Ellen, Topaloglu, Ozan, Steehouwer, Marloes, Gilissen, Christian, Ishorst, Nina, van Rooij, Iris A. L. M., Roeleveld, Nel, Christensen, Kaare, Schoenaers, Joseph, Bergé, Stefaan, Murray, Jeffrey C., Hens, Greet, Devriendt, Koen, Ludwig, Kerstin U., Mangold, Elisabeth, Hoischen, Alexander, Zhou, Huiqing, Dötsch, Volker, Carels, Carine E. L., and van Bokhoven, Hans

Abstract

We aimed to identify novel deletions and variants of TP63associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected.

Published
2019
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29. De novo mutations in PLXND1 and REV3L cause Möbius syndrome

Author

Tomas-Roca, Laura, primary, Tsaalbi-Shtylik, Anastasia, additional, Jansen, Jacob G., additional, Singh, Manvendra K., additional, Epstein, Jonathan A., additional, Altunoglu, Umut, additional, Verzijl, Harriette, additional, Soria, Laura, additional, van Beusekom, Ellen, additional, Roscioli, Tony, additional, Iqbal, Zafar, additional, Gilissen, Christian, additional, Hoischen, Alexander, additional, de Brouwer, Arjan P. M., additional, Erasmus, Corrie, additional, Schubert, Dirk, additional, Brunner, Han, additional, Pérez Aytés, Antonio, additional, Marin, Faustino, additional, Aroca, Pilar, additional, Kayserili, Hülya, additional, Carta, Arturo, additional, de Wind, Niels, additional, Padberg, George W., additional, and van Bokhoven, Hans, additional

Published
2015
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30. Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of α-dystroglycan

Author

Roscioli, Tony, primary, Kamsteeg, Erik-Jan, additional, Buysse, Karen, additional, Maystadt, Isabelle, additional, van Reeuwijk, Jeroen, additional, van den Elzen, Christa, additional, van Beusekom, Ellen, additional, Riemersma, Moniek, additional, Pfundt, Rolph, additional, Vissers, Lisenka E L M, additional, Schraders, Margit, additional, Altunoglu, Umut, additional, Buckley, Michael F, additional, Brunner, Han G, additional, Grisart, Bernard, additional, Zhou, Huiqing, additional, Veltman, Joris A, additional, Gilissen, Christian, additional, Mancini, Grazia M S, additional, Delrée, Paul, additional, Willemsen, Michèl A, additional, Ramadža, Danijela Petković, additional, Chitayat, David, additional, Bennett, Christopher, additional, Sheridan, Eamonn, additional, Peeters, Els A J, additional, Tan-Sindhunata, Gita M B, additional, de Die-Smulders, Christine E, additional, Devriendt, Koenraad, additional, Kayserili, Hülya, additional, El-Hashash, Osama Abd El-Fattah, additional, Stemple, Derek L, additional, Lefeber, Dirk J, additional, Lin, Yung-Yao, additional, and van Bokhoven, Hans, additional

Published
2012
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31. Novel mutations in LRP6highlight the role of WNT signaling in tooth agenesis

Author

Ockeloen, Charlotte W., Khandelwal, Kriti D., Dreesen, Karoline, Ludwig, Kerstin U., Sullivan, Robert, van Rooij, Iris A.L.M., Thonissen, Michelle, Swinnen, Steven, Phan, Milien, Conte, Federica, Ishorst, Nina, Gilissen, Christian, Roa Fuentes, Laury, van de Vorst, Maartje, Henkes, Arjen, Steehouwer, Marloes, van Beusekom, Ellen, Bloemen, Marjon, Vankeirsbilck, Bruno, Bergé, Stefaan, Hens, Greet, Schoenaers, Joseph, Vander Poorten, Vincent, Roosenboom, Jasmien, Verdonck, An, Devriendt, Koen, Roeleveldt, Nel, Jhangiani, Shalini N., Vissers, Lisenka E.L.M., Lupski, James R., de Ligt, Joep, Von den Hoff, Johannes W., Pfundt, Rolph, Brunner, Han G., Zhou, Huiqing, Dixon, Jill, Mangold, Elisabeth, van Bokhoven, Hans, Dixon, Michael J., Kleefstra, Tjitske, Hoischen, Alexander, and Carels, Carine E.L.

Abstract

We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients.

Published
2016
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32. Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice

Author

Rainger, Joe, primary, van Beusekom, Ellen, additional, Ramsay, Jacqueline K., additional, McKie, Lisa, additional, Al-Gazali, Lihadh, additional, Pallotta, Rosanna, additional, Saponari, Anita, additional, Branney, Peter, additional, Fisher, Malcolm, additional, Morrison, Harris, additional, Bicknell, Louise, additional, Gautier, Philippe, additional, Perry, Paul, additional, Sokhi, Kishan, additional, Sexton, David, additional, Bardakjian, Tanya M., additional, Schneider, Adele S., additional, Elcioglu, Nursel, additional, Ozkinay, Ferda, additional, Koenig, Rainer, additional, Mégarbané, Andre, additional, Semerci, C. Nur, additional, Khan, Ayesha, additional, Zafar, Saemah, additional, Hennekam, Raoul, additional, Sousa, Sérgio B., additional, Ramos, Lina, additional, Garavelli, Livia, additional, Furga, Andrea Superti, additional, Wischmeijer, Anita, additional, Jackson, Ian J., additional, Gillessen-Kaesbach, Gabriele, additional, Brunner, Han G., additional, Wieczorek, Dagmar, additional, van Bokhoven, Hans, additional, and FitzPatrick, David R., additional

Published
2011
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36. Mutations in the O-Mannosyltransferase Gene POMT1 Give Rise to the Severe Neuronal Migration Disorder Walker-Warburg Syndrome

Author

Beltrán-Valero de Bernabé, Daniel, primary, Currier, Sophie, additional, Steinbrecher, Alice, additional, Celli, Jacopo, additional, van Beusekom, Ellen, additional, van der Zwaag, Bert, additional, Kayserili, Hülya, additional, Merlini, Luciano, additional, Chitayat, David, additional, Dobyns, William B., additional, Cormand, Bru, additional, Lehesjoki, Ana-Elina, additional, Cruces, Jesús, additional, Voit, Thomas, additional, Walsh, Christopher A., additional, van Bokhoven, Hans, additional, and Brunner, Han G., additional

Published
2002
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38. Mutations in ISPD cause Walker-Warburg syndrome and defective glycosylation of ?-dystroglycan.

Author

Roscioli, Tony, Kamsteeg, Erik-Jan, Buysse, Karen, Maystadt, Isabelle, van Reeuwijk, Jeroen, van den Elzen, Christa, van Beusekom, Ellen, Riemersma, Moniek, Pfundt, Rolph, Vissers, Lisenka E L M, Schraders, Margit, Altunoglu, Umut, Buckley, Michael F, Brunner, Han G, Grisart, Bernard, Zhou, Huiqing, Veltman, Joris A, Gilissen, Christian, Mancini, Grazia M S, and Delrée, Paul

Subjects
MULTIPLE organ failure, EYE abnormalities, BRAIN abnormalities, MUSCULAR dystrophy, GLYCOSYLATION, DYSTROGLYCAN, GLYCOSYLTRANSFERASES, HYDROCEPHALUS
Abstract

Walker-Warburg syndrome (WWS) is an autosomal recessive multisystem disorder characterized by complex eye and brain abnormalities with congenital muscular dystrophy (CMD) and aberrant ?-dystroglycan glycosylation. Here we report mutations in the ISPD gene (encoding isoprenoid synthase domain containing) as the second most common cause of WWS. Bacterial IspD is a nucleotidyl transferase belonging to a large glycosyltransferase family, but the role of the orthologous protein in chordates is obscure to date, as this phylum does not have the corresponding non-mevalonate isoprenoid biosynthesis pathway. Knockdown of ispd in zebrafish recapitulates the human WWS phenotype with hydrocephalus, reduced eye size, muscle degeneration and hypoglycosylated ?-dystroglycan. These results implicate ISPD in ?-dystroglycan glycosylation in maintaining sarcolemma integrity in vertebrates. [ABSTRACT FROM AUTHOR]

Published
2012
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39. A Pro51Ser mutation in the COCH gene is associated with late onset autosomal dominant progressive sensorineural hearing loss with vestibular defects.

Author

de Kok, Yvette J. M., Bom, Steven J. H., Brunt, Tibor M., Kemperman, Martijn H., van Beusekom, Ellen, van der Velde-Visser, Saskia D., Robertson, Nahid G., Morton, Cynthia C., Huygen, Patrick L. M., Verhagen, Wim I. M., Brunner, Han G., Cremers, Cor W. R. J., and Cremers, Frans P. M.

Abstract

We analysed a Dutch family with autosomal dominant non-syndromic progressive sensorineural hearing loss and mapped the underlying gene defect by genetic linkage analysis to a 11.0 cM region overlapping the DFNA9 interval on chromosome 14q12-q13. Clinically, the Dutch family differs from the original DFNA9 family by a later age at onset and a more clearly established vestibular impairment. A gene that is highly and specifically expressed in the human fetal cochlea and vestibule, COCH (previously described as Coch5B2), was mapped to the DFNA9 critical region. Sequence analysis revealed a 208C→T mutation in the COCH gene, resulting in a Pro51Ser substitution in the predicted protein in all affected individuals of the family but not in unaffected family members and 200 control individuals. The same mutation was also identified in three apparently unrelated families with a similar pheno-type, suggesting the presence of a Dutch founder mutation. The function of COCH is unknown but several characteristics of the protein point to a structural role in the extracellular matrix. The mutant serine at position 51 is situated between cysteines and possibly interferes with proper COCH protein folding or its interaction with extracellular matrix proteins. [ABSTRACT FROM AUTHOR]

Published
1999
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40. De novo mutations in PLXND1 and REV3L cause Möbius syndrome

Author

Tony Roscioli, Arturo Carta, Jacob G. Jansen, Han G. Brunner, Christian Gilissen, Dirk Schubert, Zafar Iqbal, Manvendra K. Singh, Harriëtte T.F.M. Verzijl, Antonio Perez Aytes, Hülya Kayserili, George W. Padberg, Arjan P.M. de Brouwer, Faustino Marín, Pilar Aroca, Corrie E. Erasmus, Hans van Bokhoven, Umut Altunoglu, Laura Soria, Jonathan A. Epstein, Anastasia Tsaalbi-Shtylik, Ellen van Beusekom, Niels de Wind, Alexander Hoischen, Laura Tomás-Roca, Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB,The Netherlands., Department of Human Anatomy and Psychobiology, School of Medicine, University of Murcia, 30100 Espinardo (Murcia), Spain., Department of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands., Department of Cell andDevelopmental Biology, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, 9-105 SCTR, 3400 Civic Center Boulevard,Philadelphia, Pennsylvania 19104, USA, Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical SchoolSingapore, National Heart Center Singapore, 8 College Road, Singapore 169857, Singapore, Medical Genetics Department, Istanbul Medical Faculty,Istanbul University, Millet Caddesi, Capa, Fatih 34093, Turkey., Department of Neurology, Radboud University Medical Center, Donders Institute for Brain,Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands., The Kinghorn Centre for Clinical Genomics, Garvan Institute of MedicalResearch, Sydney, New South Wales 2010, Australia, Department of Human Genetics, Radboud University Medical Center, Radboud Institute for MolecularLife Sciences (RIMLS), PO Box 9101, Nijmegen 6500 HB, The Netherlands., Department of Cognitive Neuroscience, Radboud University Medical Center,Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands, Department of Clinical Genetics, MaastrichtUniversity Medical Center, PO Box 5800, Maastricht 6200AZ, The Netherlands., Dysmorphology and Reproductive Genetics Unit, Moebius SyndromeFoundation of Spain, University Hospital LA FE, Valencia 46540, Spain., Ophthalmology Unit, Department of Biomedical, Biotechnological and TranslationalSciences (S.Bi.Bi.T.), University of Parma, via Gramsci 14, 43126, Parma, Italy, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Tomas-Roca, Laura, Tsaalbi-Shtylik, Anastasia, Jansen, Jacob G., Singh, Manvendra K., Epstein, Jonathan A., Altunoglu, Umut, Verzijl, Harriette, Soria, Laura, van Beusekom, Ellen, Roscioli, Tony, Iqbal, Zafar, Gilissen, Christian, Hoischen, Alexander, de Brouwer,Arjan P. M., Erasmus, Corrie, Schubert, Dirk, Brunner, Han, Aytes, Antonio Perez, Marin, Faustino, Aroca, Pilar, Carta, Arturo, de Wind, Niels, Padberg, George W., van Bokhoven, Hans, School of Medicine, and Department of Medical Genetics

Subjects
Möbius syndrome, REV3L, Heterozygote, animal structures, DNA damage, Cell Adhesion Molecules, Neuronal, Moebius syndrome, Dna-damage, Vascular etiology, Syndrome variant, Dutch family, Gene, Sequence, Humans, Cells, Mechanisms, Neurophysiology, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], General Physics and Astronomy, Hindbrain, DNA-Directed DNA Polymerase, Biology, medicine.disease_cause, General Biochemistry, Genetics and Molecular Biology, Article, Mice, medicine, Animals, Exome, PLXND1, Genetics, Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Multidisciplinary, Membrane Glycoproteins, Intracellular Signaling Peptides and Proteins, Heterozygote advantage, General Chemistry, medicine.disease, Mice, Mutant Strains, Mobius Syndrome, DNA-Binding Proteins, Mobius syndrome, Multidisciplinary sciences, Molecular biology and genetics, 5 - Ciencias puras y naturales [CDU], DNA Damage
Abstract

Mobius syndrome (MBS) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies. The aetiology of this syndrome has been enigmatic since the initial descriptions by von Graefe in 1880 and by Mobius in 1888, and it has been debated for decades whether MBS has a genetic or a non-genetic aetiology. Here, we report de novo mutations affecting two genes, PLXND1 and REV3L in MBS patients. PLXND1 and REV3L represent totally unrelated pathways involved in hindbrain development: neural migration and DNA translesion synthesis, essential for the replication of endogenously damaged DNA, respectively. Interestingly, analysis of Plxnd1 and Rev3l mutant mice shows that disruption of these separate pathways converge at the facial branchiomotor nucleus, affecting either motoneuron migration or proliferation. The finding that PLXND1 and REV3L mutations are responsible for a proportion of MBS patients suggests that de novo mutations in other genes might account for other MBS patients., Fundacion Seneca fellowship; EMBO short-term fellowship; IBRO Project InEurope grants programme; Fundacion Cultural Privada Esteban-Romero; European Union FP7 Large-Scale Integrating Project Genetic and Epigenetic Networks in Cognitive Dysfunction; Scientific and Technological Research Council of Turkey (TÜBİTAK); CRANIRARE consortia of the European Research Area Network (E-RARE); Italian Association of Mobius Syndrome (AISMO); Dutch Cancer Society; Netherlands Organization for Health Research and Development

Published
2015

41. Loss of the BMP Antagonist, SMOC-1, Causes Ophthalmo-Acromelic (Waardenburg Anophthalmia) Syndrome in Humans and Mice

Author

Kishan Sokhi, Jacqueline Ramsay, Tanya Bardakjian, Adele Schneider, Nursel Elcioglu, Raoul C.M. Hennekam, C. Nur Semerci, Ferda Ozkinay, Joe Rainger, David Sexton, Andrea Superti Furga, Anita Saponari, Lina Ramos, Ellen van Beusekom, Malcolm E. Fisher, Gabriele Gillessen-Kaesbach, Anita Wischmeijer, Ian J. Jackson, Sérgio B. Sousa, Hans van Bokhoven, Rainer Koenig, Lihadh Al-Gazali, Paul Perry, Peter Branney, Louise S. Bicknell, Harris Morrison, Livia Garavelli, Dagmar Wieczorek, André Mégarbané, Rosanna Pallotta, Han G. Brunner, Lisa McKie, Saemah Nuzhat Zafar, Philippe Gautier, Ayesha Khan, David R. FitzPatrick, ANS - Amsterdam Neuroscience, APH - Amsterdam Public Health, Paediatrics, Ege Üniversitesi, Rainger, Joe, van Beusekom, Ellen, Ramsay, Jacqueline K., McKie, Lisa, Al-Gazali, Lihadh, Pallotta, Rosanna, Saponari, Anita, Branney, Peter, Fisher, Malcolm, Morrison, Harris, Bicknell, Louise, Gautier, Philippe, Perry, Paul, Sokhi, Kishan, Sexton, David, Bardakjian, Tanya M., Schneider, Adele S., Elcioglu, Nursel, Ozkinay, Ferda, Koenig, Rainer, Megarbane, Andre, Semerci, C. Nur, Khan, Ayesha, Zafar, Saemah, Hennekam, Raoul, Sousa, Sergio B., Ramos, Lina, Garavelli, Livia, Furga, Andrea Superti, Wischmeijer, Anita, Jackson, Ian J., Gillessen-Kaesbach, Gabriele, Brunner, Han G., Wieczorek, Dagmar, van Bokhoven, Hans, FitzPatrick, David R., and Faculteit der Geneeskunde

Subjects
ANOMALIES, DNA Mutational Analysis, PROTEIN, anophthalmia, gene targeting, Bone Morphogenetic Protein 1, hindlimb, Mice, Xenopus laevis, genetic linkage, BINDING, genetics, Waardenburg's Syndrome, Waardenburg Syndrome, clinical article, C57BL mouse, adult, Mus, microsatellite marker, DEFECTS, gene expression regulation, Disease gene identification, BMP1 protein, human, Pedigree, Medicine, down regulation, mutational analysis, drug antagonism, medicine.medical_specialty, SMOC1 protein, human, embryo, Bone morphogenetic protein, animal tissue, loss of function mutation, Smoc1 gene, Genetics, Humans, human, Biology, Molecular Biology, Waardenburg syndrome, mouse, Ecology, Evolution, Behavior and Systematics, MUTATIONS, animal model, Correction, SMOC-1 protein, mouse, school child, medicine.disease, Mice, Inbred C57BL, Human Reproduction [NCEBP 12], gene function, Endocrinology, decapentaplegic protein, Genetics and epigenetic pathways of disease Functional Neurogenomics [NCMLS 6], Mutation, Cancer Research, frameshift mutation, Medizin, nonsense mutation, Gene Expression, mouse mutant, Eye, Bmp1 protein, mouse, Autosomal Recessive, bone morphogenetic protein, Missense mutation, animal, Osteonectin, SPECIFICATION, Genetics (clinical), RECESSIVE ANOPHTHALMIA, limb, cleft palate, Mice, Knockout, child, Coloboma, ABNORMALITIES, messenger RNA, article, pedigree, female, Mammalia, Models, Animal, Drosophila, Research Article, gene locus, lcsh:QH426-470, Nonsense mutation, procollagen C proteinase, male, ddc:570, Internal medicine, medicine, Animalia, Animals, gene, SMOC 1 protein, mouse, gene identification, growth, development and aging, Clinical Genetics, Phenocopy, nonhuman, Anophthalmia, missense mutation, syndactyly, Anophthalmos, nucleotide sequence, Human Genetics, Extremities, infant, lcsh:Genetics, XENOPUS, CELL-DEATH, adolescent, Genetics of Disease, Syndactyly, homozygosity, Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6], metabolism, Animal Genetics
Abstract

WOS: 000293338600004, PubMed ID: 21750680, Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site-and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc(1tm1a)) that reduces mRNA to similar to 10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc(1tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc(1tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice., Medical Research Council (UK)Medical Research Council UK (MRC); Medical Research CouncilMedical Research Council UK (MRC) [MC_U127561093, MC_PC_U127561112, MC_U127561112], Funding for this project was provided as an intramural program grant from the Medical Research Council (UK). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Published
2011

42. A complex structural variant near SOX3 causes X-linked split-hand/foot malformation.

Author

de Boer E, Marcelis C, Neveling K, van Beusekom E, Hoischen A, Klein WM, de Leeuw N, Mantere T, Melo US, van Reeuwijk J, Smeets D, Spielmann M, Kleefstra T, van Bokhoven H, and Vissers LELM

Subjects
Humans, In Situ Hybridization, Fluorescence, Genetic Loci, SOXB1 Transcription Factors genetics, Limb Deformities, Congenital genetics
Abstract

Split-hand/foot malformation (SHFM) is a congenital limb defect most typically presenting with median clefts in hands and/or feet, that can occur in a syndromic context as well as in isolated form. SHFM is caused by failure to maintain normal apical ectodermal ridge function during limb development. Although several genes and contiguous gene syndromes are implicated in the monogenic etiology of isolated SHFM, the disorder remains genetically unexplained for many families and associated genetic loci. We describe a family with isolated X-linked SHFM, for which the causative variant could be detected after a diagnostic journey of 20 years. We combined well-established approaches including microarray-based copy number variant analysis and fluorescence in situ hybridization coupled with optical genome mapping and whole genome sequencing. This strategy identified a complex structural variant (SV) comprising a 165-kb gain of 15q26.3 material ([GRCh37/hg19] chr15:99795320-99960362dup) inserted in inverted position at the site of a 38-kb deletion on Xq27.1 ([GRCh37/hg19] chrX:139481061-139518989del). In silico analysis suggested that the SV disrupts the regulatory framework on the X chromosome and may lead to SOX3 misexpression. We hypothesize that SOX3 dysregulation in the developing limb disturbed the fine balance between morphogens required for maintaining AER function, resulting in SHFM in this family., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Published
2023
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