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2. Creativity in Mathematics Performance: The Role of Divergent and Convergent Thinking

Author

de Vink, Isabelle C., Willemsen, Robin H., Lazonder, Ard. W., and Kroesbergen, Evelyn H.

Abstract

Background: Creativity requires both divergent and convergent thinking. Previous research established that "divergent" thinking relates to mathematics performance, but generally ignored the role of "convergent" thinking and, hence, leaves it unclear how both might interact when children work on mathematical tasks. This study addressed this paucity in the research literature, with the goal of improving our understanding of the role of creative thinking in primary school mathematics. Aims: This study examined how divergent and convergent thinking contribute to mathematics performance, both directly and jointly, on single- and multiple-solution tasks. Sample: The study was conducted with 229 Dutch fifth graders of 12 primary schools. Method: Divergent and convergent thinking were measured with a visual and verbal task. Path analysis was used including verbal and visual divergent and convergent thinking tasks in relation to single- and multiple-solution mathematics task performance. Working memory was included as a covariate. Results: Verbal convergent thinking positively predicted single- and multiple-solution task performance. Verbal divergent and convergent thinking interacted in relation to single-solution task performance, while visual divergent and convergent thinking interacted in relation to multiple-solution task performance. Conclusions: Children's mathematics performance mainly relies on convergent thinking. The role of divergent thinking is twofold: it complements convergent thinking on multiple-solution tasks and compensates convergent thinking on single-solution tasks.

Published
2022
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4. Functional and clinical studies reveal pathophysiological complexity of CLCN4-related neurodevelopmental condition

Author

Palmer, Elizabeth E., Pusch, Michael, Picollo, Alessandra, Forwood, Caitlin, Nguyen, Matthew H., Suckow, Vanessa, Gibbons, Jessica, Hoff, Alva, Sigfrid, Lisa, Megarbane, Andre, Nizon, Mathilde, Cogné, Benjamin, Beneteau, Claire, Alkuraya, Fowzan S., Chedrawi, Aziza, Hashem, Mais O., Stamberger, Hannah, Weckhuysen, Sarah, Vanlander, Arnaud, Ceulemans, Berten, Rajagopalan, Sulekha, Nunn, Kenneth, Arpin, Stéphanie, Raynaud, Martine, Motter, Constance S., Ward-Melver, Catherine, Janssens, Katrien, Meuwissen, Marije, Beysen, Diane, Dikow, Nicola, Grimmel, Mona, Haack, Tobias B., Clement, Emma, McTague, Amy, Hunt, David, Townshend, Sharron, Ward, Michelle, Richards, Linda J., Simons, Cas, Costain, Gregory, Dupuis, Lucie, Mendoza-Londono, Roberto, Dudding-Byth, Tracy, Boyle, Jackie, Saunders, Carol, Fleming, Emily, El Chehadeh, Salima, Spitz, Marie-Aude, Piton, Amelie, Gerard, Bénédicte, Abi Warde, Marie-Thérèse, Rea, Gillian, McKenna, Caoimhe, Douzgou, Sofia, Banka, Siddharth, Akman, Cigdem, Bain, Jennifer M., Sands, Tristan T., Wilson, Golder N., Silvertooth, Erin J., Miller, Lauren, Lederer, Damien, Sachdev, Rani, Macintosh, Rebecca, Monestier, Olivier, Karadurmus, Deniz, Collins, Felicity, Carter, Melissa, Rohena, Luis, Willemsen, Marjolein H., Ockeloen, Charlotte W., Pfundt, Rolph, Kroft, Sanne D., Field, Michael, Laranjeira, Francisco E. R., Fortuna, Ana M., Soares, Ana R., Michaud, Vincent, Naudion, Sophie, Golla, Sailaja, Weaver, David D., Bird, Lynne M., Friedman, Jennifer, Clowes, Virginia, Joss, Shelagh, Pölsler, Laura, Campeau, Philippe M., Blazo, Maria, Bijlsma, Emilia K., Rosenfeld, Jill A., Beetz, Christian, Powis, Zöe, McWalter, Kirsty, Brandt, Tracy, Torti, Erin, Mathot, Mikaël, Mohammad, Shekeeb S., Armstrong, Ruth, and Kalscheuer, Vera M.

Published
2023
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5. The Structure of Creativity in Primary Education: An Empirical Confirmation of the Amusement Park Theory

Author

Willemsen, Robin H., Schoevers, Eveline M., and Kroesbergen, Evelyn H.

Abstract

In this study, we explored the structure of pupils' creativity in primary education following the Amusement Park Theory, by investigating undiscovered linkages between the domains of writing, mathematics, and drawing. More specifically, we examined: (a) whether some domains and general thematic areas are more closely related to each other than to others, (b) whether literacy and mathematical ability are specific underlying traits of creativity in writing and mathematics, respectively, and (c) whether intelligence and divergent thinking are related to creativity in all domains. The sample consisted of 331 Dutch 4th grade pupils. For each research question, a model was analyzed using structural equation modeling. We found creativity in mathematics and creativity in writing to be most similar, followed by creativity in mathematics and creativity in drawing, with creativity in writing and creativity in drawing being least similar. Additionally, we found evidence for several underlying traits (i.e., literacy ability and mathematical ability) and initial requirements of creativity (i.e., intelligence and divergent thinking), none of which were important for creativity in only one domain, and of which only intelligence was important for creativity in all domains. Herewith, our study provides insights regarding the complexity of the structure of creativity in primary education.

Published
2020
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7. The effect of finger spreading on drag of the hand in human swimming

Author

van Houwelingen, Josje, Willemsen, Dennis H. J., Kunnen, Rudie P. J., van Heijst, GertJan F., Grift, Ernst Jan, Breugem, Wim Paul, Delfos, Rene, Westerweel, Jerry, Clercx, Herman J. H., and van de Water, Willem

Subjects
Physics - Fluid Dynamics
Abstract

The effect of finger spreading on hydrodynamic drag in swimming is studied both with a numerical simulation and with laboratory experiments. Both approaches are based on the exact same 3D model of the hand with attached forearm. The virtual version of the hand with forearm was implemented in a numerical code by means of an immersed boundary method and the physical version was studied in a wind tunnel experiment. An enhancement of the drag coefficient of 2 and 5% compared to the case with closed fingers was found for the numerical simulation and experiment, respectively. A 5 and 8% favourable effect on the (dimensionless) force moment at an optimal finger spreading of 10 degrees was found, which indicates that the difference is more outspoken in the force moment. Also an analytical model is proposed, using scaling arguments similar to the Betz actuator disk model, to explain the drag coefficient as a function of finger spacing.

Published
2016

8. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Author

Kanoni, Stavroula, Graham, Sarah E., Wang, Yuxuan, Surakka, Ida, Ramdas, Shweta, Zhu, Xiang, Clarke, Shoa L., Bhatti, Konain Fatima, Vedantam, Sailaja, Winkler, Thomas W., Locke, Adam E., Marouli, Eirini, Zajac, Greg J. M., Wu, Kuan-Han H., Ntalla, Ioanna, Hui, Qin, Klarin, Derek, Hilliard, Austin T., Wang, Zeyuan, Xue, Chao, Thorleifsson, Gudmar, Helgadottir, Anna, Gudbjartsson, Daniel F., Holm, Hilma, Olafsson, Isleifur, Hwang, Mi Yeong, Han, Sohee, Akiyama, Masato, Sakaue, Saori, Terao, Chikashi, Kanai, Masahiro, Zhou, Wei, Brumpton, Ben M., Rasheed, Humaira, Havulinna, Aki S., Veturi, Yogasudha, Pacheco, Jennifer Allen, Rosenthal, Elisabeth A., Lingren, Todd, Feng, QiPing, Kullo, Iftikhar J., Narita, Akira, Takayama, Jun, Martin, Hilary C., Hunt, Karen A., Trivedi, Bhavi, Haessler, Jeffrey, Giulianini, Franco, Bradford, Yuki, Miller, Jason E., Campbell, Archie, Lin, Kuang, Millwood, Iona Y., Rasheed, Asif, Hindy, George, Faul, Jessica D., Zhao, Wei, Weir, David R., Turman, Constance, Huang, Hongyan, Graff, Mariaelisa, Choudhury, Ananyo, Sengupta, Dhriti, Mahajan, Anubha, Brown, Michael R., Zhang, Weihua, Yu, Ketian, Schmidt, Ellen M., Pandit, Anita, Gustafsson, Stefan, Yin, Xianyong, Luan, Jian’an, Zhao, Jing-Hua, Matsuda, Fumihiko, Jang, Hye-Mi, Yoon, Kyungheon, Medina-Gomez, Carolina, Pitsillides, Achilleas, Hottenga, Jouke Jan, Wood, Andrew R., Ji, Yingji, Gao, Zishan, Haworth, Simon, Yousri, Noha A., Mitchell, Ruth E., Chai, Jin Fang, Aadahl, Mette, Bjerregaard, Anne A., Yao, Jie, Manichaikul, Ani, Hwu, Chii-Min, Hung, Yi-Jen, Warren, Helen R., Ramirez, Julia, Bork-Jensen, Jette, Kårhus, Line L., Goel, Anuj, Sabater-Lleal, Maria, Noordam, Raymond, Mauro, Pala, Matteo, Floris, McDaid, Aaron F., Marques-Vidal, Pedro, Wielscher, Matthias, Trompet, Stella, Sattar, Naveed, Møllehave, Line T., Munz, Matthias, Zeng, Lingyao, Huang, Jianfeng, Yang, Bin, Poveda, Alaitz, Kurbasic, Azra, Lamina, Claudia, Forer, Lukas, Scholz, Markus, Galesloot, Tessel E., Bradfield, Jonathan P., Ruotsalainen, Sanni E., Daw, EWarwick, Zmuda, Joseph M., Mitchell, Jonathan S., Fuchsberger, Christian, Christensen, Henry, Brody, Jennifer A., Vazquez-Moreno, Miguel, Feitosa, Mary F., Wojczynski, Mary K., Wang, Zhe, Preuss, Michael H., Mangino, Massimo, Christofidou, Paraskevi, Verweij, Niek, Benjamins, Jan W., Engmann, Jorgen, Tsao, Noah L., Verma, Anurag, Slieker, Roderick C., Lo, Ken Sin, Zilhao, Nuno R., Le, Phuong, Kleber, Marcus E., Delgado, Graciela E., Huo, Shaofeng, Ikeda, Daisuke D., Iha, Hiroyuki, Yang, Jian, Liu, Jun, Demirkan, Ayşe, Leonard, Hampton L., Marten, Jonathan, Frank, Mirjam, Schmidt, Börge, Smyth, Laura J., Cañadas-Garre, Marisa, Wang, Chaolong, Nakatochi, Masahiro, Wong, Andrew, Hutri-Kähönen, Nina, Sim, Xueling, Xia, Rui, Huerta-Chagoya, Alicia, Fernandez-Lopez, Juan Carlos, Lyssenko, Valeriya, Nongmaithem, Suraj S., Bayyana, Swati, Stringham, Heather M., Irvin, Marguerite R., Oldmeadow, Christopher, Kim, Han-Na, Ryu, Seungho, Timmers, Paul R. H. J., Arbeeva, Liubov, Dorajoo, Rajkumar, Lange, Leslie A., Prasad, Gauri, Lorés-Motta, Laura, Pauper, Marc, Long, Jirong, Li, Xiaohui, Theusch, Elizabeth, Takeuchi, Fumihiko, Spracklen, Cassandra N., Loukola, Anu, Bollepalli, Sailalitha, Warner, Sophie C., Wang, Ya Xing, Wei, Wen B., Nutile, Teresa, Ruggiero, Daniela, Sung, Yun Ju, Chen, Shufeng, Liu, Fangchao, Yang, Jingyun, Kentistou, Katherine A., Banas, Bernhard, Nardone, Giuseppe Giovanni, Meidtner, Karina, Bielak, Lawrence F., Smith, Jennifer A., Hebbar, Prashantha, Farmaki, Aliki-Eleni, Hofer, Edith, Lin, Maoxuan, Concas, Maria Pina, Vaccargiu, Simona, van der Most, Peter J., Pitkänen, Niina, Cade, Brian E., van der Laan, Sander W., Chitrala, Kumaraswamy Naidu, Weiss, Stefan, Bentley, Amy R., Doumatey, Ayo P., Adeyemo, Adebowale A., Lee, Jong Young, Petersen, Eva R. B., Nielsen, Aneta A., Choi, Hyeok Sun, Nethander, Maria, Freitag-Wolf, Sandra, Southam, Lorraine, Rayner, Nigel W., Wang, Carol A., Lin, Shih-Yi, Wang, Jun-Sing, Couture, Christian, Lyytikäinen, Leo-Pekka, Nikus, Kjell, Cuellar-Partida, Gabriel, Vestergaard, Henrik, Hidalgo, Bertha, Giannakopoulou, Olga, Cai, Qiuyin, Obura, Morgan O., van Setten, Jessica, Li, Xiaoyin, Liang, Jingjing, Tang, Hua, Terzikhan, Natalie, Shin, Jae Hun, Jackson, Rebecca D., Reiner, Alexander P., Martin, Lisa Warsinger, Chen, Zhengming, Li, Liming, Kawaguchi, Takahisa, Thiery, Joachim, Bis, Joshua C., Launer, Lenore J., Li, Huaixing, Nalls, Mike A., Raitakari, Olli T., Ichihara, Sahoko, Wild, Sarah H., Nelson, Christopher P., Campbell, Harry, Jäger, Susanne, Nabika, Toru, Al-Mulla, Fahd, Niinikoski, Harri, Braund, Peter S., Kolcic, Ivana, Kovacs, Peter, Giardoglou, Tota, Katsuya, Tomohiro, de Kleijn, Dominique, de Borst, Gert J., Kim, Eung Kweon, Adams, Hieab H. H., Ikram, M. Arfan, Zhu, Xiaofeng, Asselbergs, Folkert W., Kraaijeveld, Adriaan O., Beulens, Joline W. J., Shu, Xiao-Ou, Rallidis, Loukianos S., Pedersen, Oluf, Hansen, Torben, Mitchell, Paul, Hewitt, Alex W., Kähönen, Mika, Pérusse, Louis, Bouchard, Claude, Tönjes, Anke, Chen, Yii-Der Ida, Pennell, Craig E., Mori, Trevor A., Lieb, Wolfgang, Franke, Andre, Ohlsson, Claes, Mellström, Dan, Cho, Yoon Shin, Lee, Hyejin, Yuan, Jian-Min, Koh, Woon-Puay, Rhee, Sang Youl, Woo, Jeong-Taek, Heid, Iris M., Stark, Klaus J., Zimmermann, Martina E., Völzke, Henry, Homuth, Georg, Evans, Michele K., Zonderman, Alan B., Polasek, Ozren, Pasterkamp, Gerard, Hoefer, Imo E., Redline, Susan, Pahkala, Katja, Oldehinkel, Albertine J., Snieder, Harold, Biino, Ginevra, Schmidt, Reinhold, Schmidt, Helena, Bandinelli, Stefania, Dedoussis, George, Thanaraj, Thangavel Alphonse, Kardia, Sharon L. R., Peyser, Patricia A., Kato, Norihiro, Schulze, Matthias B., Girotto, Giorgia, Böger, Carsten A., Jung, Bettina, Joshi, Peter K., Bennett, David A., De Jager, Philip L., Lu, Xiangfeng, Mamakou, Vasiliki, Brown, Morris, Caulfield, Mark J., Munroe, Patricia B., Guo, Xiuqing, Ciullo, Marina, Jonas, Jost B., Samani, Nilesh J., Kaprio, Jaakko, Pajukanta, Päivi, Tusié-Luna, Teresa, Aguilar-Salinas, Carlos A., Adair, Linda S., Bechayda, Sonny Augustin, de Silva, H. Janaka, Wickremasinghe, Ananda R., Krauss, Ronald M., Wu, Jer-Yuarn, Zheng, Wei, Hollander, Anneke Iden, Bharadwaj, Dwaipayan, Correa, Adolfo, Wilson, James G., Lind, Lars, Heng, Chew-Kiat, Nelson, Amanda E., Golightly, Yvonne M., Wilson, James F., Penninx, Brenda, Kim, Hyung-Lae, Attia, John, Scott, Rodney J., Rao, D. C., Arnett, Donna K., Hunt, Steven C., Walker, Mark, Koistinen, Heikki A., Chandak, Giriraj R., Mercader, Josep M., Costanzo, Maria C., Jang, Dongkeun, Burtt, Noël P., Villalpando, Clicerio Gonzalez, Orozco, Lorena, Fornage, Myriam, Tai, EShyong, van Dam, Rob M., Lehtimäki, Terho, Chaturvedi, Nish, Yokota, Mitsuhiro, Liu, Jianjun, Reilly, Dermot F., McKnight, Amy Jayne, Kee, Frank, Jöckel, Karl-Heinz, McCarthy, Mark I., Palmer, Colin N. A., Vitart, Veronique, Hayward, Caroline, Simonsick, Eleanor, van Duijn, Cornelia M., Jin, Zi-Bing, Qu, Jia, Hishigaki, Haretsugu, Lin, Xu, März, Winfried, Gudnason, Vilmundur, Tardif, Jean-Claude, Lettre, Guillaume, Hart, Leen M.‘t, Elders, Petra J. M., Damrauer, Scott M., Kumari, Meena, Kivimaki, Mika, van der Harst, Pim, Spector, Tim D., Loos, Ruth J. F., Province, Michael A., Parra, Esteban J., Cruz, Miguel, Psaty, Bruce M., Brandslund, Ivan, Pramstaller, Peter P., Rotimi, Charles N., Christensen, Kaare, Ripatti, Samuli, Widén, Elisabeth, Hakonarson, Hakon, Grant, Struan F. A., Kiemeney, Lambertus A. L. M., de Graaf, Jacqueline, Loeffler, Markus, Kronenberg, Florian, Gu, Dongfeng, Erdmann, Jeanette, Schunkert, Heribert, Franks, Paul W., Linneberg, Allan, Jukema, J. Wouter, Khera, Amit V., Männikkö, Minna, Jarvelin, Marjo-Riitta, Kutalik, Zoltan, Francesco, Cucca, Mook-Kanamori, Dennis O., van Dijk, Ko Willems, Watkins, Hugh, Strachan, David P., Grarup, Niels, Sever, Peter, Poulter, Neil, Chuang, Lee-Ming, Rotter, Jerome I., Dantoft, Thomas M., Karpe, Fredrik, Neville, Matt J., Timpson, Nicholas J., Cheng, Ching-Yu, Wong, Tien-Yin, Khor, Chiea Chuen, Li, Hengtong, Sabanayagam, Charumathi, Peters, Annette, Gieger, Christian, Hattersley, Andrew T., Pedersen, Nancy L., Magnusson, Patrik K. E., Boomsma, Dorret I., Willemsen, Allegonda H. M., Cupples, LAdrienne, van Meurs, Joyce B. J., Ghanbari, Mohsen, Gordon-Larsen, Penny, Huang, Wei, Kim, Young Jin, Tabara, Yasuharu, Wareham, Nicholas J., Langenberg, Claudia, Zeggini, Eleftheria, Kuusisto, Johanna, Laakso, Markku, Ingelsson, Erik, Abecasis, Goncalo, Chambers, John C., Kooner, Jaspal S., de Vries, Paul S., Morrison, Alanna C., Hazelhurst, Scott, Ramsay, Michèle, North, Kari E., Daviglus, Martha, Kraft, Peter, Martin, Nicholas G., Whitfield, John B., Abbas, Shahid, Saleheen, Danish, Walters, Robin G., Holmes, Michael V., Black, Corri, Smith, Blair H., Baras, Aris, Justice, Anne E., Buring, Julie E., Ridker, Paul M., Chasman, Daniel I., Kooperberg, Charles, Tamiya, Gen, Yamamoto, Masayuki, van Heel, David A., Trembath, Richard C., Wei, Wei-Qi, Jarvik, Gail P., Namjou, Bahram, Hayes, M. Geoffrey, Ritchie, Marylyn D., Jousilahti, Pekka, Salomaa, Veikko, Hveem, Kristian, Åsvold, Bjørn Olav, Kubo, Michiaki, Kamatani, Yoichiro, Okada, Yukinori, Murakami, Yoshinori, Kim, Bong-Jo, Thorsteinsdottir, Unnur, Stefansson, Kari, Zhang, Jifeng, Chen, YEugene, Ho, Yuk-Lam, Lynch, Julie A., Rader, Daniel J., Tsao, Philip S., Chang, Kyong-Mi, Cho, Kelly, O’Donnell, Christopher J., Gaziano, John M., Wilson, Peter W. F., Frayling, Timothy M., Hirschhorn, Joel N., Kathiresan, Sekar, Mohlke, Karen L., Sun, Yan V., Morris, Andrew P., Boehnke, Michael, Brown, Christopher D., Natarajan, Pradeep, Deloukas, Panos, Willer, Cristen J., Assimes, Themistocles L., and Peloso, Gina M.

Published
2022
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9. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome

Author

Kummeling, Joost, Stremmelaar, Diante E., Raun, Nicholas, Reijnders, Margot R. F., Willemsen, Marjolein H., Ruiterkamp-Versteeg, Martina, Schepens, Marga, Man, Calvin C. O., Gilissen, Christian, Cho, Megan T., McWalter, Kirsty, Sinnema, Margje, Wheless, James W., Simon, Marleen E. H., Genetti, Casie A., Casey, Alicia M., Terhal, Paulien A., van der Smagt, Jasper J., van Gassen, Koen L. I., Joset, Pascal, Bahr, Angela, Steindl, Katharina, Rauch, Anita, Keller, Elmar, Raas-Rothschild, Annick, Koolen, David A., Agrawal, Pankaj B., Hoffman, Trevor L., Powell-Hamilton, Nina N., Thiffault, Isabelle, Engleman, Kendra, Zhou, Dihong, Bodamer, Olaf, Hoefele, Julia, Riedhammer, Korbinian M., Schwaibold, Eva M. C., Tasic, Velibor, Schubert, Dirk, Top, Deniz, Pfundt, Rolph, Higgs, Martin R., Kramer, Jamie M., and Kleefstra, Tjitske

Published
2021
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10. The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant

Author

Koolen, David A, Pfundt, Rolph, Linda, Katrin, Beunders, Gea, Veenstra-Knol, Hermine E, Conta, Jessie H, Fortuna, Ana Maria, Gillessen-Kaesbach, Gabriele, Dugan, Sarah, Halbach, Sara, Abdul-Rahman, Omar A, Winesett, Heather M, Chung, Wendy K, Dalton, Marguerite, Dimova, Petia S, Mattina, Teresa, Prescott, Katrina, Zhang, Hui Z, Saal, Howard M, Hehir-Kwa, Jayne Y, Willemsen, Marjolein H, Ockeloen, Charlotte W, Jongmans, Marjolijn C, Van der Aa, Nathalie, Failla, Pinella, Barone, Concetta, Avola, Emanuela, Brooks, Alice S, Kant, Sarina G, Gerkes, Erica H, Firth, Helen V, Õunap, Katrin, Bird, Lynne M, Masser-Frye, Diane, Friedman, Jennifer R, Sokunbi, Modupe A, Dixit, Abhijit, Splitt, Miranda, Kukolich, Mary K, McGaughran, Julie, Coe, Bradley P, Flórez, Jesús, Nadif Kasri, Nael, Brunner, Han G, Thompson, Elizabeth M, Gecz, Jozef, Romano, Corrado, Eichler, Evan E, and de Vries, Bert BA

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Pediatric, Neurosciences, Congenital Structural Anomalies, Brain Disorders, Clinical Research, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Congenital, Abnormalities, Multiple, Adolescent, Adult, Child, Chromosome Deletion, Chromosomes, Human, Pair 17, Female, Humans, Intellectual Disability, Male, Middle Aged, Nuclear Proteins, Phenotype, Polymorphism, Single Nucleotide, DDD Study, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

The Koolen-de Vries syndrome (KdVS; OMIM #610443), also known as the 17q21.31 microdeletion syndrome, is a clinically heterogeneous disorder characterised by (neonatal) hypotonia, developmental delay, moderate intellectual disability, and characteristic facial dysmorphism. Expressive language development is particularly impaired compared with receptive language or motor skills. Other frequently reported features include social and friendly behaviour, epilepsy, musculoskeletal anomalies, congenital heart defects, urogenital malformations, and ectodermal anomalies. The syndrome is caused by a truncating variant in the KAT8 regulatory NSL complex unit 1 (KANSL1) gene or by a 17q21.31 microdeletion encompassing KANSL1. Herein we describe a novel cohort of 45 individuals with KdVS of whom 33 have a 17q21.31 microdeletion and 12 a single-nucleotide variant (SNV) in KANSL1 (19 males, 26 females; age range 7 months to 50 years). We provide guidance about the potential pitfalls in the laboratory testing and emphasise the challenges of KANSL1 variant calling and DNA copy number analysis in the complex 17q21.31 region. Moreover, we present detailed phenotypic information, including neuropsychological features, that contribute to the broad phenotypic spectrum of the syndrome. Comparison of the phenotype of both the microdeletion and SNV patients does not show differences of clinical importance, stressing that haploinsufficiency of KANSL1 is sufficient to cause the full KdVS phenotype.

Published
2016

12. Strengthening Creative Problem‐Solving within Upper‐Elementary Science Education.

Author

Willemsen, Robin H., de Vink, Isabelle C., Kroesbergen, Evelyn H., and Lazonder, Ard W.

Subjects
DIVERGENT thinking, SCIENCE education, SCHOOL children, PROBLEM solving, MATHEMATICAL ability, ANALYSIS of covariance
Abstract

This intervention study examined the effectiveness of instructional support tailored toward two techniques (i.e., random associations and constraint identification) to strengthen children's creative problem‐solving skills within upper‐elementary science education. Five inquiry‐based science lessons with ample opportunity for creative problem‐solving (i.e., divergent and convergent thinking) were provided. Children were assigned to a condition with instructional support (n = 107) or without (n = 134). Domain‐general and specific measures of divergent and convergent thinking were included, and reading comprehension as well as mathematical ability were taken into account. Repeated measures multivariate analyses of covariance revealed how all children improved in terms of domain‐general convergent thinking, with a larger increase for children who performed better in mathematics. This shows a promising premise for future research focusing on the domain generality of convergent thinking and for the potential of transfer across domains. No additional improvement based on instructional support was found and children did not improve in terms of divergent thinking. The constraint identification and random associations technique might not be suitable for elementary school children, yet future research is necessary to validate such claims. Meanwhile, teachers could possibly support convergent thinking by simply providing exercises for divergent and convergent thinking. [ABSTRACT FROM AUTHOR]

Published
2024
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15. De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum

Author

Kuechler, Alma, Willemsen, Marjolein H., Albrecht, Beate, Bacino, Carlos A., Bartholomew, Dennis W., van Bokhoven, Hans, van den Boogaard, Marie Jose H., Bramswig, Nuria, Büttner, Christian, Cremer, Kirsten, Czeschik, Johanna Christina, Engels, Hartmut, van Gassen, Koen, Graf, Elisabeth, van Haelst, Mieke, He, Weimin, Hogue, Jacob S., Kempers, Marlies, Koolen, David, Monroe, Glen, de Munnik, Sonja, Pastore, Matthew, Reis, André, Reuter, Miriam S., Tegay, David H., Veltman, Joris, Visser, Gepke, van Hasselt, Peter, Smeets, Eric E. J., Vissers, Lisenka, Wieland, Thomas, Wissink, Willemijn, Yntema, Helger, Zink, Alexander Michael, Strom, Tim M., Lüdecke, Hermann-Josef, Kleefstra, Tjitske, and Wieczorek, Dagmar

Published
2015
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23. Characterization of SETD1Ahaploinsufficiency in humans and Drosophiladefines a novel neurodevelopmental syndrome

Author

Kummeling, Joost, Stremmelaar, Diante E., Raun, Nicholas, Reijnders, Margot R. F., Willemsen, Marjolein H., Ruiterkamp-Versteeg, Martina, Schepens, Marga, Man, Calvin C. O., Gilissen, Christian, Cho, Megan T., McWalter, Kirsty, Sinnema, Margje, Wheless, James W., Simon, Marleen E. H., Genetti, Casie A., Casey, Alicia M., Terhal, Paulien A., van der Smagt, Jasper J., van Gassen, Koen L. I., Joset, Pascal, Bahr, Angela, Steindl, Katharina, Rauch, Anita, Keller, Elmar, Raas-Rothschild, Annick, Koolen, David A., Agrawal, Pankaj B., Hoffman, Trevor L., Powell-Hamilton, Nina N., Thiffault, Isabelle, Engleman, Kendra, Zhou, Dihong, Bodamer, Olaf, Hoefele, Julia, Riedhammer, Korbinian M., Schwaibold, Eva M. C., Tasic, Velibor, Schubert, Dirk, Top, Deniz, Pfundt, Rolph, Higgs, Martin R., Kramer, Jamie M., and Kleefstra, Tjitske

Abstract

Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1Ainvolved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1Aby investigating 15 predominantly pediatric individuals who all have de novo SETD1Avariants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient-derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as loss-of-function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1Avariants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila melanogasterSETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1Aand further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.

Published
2021
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26. The role of creative thinking in children's scientific reasoning.

Author

Willemsen, Robin H., de Vink, Isabelle C., Kroesbergen, Evelyn H., and Lazonder, Ard W.

Subjects
DIVERGENT thinking, CREATIVE thinking, MATHEMATICAL ability, RESEARCH questions, READING comprehension, PATH analysis (Statistics)
Abstract

• Convergent thinking positively predicted the construction of research questions. • Convergent thinking positively predicted evaluation of evidence. • Divergent thinking might be disadvantageous for scientific reasoning. • Reading comprehension is important for research questions and evidence evaluation. Theories advocate that creative thinking could be strengthened within the science curriculum, yet empirical evidence supporting a connection between the two remains limited. This study is one of the first to examine the predictive value of creative thinking (divergent and convergent thinking) for scientific reasoning, while taking task specificity and academic achievement into account. A path analysis based on data of 225 fifth graders revealed that verbal and visual convergent thinking positively predicted the construction of research questions and evaluation of evidence, whereas visual divergent thinking negatively predicted the construction of research questions. Mathematical ability proved of no predictive value for any of the creative thinking and scientific reasoning measures, while reading comprehension positively predicted verbal convergent thinking, the construction of research questions and evidence evaluation. This study illustrates how convergent thinking could be of particular relevance for children's scientific reasoning, and can serve as a starting point for in-depth research examining the role of creative thinking within scientific reasoning. [ABSTRACT FROM AUTHOR]

Published
2023
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29. Frequent Monitoring of C-Peptide Levels in Newly Diagnosed Type 1 Subjects Using Dried Blood Spots Collected at Home.

Author

Willemsen, Ruben H, Burling, Keith, Barker, Peter, Ackland, Fran, Dias, Renuka P, Edge, Julie, Smith, Anne, Todd, John, Lopez, Boryana, Mander, Adrian P, Guy, Catherine, and Dunger, David B

Abstract

To evaluate an approach to measure β-cell function by frequent testing of C-peptide concentrations in dried blood spots (DBSs).

Published
2018
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30. Supporting creative problem solving in primary geometry education.

Author

de Vink, Isabelle C., Willemsen, Robin H., Keijzer, Ronald, Lazonder, Ard W., and Kroesbergen, Evelyn H.

Subjects
GEOMETRY education, DIVERGENT thinking, PROBLEM solving, PRIMARY education, CREATIVE thinking, TASK analysis
Abstract

• Instructional support for creative thinking improved children's divergent thinking. • Support for divergent and convergent thinking helped children generate more ideas. • Support for divergent thinking improved originality and flexibility of these ideas. • Neither form of instructional support promoted children's convergent thinking. • Nor did it interfere with children's learning of domain-specific concepts. This intervention study aimed to identify how creative thinking can be supported in geometry education. Fifth-graders received five geometry lessons that incorporated divergent and convergent thinking. Children were assigned to a condition with either no creative thinking support (n = 60), support for divergent thinking (partial support; n = 55) or support for divergent and convergent thinking (full support; n = 59). Divergent thinking was assessed by a multiple-solution task and scored in terms of fluency, flexibility and originality. Convergent thinking was assessed by an idea evaluation task. Repeated measures MANOVA showed that different aspects of divergent thinking (i.e., fluency, flexibility and originality) benefited from different types of support. Students' fluency scores improved in the full support condition, but decreased in the other two conditions. A reverse pattern was found for flexibility and originality, which decreased in the full support condition but increased in the other conditions. No time and condition effects were found for convergent thinking. In all conditions, there was a non-significant increase in geometry scores. However, geometry performance differed between conditions, and was lower (across pretest and posttest) in the full support condition than in the no support and partial support conditions. These results provide some initial evidence that divergent thinking can be promoted in geometry education. Convergent thinking, on the other hand, might be more difficult to support effectively. As different types of support seem to affect different aspects of divergent thinking, teachers might consider adapting support to the specific task or individual needs of children. [ABSTRACT FROM AUTHOR]

Published
2023
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31. STXBP1 encephalopathy: A neurodevelopmental disorder including epilepsy.

Author

Stamberger, Hannah, Nikanorova, Marina, Willemsen, Marjolein H, Accorsi, Patrizia, Angriman, Marco, Baier, Hartmut, Benkel-Herrenbrueck, Ira, Benoit, Valérie, Budetta, Mauro, Caliebe, Almuth, Cantalupo, Gaetano, Capovilla, Giuseppe, Casara, Gianluca, Courage, Carolina, Deprez, Marie, Destrée, Anne, Dilena, Robertino, Erasmus, Corrie E, Fannemel, Madeleine, and Fjær, Roar

Published
2016
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34. STAG1mutations cause a novel cohesinopathy characterised by unspecific syndromic intellectual disability

Author

Lehalle, Daphné, Mosca-Boidron, Anne-Laure, Begtrup, Amber, Boute-Benejean, Odile, Charles, Perrine, Cho, Megan T, Clarkson, Amanda, Devinsky, Orrin, Duffourd, Yannis, Duplomb-Jego, Laurence, Géééérard, Béénééédicte, Jacquette, Aurééééélia, Kuentz, Paul, Masurel-Paulet, Alice, McDougall, Carey, Moutton, Séééééébastien, Oliviééééééé, Hilde, Park, Soo-Mi, Rauch, Anita, Revencu, Nicole, Riviéééééééère, Jean-Baptiste, Rubin, Karol, Simonic, Ingrid, Shears, Deborah J, Smol, Thomas, Taylor Tavares, Ana Lisa, Terhal, Paulien, Thevenon, Julien, Van Gassen, Koen, Vincent-Delorme, Catherine, Willemsen, Marjolein H, Wilson, Golder N, Zackai, Elaine, Zweier, Christiane, Callier, Patrick, Thauvin-Robinet, Christel, and Faivre, Laurence

Abstract

BackgroundCohesinopathies are rare neurodevelopmental disorders arising from a dysfunction in the cohesin pathway, which enables chromosome segregation and regulates gene transcription. So far, eight genes from this pathway have been reported in human disease. STAG1belongs to the STAG subunit of the core cohesin complex, along with five other subunits. This work aimed to identify the phenotype ascribed to STAG1mutations.MethodsAmong patients referred for intellectual disability (ID) in genetics departments worldwide, array-comparative genomic hybridisation (CGH), gene panel, whole-exome sequencing or whole-genome sequencing were performed following the local diagnostic standards.ResultsA mutation in STAG1was identified in 17 individuals from 16 families, 9 males and 8 females aged 2–33 years. Four individuals harboured a small microdeletion encompassing STAG1; three individuals from two families had an intragenic STAG1deletion. Six deletions were identified by array-CGH, one by whole-exome sequencing. Whole-exome sequencing found de novo heterozygous missense or frameshift STAG1variants in eight patients, a panel of genes involved in ID identified a missense and a frameshift variant in two individuals. The 17 patients shared common facial features, with wide mouth and deep-set eyes. Four individuals had mild microcephaly, seven had epilepsy.ConclusionsWe report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a STAG1deletion or point mutation. This first series reporting the phenotype ascribed to mutation in STAG1highlights the importance of data sharing in the field of rare disorders.

Published
2017
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35. Haploinsufficiency of MeCP2-interacting transcriptional co-repressor SIN3A causes mild intellectual disability by affecting the development of cortical integrity

Author

Witteveen, Josefine S, Willemsen, Marjolein H, Dombroski, Thaís C D, van Bakel, Nick H M, Nillesen, Willy M, van Hulten, Josephus A, Jansen, Eric J R, Verkaik, Dave, Veenstra-Knol, Hermine E, van Ravenswaaij-Arts, Conny M A, Wassink-Ruiter, Jolien S Klein, Vincent, Marie, David, Albert, Le Caignec, Cedric, Schieving, Jolanda, Gilissen, Christian, Foulds, Nicola, Rump, Patrick, Strom, Tim, Cremer, Kirsten, Zink, Alexander M, Engels, Hartmut, de Munnik, Sonja A, Visser, Jasper E, Brunner, Han G, Martens, Gerard J M, Pfundt, Rolph, Kleefstra, Tjitske, and Kolk, Sharon M

Abstract

Numerous genes are associated with neurodevelopmental disorders such as intellectual disability and autism spectrum disorder (ASD), but their dysfunction is often poorly characterized. Here we identified dominant mutations in the gene encoding the transcriptional repressor and MeCP2 interactor switch-insensitive 3 family member A (SIN3A; chromosome 15q24.2) in individuals who, in addition to mild intellectual disability and ASD, share striking features, including facial dysmorphisms, microcephaly and short stature. This phenotype is highly related to that of individuals with atypical 15q24 microdeletions, linking SIN3A to this microdeletion syndrome. Brain magnetic resonance imaging showed subtle abnormalities, including corpus callosum hypoplasia and ventriculomegaly. Intriguingly, in vivo functional knockdown of Sin3a led to reduced cortical neurogenesis, altered neuronal identity and aberrant corticocortical projections in the developing mouse brain. Together, our data establish that haploinsufficiency of SIN3A is associated with mild syndromic intellectual disability and that SIN3A can be considered to be a key transcriptional regulator of cortical brain development.

Published
2016
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36. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Denommé-Pichon, Anne-Sophie, Matalonga, Leslie, de Boer, Elke, Jackson, Adam, Benetti, Elisa, Banka, Siddharth, Bruel, Ange-Line, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Duffourd, Yannis, Ellwanger, Kornelia, Fallerini, Chiara, Gilissen, Christian, Graessner, Holm, Haack, Tobias B., Havlovicova, Marketa, Hoischen, Alexander, Jean-Marçais, Nolwenn, Kleefstra, Tjitske, López-Martín, Estrella, Macek, Milan, Mencarelli, Maria Antonietta, Moutton, Sébastien, Pfundt, Rolph, Pizzi, Simone, Posada, Manuel, Radio, Francesca Clementina, Renieri, Alessandra, Rooryck, Caroline, Ryba, Lukas, Safraou, Hana, Schwarz, Martin, Tartaglia, Marco, Thauvin-Robinet, Christel, Thevenon, Julien, Mau-Them, Frédéric Tran, Trimouille, Aurélien, Votypka, Pavel, de Vries, Bert B.A., Willemsen, Marjolein H., Zurek, Birte, Verloes, Alain, Philippe, Christophe, Abbott, Kristin M., Banka, Siddharth, de Boer, Elke, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Denommé-Pichon, Anne-Sophie, Faivre, Laurence, Gilissen, Christian, Haack, Tobias B., Havlovicova, Marketa, Hoischen, Alexander, Jackson, Adam, Kerstjens, Mieke, Kleefstra, Tjitske, Martín, Estrella López, Macek, Milan, Matalonga, Leslie, Maystadt, Isabelle, Morleo, Manuela, Nigro, Vicenzo, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca C., Renieri, Alessandra, Riess, Olaf, Rooryck, Caroline, Ryba, Lukas, Agathe, Jean-Madeleine de Sainte, Santen, Gijs W.E., Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Trimouille, Aurélien, Verloes, Alain, Vissers, Lisenka, Vitobello, Antonio, Votypka, Pavel, Zguro, Kristina, Boer, Elke de, Cohen, Enzo, Danis, Daniel, Denommé-Pichon, Anne-Sophie, Gao, Fei, Gilissen, Christian, Horvath, Rita, Johari, Mridul, Johanson, Lennart, Li, Shuang, Matalonga, Leslie, Morsy, Heba, Nelson, Isabelle, Paramonov, Ida, te Paske, Iris B.A.W., Robinson, Peter, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, Trimouille, Aurélien, van der Velde, Joeri K., Vandrovcova, Jana, Vitobello, Antonio, Riess, Olaf, Haack, Tobias B., Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, Hoischen, Alexander, ‘t Hoen, Peter A.C., Vissers, Lisenka E.L.M., Gilissen, Christian, Steyaert, Wouter, Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, Paske, Iris te, Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Yaldiz, Burcu, Kleefstra, Tjitske, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Töpf, Ana, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Matalonga, Leslie, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Nelson, Isabelle, Ben Yaou, Rabah, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Vandrovcova, Jana, Efthymiou, Stephanie, Morsy, Heba, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Abbott, Kristin M., Kerstjens Frederikse, Wilhemina S., Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Verloes, Alain, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, Agathe, Jean-Madeleine de Sainte, Rooryck, Caroline, Lacombe, Didier, Trimouille, Aurelien, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Osorio, Andrés Nascimento, Depienne, Christel, Roos, Andreas, Maystadt, Isabelle, Cordts, Isabell, Deschauer, Marcus, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Başak, Ayşe Nazlı, Claeys, Kristl, Boztug, Kaan, Haimel, Matthias, W.E, Gijs, Ruivenkamp, Claudia A.L., Natera de Benito, Daniel, Lochmüller, Hanns, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Balicza, Peter, Molnar, Maria Judit, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, Alonso García de la Rosa, F. Javier, Schröck, Evelin, Rump, Andreas, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Horvath, Rita, Chinnery, Patrick F., Ratnaike, Thiloka, Gao, Fei, Schon, Katherine, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, May, Patrick, Beeson, David, Cossins, Judith, Renieri, Alessandra, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Afenjar, Alexandra, Goldenberg, Alice, Masurel, Alice, Phan, Alice, Dieux-Coeslier, Anne, Fargeot, Anne, Guerrot, Anne-Marie, Toutain, Annick, Molin, Arnaud, Sorlin, Arthur, Putoux, Audrey, Jouret, Béatrice, Laudier, Béatrice, Demeer, Bénédicte, Doray, Bérénice, Bonniaud, Bertille, Isidor, Bertrand, Gilbert-Dussardier, Brigitte, Leheup, Bruno, Reversade, Bruno, Paul, Carle, Vincent-Delorme, Catherine, Neiva, Cecilia, Poirsier, Céline, Quélin, Chloé, Chiaverini, Christine, Coubes, Christine, Francannet, Christine, Colson, Cindy, Desplantes, Claire, Wells, Constance, Goizet, Cyril, Lederer, Damien, Sanlaville, Damien, Amram, Daniel, Lehalle, Daphné, Geneviève, David, Heron, Delphine, Lacombe, Didier, Gaillard, Dominique, Zivi, Einat, Sarrazin, Elisabeth, Steichen, Elisabeth, Schaefer, Élise, Lacaze, Elodie, Jacquemin, Emmanuel, Bongers, Ernie, Kilic, Esra, Colin, Estelle, Giuliano, Fabienne, Prieur, Fabienne, Laffargue, Fanny, Morice-Picard, Fanny, Petit, Florence, Cartault, François, Feillet, François, Baujat, Geneviève, Morin, Gilles, Diene, Gwenaëlle, Journel, Hubert, Maystadt, Isabelle, Perthus, Isabelle, Lespinasse, James, Alessandri, Jean-Luc, Amiel, Jeanne, Martinovic, Jelena, Delanne, Julian, Albuisson, Juliette, Lambert, Laëtitia, Perrin, Laurence, Ousager, Lilian Bomme, Van Maldergem, Lionel, Pinson, Lucile, Ruaud, Lyse, Samimi, Mahtab, Bournez, Marie, Bonnet-Dupeyron, Marie Noëlle, Vincent, Marie, Jacquemont, Marie-Line, Cordier-Alex, Marie-Pierre, Gérard-Blanluet, Marion, Willems, Marjolaine, Spodenkiewicz, Marta, Doco-Fenzy, Martine, Rossi, Massimiliano, Renaud, Mathilde, Fradin, Mélanie, Mathieu, Michèle, Holder-Espinasse, Muriel H., Houcinat, Nada, Hanna, Nadine, Leperrier, Nathalie, Chassaing, Nicolas, Philip, Nicole, Boute, Odile, Van Kien, Philippe Khau, Parent, Philippe, Bitoun, Pierre, Sarda, Pierre, Vabres, Pierre, Jouk, Pierre-Simon, Touraine, Renaud, El Chehadeh, Salima, Whalen, Sandra, Marlin, Sandrine, Passemard, Sandrine, Grotto, Sarah, Bellanger, Séverine Audebert, Blesson, Sophie, Nambot, Sophie, Naudion, Sophie, Lyonnet, Stanislas, Odent, Sylvie, Attie-Bitach, Tania, Busa, Tiffany, Drouin-Garraud, Valérie, Layet, Valérie, Bizaoui, Varoona, Cusin, Véronica, Capri, Yline, Alembik, Yves, Vitobello, Antonio, Vissers, Lisenka E.L.M., and Faivre, Laurence

Abstract

Within the Solve-RD project (https://solve-rd.eu/), the European Reference Network for Intellectual disability, TeleHealth, Autism, and Congenital Anomalies aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses, and lessons learned.

Published
2023
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37. STXBP1encephalopathy

Author

Stamberger, Hannah, Nikanorova, Marina, Willemsen, Marjolein H., Accorsi, Patrizia, Angriman, Marco, Baier, Hartmut, Benkel-Herrenbrueck, Ira, Benoit, Valérie, Budetta, Mauro, Caliebe, Almuth, Cantalupo, Gaetano, Capovilla, Giuseppe, Casara, Gianluca, Courage, Carolina, Deprez, Marie, Destrée, Anne, Dilena, Robertino, Erasmus, Corrie E., Fannemel, Madeleine, Fjær, Roar, Giordano, Lucio, Helbig, Katherine L., Heyne, Henrike O., Klepper, Joerg, Kluger, Gerhard J., Lederer, Damien, Lodi, Monica, Maier, Oliver, Merkenschlager, Andreas, Michelberger, Nina, Minetti, Carlo, Muhle, Hiltrud, Phalin, Judith, Ramsey, Keri, Romeo, Antonino, Schallner, Jens, Schanze, Ina, Shinawi, Marwan, Sleegers, Kristel, Sterbova, Katalin, Syrbe, Steffen, Traverso, Monica, Tzschach, Andreas, Uldall, Peter, Van Coster, Rudy, Verhelst, Helene, Viri, Maurizio, Winter, Susan, Wolff, Markus, Zenker, Martin, Zoccante, Leonardo, De Jonghe, Peter, Helbig, Ingo, Striano, Pasquale, Lemke, Johannes R., Møller, Rikke S., and Weckhuysen, Sarah

Published
2016
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38. Disruptive de novomutations of DYRK1Alead to a syndromic form of autism and ID

Author

van Bon, B W M, Coe, B P, Bernier, R, Green, C, Gerdts, J, Witherspoon, K, Kleefstra, T, Willemsen, M H, Kumar, R, Bosco, P, Fichera, M, Li, D, Amaral, D, Cristofoli, F, Peeters, H, Haan, E, Romano, C, Mefford, H C, Scheffer, I, Gecz, J, de Vries, B B A, and Eichler, E E

Abstract

Dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1 A (DYRK1A) maps to the Down syndrome critical region; copy number increase of this gene is thought to have a major role in the neurocognitive deficits associated with Trisomy 21. Truncation of DYRK1Ain patients with developmental delay (DD) and autism spectrum disorder (ASD) suggests a different pathology associated with loss-of-function mutations. To understand the phenotypic spectrum associated with DYRK1Amutations, we resequenced the gene in 7162 ASD/DD patients (2446 previously reported) and 2169 unaffected siblings and performed a detailed phenotypic assessment on nine patients. Comparison of our data and published cases with 8696 controls identified a significant enrichment of DYRK1Atruncating mutations (P=0.00851) and an excess of de novomutations (P=2.53 × 10-10) among ASD/intellectual disability (ID) patients. Phenotypic comparison of all novel (n=5) and recontacted (n=3) cases with previous case reports, including larger CNV and translocation events (n=7), identified a syndromal disorder among the 15 patients. It was characterized by ID, ASD, microcephaly, intrauterine growth retardation, febrile seizures in infancy, impaired speech, stereotypic behavior, hypertonia and a specific facial gestalt. We conclude that mutations in DYRK1Adefine a syndromic form of ASD and ID with neurodevelopmental defects consistent with murine and Drosophilaknockout models.

Published
2016
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42. Development and validation of RATje: A Remote Associates Test for Dutch children.

Author

Lazonder, Ard W., Willemsen, Robin H., Vink, Isabelle C. de, Roseboom-Folmer, Janine, Arends, Olivia, Jongen, Annet P., van Keulen, Yolani Q., Oudenhoven, Lise J.G., and Kroesbergen, Evelyn H.

Subjects
PSYCHOMETRICS, DIVERGENT thinking, SEX discrimination, READING comprehension, PROBLEM solving
Abstract

• RAT problems can be solved by children. • Our 10-item RAT test has sufficient internal consistency. • The test has good item difficulty and acceptable discriminatory power. • The test has good discriminant and convergent validity. • Test scores are not biased by gender, SES and reading comprehension skills. The Remote Associates Test (RAT) is increasingly being used as a measure of convergent thinking, one of the pillars of creative problem solving. As creativity is gaining momentum in Dutch elementary education, there is a growing need for a Dutch version of the RAT suitable for children. We therefore developed a child-appropriate 10-item RAT and examined its psychometric properties in a study with 531 Dutch fifth graders (M age = 10.35, 52% boys). Results showed that the items were internally consistent (α = 0.73) and accorded with a 1PL-logistic IRT model. Item difficulty ranged from −0.82 (easy) to 1.49 (hard), item discrimination was 1.19 and there were very few signs of differential item functioning based on children's gender, socioeconomic status and language proficiency. However, as strong validity-supporting evidence was lacking, a second study was conducted with 202 fourth, fifth and sixth graders (M age = 10.82, 46% boys). Internal consistency and item properties were essentially equivalent to Study 1. Validity of the RAT was supported by significant correlations with scores on other convergent thinking tests (0.39 ≤ r ≤ 0.42) and a lack of association with achievement on a divergent thinking test (r = 0.07). [ABSTRACT FROM AUTHOR]

Published
2022
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44. Myocardial function in normal and spontaneously hypertensive rats during reperfusion after a period of global ischaemia.

Author

SNOECKX, L H E H, VAN DER VUSSE, G J, COUMANS, W A, WILLEMSEN, P H M, VAN DER NAGEL, T, and RENEMAN, R S

Abstract

Isolated working hearts of 16 month old spontaneously hypertensive rats (SHR, n=8) and age matched Wistar-Kyoto (WKY, n=8) rats were exposed to 30 min global normothermic ischaemia followed by 60 min reperfusion. The hearts were routinely perfused at an afterload level of 13.3 kPa and a preload level of 1.0 kPa. The control values of left ventricular pressure, its maximal positive first derivative (dPlv/dtmax), coronary flow per gram heart tissue, and release of lactate and enzymes such as lactate dehydrogenase and aspartate aminotransferase were comparable in both groups. WKY rat hearts ejected almost twice as much perfusate per gram heart weight as the SHR hearts. In pressure-flow curves, obtained during the control period in SHR hearts, cardiac output was independent of changes in afterload, varying between 10.7 and 18.7 kPa. In contrast, in WKY rat hearts increases in afterload resulted in a progressive decrease in cardiac output. Reperfusion of the SHR hearts after 30 min of global normothermic ischaemia resulted in a poor recovery of cardiac output (13% of the control values) and dPlv/dtmax (32%) compared with the values in the WKY rat hearts (66% and 91% of the control values respectively). Reactive hyperaemia was prominent in the WKY rat hearts but completely absent in the SHR hearts. During one hour reperfusion, SHR hearts lost 3.5 times more lactate dehydrogenase and 2.5 times more aspartate aminotransferase than the WKY rat hearts. Pressure-flow curves, obtained during the reperfusion period, showed modest recovery of myocardial function of the WKY rat hearts at the lowest afterload level tested but completely depressed myocardial function of the SHR hearts at all afterload levels. Heart tissue contents of adenosine triphosphate and creatine phosphate after one hour of reperfusion were lower in the SHR than in the WKY rats, but compared with native values a comparable percentage decrease was seen in both groups of rats. [ABSTRACT FROM PUBLISHER]

Published
1986

45. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability

Author

Lelieveld, Stefan H, Reijnders, Margot R F, Pfundt, Rolph, Yntema, Helger G, Kamsteeg, Erik-Jan, de Vries, Petra, de Vries, Bert B A, Willemsen, Marjolein H, Kleefstra, Tjitske, Löhner, Katharina, Vreeburg, Maaike, Stevens, Servi J C, van der Burgt, Ineke, Bongers, Ernie M H F, Stegmann, Alexander P A, Rump, Patrick, Rinne, Tuula, Nelen, Marcel R, Veltman, Joris A, Vissers, Lisenka E L M, Brunner, Han G, and Gilissen, Christian

Abstract

To identify candidate genes for intellectual disability, we performed a meta-analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient–parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4, PPM1D, RAC1, SMAD6, SON, SOX5, SYNCRIP, TCF20, TLK2 and TRIP12. In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes.

Published
2016
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46. Cardiovascular Risk Factors in Parents of Short Children Born Small for Gestational Age

Author

KORT, SANDRA W. K. DE, VAN DIJK, MARIJE, WILLEMSEN, RUBEN H., ESTER, WIETSKE A., VIET, LUCIE, RIJKE, YOLANDA B. DE, and HOKKEN-KOELEGA, ANITA C. S.

Abstract

Small for gestational age (SGA) children have a higher prevalence of cardiovascular risk factors at a young age. It is not known whether this increased risk is caused by their size at birth, a familial predisposition for cardiovascular disease or smallness at birth or a combination of these factors. The cardiovascular risk profile of parents of SGA children is unknown. We compared anthropometry, blood pressure, fasting serum lipid, glucose, and insulin levels of 482 parents (mean age 41 y) and 286 short SGA children with age- and sex-matched references. We also investigated whether these parameters correlated between parents and their offspring. Mothers had higher systolic blood pressure, fathers had a higher body mass index and parents had more frequently high fasting glucose levels than age- and sex-matched references. Children had significantly higher systolic and diastolic blood pressure than sex- and height-matched references. Twenty-four percent (mothers) and 10% (fathers) were born SGA but they did not have more cardiovascular risk factors than those born appropriate for gestational age. Cardiovascular risk factors did not correlate between parents and children. In conclusion, parents of short SGA children have a modest increase in some cardiovascular risk factors but risk factors did not correlate between parents and children.

Published
2008
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47. Cardiovascular Risk Factors in Parents of Short Children Born Small for Gestational Age

Author

de Kort, Sandra W K, van Dijk, Marije, Willemsen, Ruben H, Ester, Wietske A, Viet, Lucie, de Rijke, Yolanda B, and Hokken-Koelega, Anita C S

Abstract

Small for gestational age (SGA) children have a higher prevalence of cardiovascular risk factors at a young age. It is not known whether this increased risk is caused by their size at birth, a familial predisposition for cardiovascular disease or smallness at birth or a combination of these factors. The cardiovascular risk profile of parents of SGA children is unknown. We compared anthropometry, blood pressure, fasting serum lipid, glucose, and insulin levels of 482 parents (mean age 41 y) and 286 short SGA children with age- and sex-matched references. We also investigated whether these parameters correlated between parents and their offspring. Mothers had higher systolic blood pressure, fathers had a higher body mass index and parents had more frequently high fasting glucose levels than age- and sex-matched references. Children had significantly higher systolic and diastolic blood pressure than sex- and height-matched references. Twenty-four percent (mothers) and 10% (fathers) were born SGA but they did not have more cardiovascular risk factors than those born appropriate for gestational age. Cardiovascular risk factors did not correlate between parents and children. In conclusion, parents of short SGA children have a modest increase in some cardiovascular risk factors but risk factors did not correlate between parents and children.

Published
2008
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48. Fasting-induced changes in the expression of genes controlling substrate metabolism in the rat heart.

Author

Van der Lee, K A, Willemsen, P H, Samec, S, Seydoux, J, Dulloo, A G, Pelsers, M M, Glatz, J F, Van der Vusse, G J, and Van Bilsen, M

Abstract

During fasting, when overall metabolism changes, the contribution of glucose and fatty acids (FA) to cardiac energy production alters as well. Here, we examined if the heart is able to adapt to such fasting-induced changes by modulation of its gene expression. Rats were fed ad libitum or fasted for 46 h, resulting in reduced circulating glucose levels and a 3-fold rise in FA. Besides changes in the cardiac activity or content of proteins involved in glucose or FA metabolism, mRNA levels also altered. The cardiac expression of genes coding for glucose-handling proteins (glucose transporter GLUT4, hexokinase I and II) was up to 70% lower in fasted than in fed rats. In contrast, the mRNA levels of various genes involved in FA transport and metabolism (FA translocase/CD36, muscle-type carnitine palmitoyl transferase 1, long-chain acyl-CoA dehydrogenase) and of the uncoupling protein UCP-3 increased over 50% in hearts of fasted rats. Surprisingly, mRNA levels of the fatty acid- activated transcription factors PPARalpha and PPARbeta/delta were reduced in hearts of fasted rats, whereas in livers, fasting led to a marked rise in PPARalpha mRNA. Reducing FA levels by nicotinic acid administration during the final 8 h of fasting did not affect the expression of the majority of metabolic genes, but totally abolished the induction of UCP-3. In conclusion, the adult rat heart responds to changes in nutritional status, as provoked by 46 h fasting, through adjustment of glucose as well as FA metabolism at the level of gene expression.

Published
2001

50. Biomolecular Interactions Measured by Atomic Force Microscopy

Author

Willemsen, Oscar H., Snel, Margot M.E., Cambi, Alessandra, Greve, Jan, De Grooth, Bart G., and Figdor, Carl G.

Abstract

Atomic force microscopy (AFM) is nowadays frequently applied to determine interaction forces between biological molecules. Starting with the detection of the first discrete unbinding forces between ligands and receptors by AFM only several years ago, measurements have become more and more quantitative. At the same time, theories have been developed to describe and understand the dynamics of the unbinding process and experimental techniques have been refined to verify this theory. In addition, the detection of molecular recognition forces has been exploited to map and image the location of binding sites. In this review we discuss the important contributions that have led to the development of this field. In addition, we emphasize the potential of chemically well-defined surface modification techniques to further improve reproducible measurements by AFM. This increased reproducibility will pave the way for a better understanding of molecular interactions in cell biology.

Published
2000
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