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2. Author Correction: Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, Tianyun, Hoekzema, Kendra, Vecchio, Davide, Wu, Huidan, Sulovari, Arvis, Coe, Bradley P, Gillentine, Madelyn A, Wilfert, Amy B, Perez-Jurado, Luis A, Kvarnung, Malin, Sleyp, Yoeri, Earl, Rachel K, Rosenfeld, Jill A, Geisheker, Madeleine R, Han, Lin, Du, Bing, Barnett, Chris, Thompson, Elizabeth, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Catford, Rachael, Palmer, Elizabeth E, Zou, Xiaobing, Ou, Jianjun, Li, Honghui, Guo, Hui, Gerdts, Jennifer, Avola, Emanuela, Calabrese, Giuseppe, Elia, Maurizio, Greco, Donatella, Lindstrand, Anna, Nordgren, Ann, Anderlid, Britt-Marie, Vandeweyer, Geert, Van Dijck, Anke, Van der Aa, Nathalie, McKenna, Brooke, Hancarova, Miroslava, Bendova, Sarka, Havlovicova, Marketa, Malerba, Giovanni, Bernardina, Bernardo Dalla, Muglia, Pierandrea, van Haeringen, Arie, Hoffer, Mariette JV, Franke, Barbara, Cappuccio, Gerarda, Delatycki, Martin, Lockhart, Paul J, Manning, Melanie A, Liu, Pengfei, Scheffer, Ingrid E, Brunetti-Pierri, Nicola, Rommelse, Nanda, Amaral, David G, Santen, Gijs WE, Trabetti, Elisabetta, Sedláček, Zdeněk, Michaelson, Jacob J, Pierce, Karen, Courchesne, Eric, Kooy, R Frank, Nordenskjöld, Magnus, Romano, Corrado, Peeters, Hilde, Bernier, Raphael A, Gecz, Jozef, Xia, Kun, and Eichler, Evan E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Commerce, Management, Tourism and Services, SPARK Consortium
Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

3. Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders

Author

Wang, Tianyun, Hoekzema, Kendra, Vecchio, Davide, Wu, Huidan, Sulovari, Arvis, Coe, Bradley P, Gillentine, Madelyn A, Wilfert, Amy B, Perez-Jurado, Luis A, Kvarnung, Malin, Sleyp, Yoeri, Earl, Rachel K, Rosenfeld, Jill A, Geisheker, Madeleine R, Han, Lin, Du, Bing, Barnett, Chris, Thompson, Elizabeth, Shaw, Marie, Carroll, Renee, Friend, Kathryn, Catford, Rachael, Palmer, Elizabeth E, Zou, Xiaobing, Ou, Jianjun, Li, Honghui, Guo, Hui, Gerdts, Jennifer, Avola, Emanuela, Calabrese, Giuseppe, Elia, Maurizio, Greco, Donatella, Lindstrand, Anna, Nordgren, Ann, Anderlid, Britt-Marie, Vandeweyer, Geert, Van Dijck, Anke, Van der Aa, Nathalie, McKenna, Brooke, Hancarova, Miroslava, Bendova, Sarka, Havlovicova, Marketa, Malerba, Giovanni, Bernardina, Bernardo Dalla, Muglia, Pierandrea, van Haeringen, Arie, Hoffer, Mariette JV, Franke, Barbara, Cappuccio, Gerarda, Delatycki, Martin, Lockhart, Paul J, Manning, Melanie A, Liu, Pengfei, Scheffer, Ingrid E, Brunetti-Pierri, Nicola, Rommelse, Nanda, Amaral, David G, Santen, Gijs WE, Trabetti, Elisabetta, Sedláček, Zdeněk, Michaelson, Jacob J, Pierce, Karen, Courchesne, Eric, Kooy, R Frank, Nordenskjöld, Magnus, Romano, Corrado, Peeters, Hilde, Bernier, Raphael A, Gecz, Jozef, Xia, Kun, and Eichler, Evan E

Subjects
Genetics, Prevention, 2.1 Biological and endogenous factors, Aetiology, Basic Helix-Loop-Helix Transcription Factors, CCCTC-Binding Factor, Case-Control Studies, Cohort Studies, DNA Mutational Analysis, DNA-Binding Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Heterogeneous-Nuclear Ribonucleoprotein U, High-Throughput Nucleotide Sequencing, Humans, KCNQ3 Potassium Channel, Male, Mutation, Neurodevelopmental Disorders, RNA-Binding Proteins, Repressor Proteins, Transcription Factors, SPARK Consortium
Abstract

Most genes associated with neurodevelopmental disorders (NDDs) were identified with an excess of de novo mutations (DNMs) but the significance in case-control mutation burden analysis is unestablished. Here, we sequence 63 genes in 16,294 NDD cases and an additional 62 genes in 6,211 NDD cases. By combining these with published data, we assess a total of 125 genes in over 16,000 NDD cases and compare the mutation burden to nonpsychiatric controls from ExAC. We identify 48 genes (25 newly reported) showing significant burden of ultra-rare (MAF

Published
2020

6. Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort

Author

Meester, Josephina A.N., Peeters, Silke, Van Den Heuvel, Lotte, Vandeweyer, Geert, Fransen, Erik, Cappella, Elizabeth, Dietz, Harry C., Forbus, Geoffrey, Gelb, Bruce D., Goldmuntz, Elizabeth, Hoskoppal, Arvind, Landstrom, Andrew P., Lee, Teresa, Mital, Seema, Morris, Shaine, Olson, Aaron K., Renard, Marjolijn, Roden, Dan M., Singh, Michael N., Selamet Tierney, Elif Seda, Tretter, Justin T., Van Driest, Sara L., Willing, Marcia, Verstraeten, Aline, Van Laer, Lut, Lacro, Ronald V., and Loeys, Bart L.

Published
2022
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10. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases

Author

Stessman, Holly AF, Xiong, Bo, Coe, Bradley P, Wang, Tianyun, Hoekzema, Kendra, Fenckova, Michaela, Kvarnung, Malin, Gerdts, Jennifer, Trinh, Sandy, Cosemans, Nele, Vives, Laura, Lin, Janice, Turner, Tychele N, Santen, Gijs, Ruivenkamp, Claudia, Kriek, Marjolein, van Haeringen, Arie, Aten, Emmelien, Friend, Kathryn, Liebelt, Jan, Barnett, Christopher, Haan, Eric, Shaw, Marie, Gecz, Jozef, Anderlid, Britt-Marie, Nordgren, Ann, Lindstrand, Anna, Schwartz, Charles, Kooy, R Frank, Vandeweyer, Geert, Helsmoortel, Celine, Romano, Corrado, Alberti, Antonino, Vinci, Mirella, Avola, Emanuela, Giusto, Stefania, Courchesne, Eric, Pramparo, Tiziano, Pierce, Karen, Nalabolu, Srinivasa, Amaral, David G, Scheffer, Ingrid E, Delatycki, Martin B, Lockhart, Paul J, Hormozdiari, Fereydoun, Harich, Benjamin, Castells-Nobau, Anna, Xia, Kun, Peeters, Hilde, Nordenskjöld, Magnus, Schenck, Annette, Bernier, Raphael A, and Eichler, Evan E

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Brain Disorders, Behavioral and Social Science, Genetic Testing, Intellectual and Developmental Disabilities (IDD), Mental Health, Neurosciences, Pediatric, Autism, Aetiology, 2.1 Biological and endogenous factors, Mental health, Autistic Disorder, Developmental Disabilities, Female, Humans, Intellectual Disability, Male, Mutation, Phenotype, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.7% of cases. Drosophila functional assays revealed a subset with increased involvement in NDDs. We identified 25 genes showing a bias for autism versus intellectual disability and highlighted a network associated with high-functioning autism (full-scale IQ >100). Clinical follow-up for NAA15, KMT5B, and ASH1L highlighted new syndromic and nonsyndromic forms of disease.

Published
2017

11. A Case–Control Study Supports Genetic Contribution of the PON Gene Family in Obesity and Metabolic Dysfunction Associated Steatotic Liver Disease.

Author

Van Dijck, Evelien, Diels, Sara, Fransen, Erik, Cremers, Tycho Canter, Verrijken, An, Dirinck, Eveline, Hoischen, Alexander, Vandeweyer, Geert, Vanden Berghe, Wim, Van Gaal, Luc, Francque, Sven, and Van Hul, Wim

Subjects
HEPATIC fibrosis, METABOLIC disorders, MOLECULAR probes, GENE families, LIVER diseases
Abstract

The paraoxonase (PON) gene family (including PON1, PON2, and PON3), is known for its anti-oxidative and anti-inflammatory properties, protecting against metabolic diseases such as obesity and metabolic dysfunction-associated steatotic liver disease (MASLD). In this study, the influence of common and rare PON variants on both conditions was investigated. A total of 507 healthy weight individuals and 744 patients with obesity including 433 with histological liver assessment, were sequenced with single-molecule molecular inversion probes (smMIPs), allowing the identification of genetic contributions to obesity and MASLD-related liver features. Polymorphisms rs705379 and rs854552 in the PON1 gene displayed significant association with MASLD stage and fibrosis, respectively. Additionally, rare PON1 variants were strongly associated with obesity. This study thereby reinforces the genetic foundation of PON1 in obesity and various MASLD-related liver features, by extending previous findings from common variants to include rare variants. Additionally, rare and very rare variants in PON2 were discovered to be associated with MASLD-related hepatic fibrosis. Notably, we are the first to report an association between naturally occurring rare PON2 variants and MASLD-related liver fibrosis. Considering the critical role of liver fibrosis in MASLD outcome, PON2 emerges as a possible candidate for future research endeavors including exploration of biomarker potential. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Identification of a DLG3 stop mutation in the MRX20 family

Author

Huyghebaert, Jolien, primary, Mateiu, Ligia, additional, Elinck, Ellen, additional, Van Rossem, Kirsten Esther, additional, Christiaenssen, Bregje, additional, D’Incal, Claudio Peter, additional, McCormack, Michael K., additional, Lazzarini, Alice, additional, Vandeweyer, Geert, additional, and Kooy, R. Frank, additional

Published
2024
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15. Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Author

Bakshi, Madhura, Wilson, Meredith, Berman, Yemina, Dickson, Rebecca, Fransen, Erik, Helsmoortel, Céline, Van den Ende, Jenneke, Van der Aa, Nathalie, van de Wijdeven, Marina J., Rosenblum, Jessica, Monteiro, Fabíola, Kok, Fernando, Quercia, Nada, Bowdin, Sarah, Dyment, David, Chitayat, David, Alkhunaizi, Ebba, Boonen, Susanne E., Keren, Boris, Jacquette, Aurelia, Faivre, Laurence, Bezieau, Stephane, Isidor, Bertrand, Rieß, Angelika, Moog, Ute, Lynch, Sally Ann, McVeigh, Terri, Elpeleg, Orly, Smeland, Marie Falkenberg, Fannemel, Madeleine, van Haeringen, Arie, Maas, Saskia M., Veenstra-Knol, H.E., Schouten, Meyke, Willemsen, Marjolein H., Marcelis, Carlo L., Ockeloen, Charlotte, van der Burgt, Ineke, Feenstra, Ilse, van der Smagt, Jasper, Jezela-Stanek, Aleksandra, Krajewska-Walasek, Malgorzata, González-Lamuño, Domingo, Anderlid, Britt-Marie, Malmgren, Helena, Nordenskjöld, Magnus, Clement, Emma, Hurst, Jane, Metcalfe, Kay, Mansour, Sahar, Lachlan, Katherine, Clayton-Smith, Jill, Hendon, Laura G., Abdulrahman, Omar A., Morrow, Eric, McMillan, Clare, Gerdts, Jennifer, Peeden, Joseph, Schrier Vergano, Samantha A., Valentino, Caitlin, Chung, Wendy K., Ozmore, Jillian R., Bedrosian-Sermone, Sandra, Dennis, Anna, Treat, Kayla, Hughes, Susan Starling, Safina, Nicole, Le Pichon, Jean-Baptiste, McGuire, Marianne, Infante, Elena, Madan-Khetarpal, Suneeta, Desai, Sonal, Benke, Paul, Krokosky, Alyson, Cristian, Ingrid, Baker, Laura, Gripp, Karen, Stessman, Holly A., Eichenberger, Jacob, Jayakar, Parul, Pizzino, Amy, Manning, Melanie Ann, Slattery, Leah, Van Dijck, Anke, Vulto-van Silfhout, Anneke T., Cappuyns, Elisa, van der Werf, Ilse M., Mancini, Grazia M., Tzschach, Andreas, Bernier, Raphael, Gozes, Illana, Eichler, Evan E., Romano, Corrado, Lindstrand, Anna, Nordgren, Ann, Kvarnung, Malin, Kleefstra, Tjitske, de Vries, Bert B.A., Küry, Sébastien, Rosenfeld, Jill A., Meuwissen, Marije E., Vandeweyer, Geert, and Kooy, R. Frank

Published
2019
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16. W54. “MINDDS-CONNECT” – FEDERATED DATA SHARING PLATFORM FOR NEURODEVELOPMENTAL DISORDERS AND RARE GENETIC MUTATIONS

Author

Mihaljevic, Marina, primary, Huremagic, Benjamin, additional, Harwood, Janet, additional, Jorge, Paola, additional, Teles, Natalia, additional, Novakowska, Beata, additional, Vandeweyer, Geert, additional, Drakulic, Danijela, additional, van Amelsvoort, Therese, additional, Linden, David, additional, Straccia, Marco, additional, Vermeersch, Joris, additional, and Harwood, Adrian, additional

Published
2023
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18. Contributors

Author

Agam, Galila, primary, Ben-Shachar, Dorit, additional, Daniele, Cartelli, additional, Gabis, Lidia V., additional, Gozes, Illana, additional, Graziella, Cappelletti, additional, Gross, Christina, additional, Gross, Raz, additional, Ifhar, Lee S., additional, Jiang, Cheng, additional, Kooy, R. Frank, additional, Levine, Joseph, additional, Mekori-Domachevsky, Ehud, additional, Salton, Stephen R., additional, Sayas, Carmen Laura, additional, Segal-Gavish, Hadar, additional, Seroogy, Kim B., additional, van der Werf, Ilse M., additional, and Vandeweyer, Geert, additional

Published
2020
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19. Insufficient evidence for a role of SERPINF1 in otosclerosis

Author

Valgaeren, Hanne, Sommen, Manou, Beyens, Matthias, Vandeweyer, Geert, Schrauwen, Isabelle, Schepers, Anne, Schatteman, Isabelle, Topsakal, Vedat, Dhooge, Ingeborg, Kunst, Henricus, Zanetti, Diego, Huber, Alexander M., Hoischen, Alexander, Fransen, Erik, and Van Camp, Guy

Published
2019
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20. Confirmation of the role of pathogenic SMAD6 variants in bicuspid aortic valve-related aortopathy

Author

Luyckx, Ilse, MacCarrick, Gretchen, Kempers, Marlies, Meester, Josephina, Geryl, Céline, Rombouts, Olivier, Peeters, Nils, Claes, Charlotte, Boeckx, Nele, Sakalihasan, Natzi, Jacquinet, Adeline, Hoischen, Alexander, Vandeweyer, Geert, Van Lent, Sarah, Saenen, Johan, Van Craenenbroeck, Emeline, Timmermans, Janneke, Duijnhouwer, Anthonie, Dietz, Harry, Van Laer, Lut, Loeys, Bart, and Verstraeten, Aline

Published
2019
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21. Copy number variation analysis in bicuspid aortic valve-related aortopathy identifies TBX20 as a contributing gene

Author

Luyckx, Ilse, Kumar, Ajay A., Reyniers, Edwin, Dekeyser, Emily, Vanderstraeten, Kathleen, Vandeweyer, Geert, Wünnemann, Florian, Preuss, Christoph, Mazzella, Jean-Michaël, Goudot, Guillaume, Messas, Emmanuel, Albuisson, Juliette, Jeunemaitre, Xavier, Eriksson, Per, Mohamed, Salah A., Kempers, Marlies, Salemink, Simone, Duijnhouwer, Anthonie, Andelfinger, Gregor, Dietz, Harry C, Verstraeten, Aline, Van Laer, Lut, Loeys, Bart L., and MIBAVA Leducq Consortium

Published
2019
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23. 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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24. Identification of a DLG3stop mutation in the MRX20 family

Author

Huyghebaert, Jolien, Mateiu, Ligia, Elinck, Ellen, Van Rossem, Kirsten Esther, Christiaenssen, Bregje, D’Incal, Claudio Peter, McCormack, Michael K., Lazzarini, Alice, Vandeweyer, Geert, and Kooy, R. Frank

Abstract

Here, we identified the causal mutation in the MRX20 family, one of the larger X-linked pedigrees that have been described in which no gene had been identified up till now. In 1995, the putative disease gene had been mapped to the pericentromeric region on the X chromosome, but no follow-up studies were performed. Here, whole exome sequencing (WES) on two affected and one unaffected family member revealed the c.195del/p.(Thr66ProfsTer55) mutation in the DLG3gene (NM_021120.4) that segregated with the affected individuals in the family. DLG3mutations have been consequently associated with intellectual disability and are a plausible explanation for the clinical abnormalities observed in this family. In addition, we identified two other variants co-segregating with the phenotype: a stop gain mutation in SSX1(c.358G>T/p.(Glu120Ter)) (NM_001278691.2) and a nonsynonymous SNV in USP27X(c.56 A>G/p.(Gln19Arg)) (NM_001145073.3). RNA sequencing revealed 14 differentially expressed genes (pvalue < 0.1) in 7 affected males compared to 4 unaffected males of the family, including four genes known to be associated with neurological disorders. Thus, in this paper we identified the c.195del/p.(Thr66ProfsTer55) mutation in the DLG3gene (NM_021120.4) as likely responsible for the phenotype observed in the MRX20 family.

Published
2024
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25. Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains

Author

Geisheker, Madeleine R, Heymann, Gabriel, Wang, Tianyun, Coe, Bradley P, Turner, Tychele N, Stessman, Holly A F, Hoekzema, Kendra, Kvarnung, Malin, Shaw, Marie, Friend, Kathryn, Liebelt, Jan, Barnett, Christopher, Thompson, Elizabeth M, Haan, Eric, Guo, Hui, Anderlid, Britt-Marie, Nordgren, Ann, Lindstrand, Anna, Vandeweyer, Geert, Alberti, Antonino, Avola, Emanuela, Vinci, Mirella, Giusto, Stefania, Pramparo, Tiziano, Pierce, Karen, Nalabolu, Srinivasa, Michaelson, Jacob J, Sedlacek, Zdenek, Santen, Gijs W E, Peeters, Hilde, Hakonarson, Hakon, Courchesne, Eric, Romano, Corrado, Kooy, R Frank, Bernier, Raphael A, Nordenskjöld, Magnus, Gecz, Jozef, Xia, Kun, Zweifel, Larry S, and Eichler, Evan E

Published
2017
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31. varAmpliCNV: analyzing variance of amplicons to detect CNVs in targeted NGS data.

Author

Kumar, Ajay Anand, Loeys, Bart, Beek, Gerarda Van De, Peeters, Nils, Wuyts, Wim, Laer, Lut Van, Vandeweyer, Geert, and Alaerts, Maaike

Subjects
DNA copy number variations, PRINCIPAL components analysis, AORTIC aneurysms, SIGNAL detection, ACCOUNTING methods
Abstract

Motivation Computational identification of copy number variants (CNVs) in sequencing data is a challenging task. Existing CNV-detection methods account for various sources of variation and perform different normalization strategies. However, their applicability and predictions are restricted to specific enrichment protocols. Here, we introduce a novel tool named varAmpliCNV, specifically designed for CNV-detection in amplicon-based targeted resequencing data (Haloplex™ enrichment protocol) in the absence of matched controls. VarAmpliCNV utilizes principal component analysis (PCA) and/or metric dimensional scaling (MDS) to control variances of amplicon associated read counts enabling effective detection of CNV signals. Results Performance of VarAmpliCNV was compared against three existing methods (ConVaDING, ONCOCNV and DECoN) on data of 167 samples run with an aortic aneurysm gene panel (n  = 30), including 9 positive control samples. Additionally, we validated the performance on a large deafness gene panel (n  = 145) run on 138 samples, containing 4 positive controls. VarAmpliCNV achieved higher sensitivity (100%) and specificity (99.78%) in comparison to competing methods. In addition, unsupervised clustering of CNV segments and visualization plots of amplicons spanning these regions are included as a downstream strategy to filter out false positives. Availability and implementation The tool is freely available through galaxy toolshed and at: https://hub.docker.com/r/cmgantwerpen/varamplicnv. Supplementary Data File S1 : https://tinyurl.com/2yzswyhh ; Supplementary Data File S2 : https://tinyurl.com/ycyf2fb4. Supplementary information Supplementary data are available at Bioinformatics online. [ABSTRACT FROM AUTHOR]

Published
2023
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34. Fourteen new cases contribute to the characterization of the 7q11.23 microduplication syndrome

Author

Van der Aa, Nathalie, Rooms, Liesbeth, Vandeweyer, Geert, van den Ende, Jenneke, Reyniers, Edwin, Fichera, Marco, Romano, Corrado, Delle Chiaie, Barbara, Mortier, Geert, Menten, Björn, Destrée, Anne, Maystadt, Isabelle, Männik, Katrin, Kurg, Ants, Reimand, Tiia, McMullan, Dom, Oley, Christine, Brueton, Louise, Bongers, Ernie M.H.F., van Bon, Bregje W.M., Pfund, Rolph, Jacquemont, Sebastien, Ferrarini, Alessandra, Martinet, Danielle, Schrander-Stumpel, Connie, Stegmann, Alexander P.A., Frints, Suzanna G.M., de Vries, Bert B.A., Ceulemans, Berten, and Kooy, R. Frank

Published
2009
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35. The transcriptional regulator ADNP links the BAF (SWI/SNF) complexes with autism

Author

Vandeweyer, Geert, Helsmoortel, Céline, Van Dijck, Anke, Vulto-van Silfhout, Anneke T., Coe, Bradley P., Bernier, Raphael, Gerdts, Jennifer, Rooms, Liesbeth, van den Ende, Jenneke, Bakshi, Madhura, Wilson, Meredith, Nordgren, Ann, Hendon, Laura G., Abdulrahman, Omar A., Romano, Corrado, de Vries, Bert B.A., Kleefstra, Tjitske, Eichler, Evan E., Van der Aa, Nathalie, and Kooy, Frank R.

Published
2014
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38. Homozygous and heterozygous disruptions of ANK3

Author

Iqbal, Zafar, Vandeweyer, Geert, van der Voet, Monique, Waryah, Ali Muhammad, Zahoor, Muhammad Yasir, Besseling, Judith A., Roca, Laura Tomas, Vulto-van Silfhout, Anneke T., Nijhof, Bonnie, Kramer, Jamie M., Van der Aa, Nathalie, Ansar, Muhammad, Peeters, Hilde, Helsmoortel, Céline, Gilissen, Christian, Vissers, Lisenka E.L.M., Veltman, Joris A., de Brouwer, Arjan P.M., Frank Kooy, R., Riazuddin, Sheikh, Schenck, Annette, van Bokhoven, Hans, and Rooms, Liesbeth

Published
2013
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41. Delineation of a new fibrillin-2-opathy with evidence for a role of FBN2 in the pathogenesis of carpal tunnel syndrome

Author

Peeters, Silke, primary, Decramer, Arne, additional, Cain, Stuart Alan, additional, Houpt, Peter, additional, Verstreken, Frederik, additional, Noyez, Jan, additional, Hermans, Christophe, additional, Jacobs, Werner, additional, Lammens, Martin, additional, Fransen, Erik, additional, Kumar, Ajay Anand, additional, Vandeweyer, Geert, additional, Loeys, Bart, additional, Van Hul, Wim, additional, Baldock, Clair, additional, Boudin, Eveline, additional, and Mortier, Geert, additional

Published
2020
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42. Further molecular and clinical delineation of co-locating 17p13.3 microdeletions and microduplications that show distinctive phenotypes

Author

Bruno, Damien L, Anderlid, Britt-Marie, Lindstrand, Anna, van Ravenswaaij-Arts, Conny, Ganesamoorthy, Devika, Lundin, Johanna, Martin, Christa Lese, Douglas, Jessica, Nowak, Catherine, Adam, Margaret P, Kooy, R Frank, Van der Aa, Nathalie, Reyniers, Edwin, Vandeweyer, Geert, Stolte-Dijkstra, Irene, Dijkhuizen, Trijnie, Yeung, Alison, Delatycki, Martin, Borgström, Birgit, Thelin, Lena, Cardoso, Carlos, van Bon, Bregje, Pfundt, Rolph, de Vries, Bert B, Wallin, Anders, Amor, David J, James, Paul A, Slater, Howard R, and Schoumans, Jacqueline

Published
2010
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43. Diagnostic implications of genetic copy number variation in epilepsy plus

Author

Coppola, Antonietta, Cellini, Elena, Stamberger, Hannah, Saarentaus, Elmo, Cetica, Valentina, Lal, Dennis, Djémié, Tania, Bartnik-Glaska, Magdalena, Ceulemans, Berten, Cross, J. Helen, Deconinck, Tine, De Masi, Salvatore, Dorn, Thomas, Guerrini, Renzo, Hoffman-Zacharska, Dorotha, Kooy, Frank, Lagae, Lieven, Lench, Nicholas, Lemke, Johannes R., Lucenteforte, Ersilia, Madia, Francesca, Mefford, Heather C., Morrogh, Deborah, Nuernberg, Peter, Palotie, Aarno, Schoonjans, An-Sofie, Striano, Pasquale, Szczepanik, Elzbieta, Tostevin, Anna, Vermeesch, Joris R., Van Esch, Hilde, Van Paesschen, Wim, Waters, Jonathan J., Weckhuysen, Sarah, Zara, Federico, De Jonghe, Peter, Sisodiya, Sanjay M., Marini, Carla, Lehesjioki, Anna-Elina, Craiu, Dana, Talvik, Tiina, Caglayan, Hande, Serratosa, Jose, Sterbova, Katalin, Moller, Rikke S., Hjalgrim, Helle, Lerche, Holger, Weber, Yvonne, Helbig, Ingo, von Spiczak, Sarah, Barba, Carmen, Bogaerts, Anneleen, Boni, Antonella, Galizia, Elisabeth Caruana, Chiari, Sara, Clementella, Claudia, Di Gacomo, Gianpiero, Ferrari, Annarita, Guarducci, Silvia, Giglio, Sabrina, Holmgren, Philip, Leu, Costin, Mari, Francesco, Melani, Federico, Novara, Francesca, Pantaleo, Marilena, Peeters, Elke, Pisano, Tiziana, Rosati, Anna, Sander, Josemir, Schoeler, Natasha, Stankiewicz, Pawel, Striano, Salvatore, Suls, Arvid, Traverso, Monica, Vandeweyer, Geert, Van Dijck, Anke, Zuffardi, Orsetta, EuroEPINOMICS-RES Consortium, and EpiCNV Consortium

Subjects
epilepsy genes, mental disorders, array CGH, Human medicine, SNP array, copy number variants
Abstract

OBJECTIVE: Copy number variations (CNVs) represent a significant genetic risk for several neurodevelopmental disorders including epilepsy. As knowledge increases, reanalysis of existing data is essential. Reliable estimates of the contribution of CNVs to epilepsies from sizeable populations are not available. METHODS: We assembled a cohort of 1255 patients with preexisting array comparative genomic hybridization or single nucleotide polymorphism array based CNV data. All patients had "epilepsy plus," defined as epilepsy with comorbid features, including intellectual disability, psychiatric symptoms, and other neurological and nonneurological features. CNV classification was conducted using a systematic filtering workflow adapted to epilepsy. RESULTS: Of 1097 patients remaining after genetic data quality control, 120 individuals (10.9%) carried at least one autosomal CNV classified as pathogenic; 19 individuals (1.7%) carried at least one autosomal CNV classified as possibly pathogenic. Eleven patients (1%) carried more than one (possibly) pathogenic CNV. We identified CNVs covering recently reported (HNRNPU) or emerging (RORB) epilepsy genes, and further delineated the phenotype associated with mutations of these genes. Additional novel epilepsy candidate genes emerge from our study. Comparing phenotypic features of pathogenic CNV carriers to those of noncarriers of pathogenic CNVs, we show that patients with nonneurological comorbidities, especially dysmorphism, were more likely to carry pathogenic CNVs (odds ratio = 4.09, confidence interval = 2.51-6.68; P = 2.34 × 10-9 ). Meta-analysis including data from published control groups showed that the presence or absence of epilepsy did not affect the detected frequency of CNVs. SIGNIFICANCE: The use of a specifically adapted workflow enabled identification of pathogenic autosomal CNVs in 10.9% of patients with epilepsy plus, which rose to 12.7% when we also considered possibly pathogenic CNVs. Our data indicate that epilepsy with comorbid features should be considered an indication for patients to be selected for a diagnostic algorithm including CNV detection. Collaborative large-scale CNV reanalysis leads to novel declaration of pathogenicity in unexplained cases and can promote discovery of promising candidate epilepsy genes. ispartof: EPILEPSIA vol:60 issue:4 pages:689-706 ispartof: location:United States status: published

Published
2019

45. Delineation of a new fibrillin-2-opathy with evidence for a role of FBN2 in the pathogenesis of carpal tunnel syndrome.

Author

Peeters, Silke, Decramer, Arne, Cain, Stuart Alan, Houpt, Peter, Verstreken, Frederik, Noyez, Jan, Hermans, Christophe, Jacobs, Werner, Lammens, Martin, Fransen, Erik, Kumar, Ajay Anand, Vandeweyer, Geert, Loeys, Bart, Wim Van Hul, Baldock, Clair, Boudin, Eveline, and Mortier, Geert

Abstract

Background: Although carpal tunnel syndrome (CTS) is the most common form of peripheral entrapment neuropathy, its pathogenesis remains largely unknown. An estimated heritability index of 0.46 and an increased familial occurrence indicate that genetic factors must play a role in the pathogenesis. Methods and results: We report on a family in which CTS occurred in subsequent generations at an unusually young age. Additional clinical features included brachydactyly and short Achilles tendons resulting in toe walking in childhood. Using exome sequencing, we identified a heterozygous variant (c.5009T>G; p.Phe1670Cys) in the fibrillin-2 (FBN2) gene that cosegregated with the phenotype in the family. Functional assays showed that the missense variant impaired integrin-mediated cell adhesion and migration. Moreover, we observed an increased transforming growth factor-ß signalling and fibrosis in the carpal tissues of affected individuals. A variant burden test in a large cohort of patients with CTS revealed a significantly increased frequency of rare (6.7% vs 2.5%-3.4%, p<0.001) and high-impact (6.9% vs 2.7%, p<0.001) FBN2 variants in patient alleles compared with controls. Conclusion: The identification of a novel FBN2 variant (p.Phe1670Cys) in a unique family with early onset CTS, together with the observed increased frequency of rare and high-impact FBN2 variants in patients with sporadic CTS, strongly suggest a role of FBN2 in the pathogenesis of CTS. [ABSTRACT FROM AUTHOR]

Published
2021
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46. Elucidating the genetic architecture of Adams-Oliver syndrome in a large European cohort

Author

Meester, Josephina A.N., Sukalo, Maja, Schröder, Kim C., Schanze, Denny, Baynam, Gareth, Borck, Guntram, Bramswig, Nuria C., Duman, Duygu, Gilbert-Dussardier, Brigitte, Holder-Espinasse, Muriel, Itin, Peter, Johnson, Diana S., Joss, Shelagh, Koillinen, Hannele, Mckenzie, Fiona, Morton, Jenny, Nelle, Heike, Reardon, Willie, Roll, Claudia, Salih, Mustafa A., Savarirayan, Ravi, Scurr, Ingrid, Splitt, Miranda, Thompson, Elizabeth, Titheradge, Hannah, Travers, Colm P., Van Maldergem, Lionel, Whiteford, Margo, Wieczorek, Dagmar, Vandeweyer, Geert, Trembath, Richard, Van Laer, Lut, Loeys, Bart L., Zenker, Martin, Southgate, Laura, Wuyts, Wim, Medicum, Clinicum, and Department of Medical and Clinical Genetics

Subjects
Male, rho GTP-Binding Proteins, MISSENSE MUTATIONS, ANOMALIES, DOMAINS, Medizin, Limb Deformities, Congenital, VARIANTS, Adams-Oliver syndrome, NOTCH1, Ectodermal Dysplasia, OF-FUNCTION MUTATIONS, Humans, genetics, Genetic Association Studies, Research Articles, Notch signaling, Scalp, Receptors, Notch, Adams–Oliver syndrome, Rho GTPase, Extremities, mutation screening, ASSOCIATION, Pedigree, CLINICAL PHENOTYPES, Scalp Dermatoses, LIMB DEFECTS, Mutation, APLASIA-CUTIS-CONGENITA, Female, 3111 Biomedicine, Human medicine, Research Article
Abstract

Adams–Oliver syndrome (AOS) is a rare developmental disorder, characterized by scalp aplasia cutis congenita (ACC) and transverse terminal limb defects (TTLD). Autosomal dominant forms of AOS are linked to mutations in ARHGAP31, DLL4, NOTCH1 or RBPJ, while DOCK6 and EOGT underlie autosomal recessive inheritance. Data on the frequency and distribution of mutations in large cohorts are currently limited. The purpose of this study was therefore to comprehensively examine the genetic architecture of AOS in an extensive cohort. Molecular diagnostic screening of 194 AOS/ACC/TTLD probands/families was conducted using next-generation and/or capillary sequencing analyses. In total, we identified 63 (likely) pathogenic mutations, comprising 56 distinct and 22 novel mutations, providing a molecular diagnosis in 30% of patients. Taken together with previous reports, these findings bring the total number of reported disease variants to 63, with a diagnostic yield of 36% in familial cases. NOTCH1 is the major contributor, underlying 10% of AOS/ACC/TTLD cases, with DLL4 (6%), DOCK6 (6%), ARHGAP31 (3%), EOGT (3%), and RBPJ (2%) representing additional causality in this cohort. We confirm the relevance of genetic screening across the AOS/ACC/TTLD spectrum, highlighting preliminary but important genotype–phenotype correlations. This cohort offers potential for further gene identification to address missing heritability. © 2018 The Authors. Human Mutation published by Wiley Periodicals, Inc.

Published
2018

47. Clinical Presentation of a Complex Neurodevelopmental Disorder Caused by Mutations in ADNP

Author

Van Dijck, Anke, primary, Vulto-van Silfhout, Anneke T., additional, Cappuyns, Elisa, additional, van der Werf, Ilse M., additional, Mancini, Grazia M., additional, Tzschach, Andreas, additional, Bernier, Raphael, additional, Gozes, Illana, additional, Eichler, Evan E., additional, Romano, Corrado, additional, Lindstrand, Anna, additional, Nordgren, Ann, additional, Kvarnung, Malin, additional, Kleefstra, Tjitske, additional, de Vries, Bert B.A., additional, Küry, Sébastien, additional, Rosenfeld, Jill A., additional, Meuwissen, Marije E., additional, Vandeweyer, Geert, additional, Kooy, R. Frank, additional, Bakshi, Madhura, additional, Wilson, Meredith, additional, Berman, Yemina, additional, Dickson, Rebecca, additional, Fransen, Erik, additional, Helsmoortel, Céline, additional, Van den Ende, Jenneke, additional, Van der Aa, Nathalie, additional, van de Wijdeven, Marina J., additional, Rosenblum, Jessica, additional, Monteiro, Fabíola, additional, Kok, Fernando, additional, Quercia, Nada, additional, Bowdin, Sarah, additional, Dyment, David, additional, Chitayat, David, additional, Alkhunaizi, Ebba, additional, Boonen, Susanne E., additional, Keren, Boris, additional, Jacquette, Aurelia, additional, Faivre, Laurence, additional, Bezieau, Stephane, additional, Isidor, Bertrand, additional, Rieß, Angelika, additional, Moog, Ute, additional, Lynch, Sally Ann, additional, McVeigh, Terri, additional, Elpeleg, Orly, additional, Smeland, Marie Falkenberg, additional, Fannemel, Madeleine, additional, van Haeringen, Arie, additional, Maas, Saskia M., additional, Veenstra-Knol, H.E., additional, Schouten, Meyke, additional, Willemsen, Marjolein H., additional, Marcelis, Carlo L., additional, Ockeloen, Charlotte, additional, van der Burgt, Ineke, additional, Feenstra, Ilse, additional, van der Smagt, Jasper, additional, Jezela-Stanek, Aleksandra, additional, Krajewska-Walasek, Malgorzata, additional, González-Lamuño, Domingo, additional, Anderlid, Britt-Marie, additional, Malmgren, Helena, additional, Nordenskjöld, Magnus, additional, Clement, Emma, additional, Hurst, Jane, additional, Metcalfe, Kay, additional, Mansour, Sahar, additional, Lachlan, Katherine, additional, Clayton-Smith, Jill, additional, Hendon, Laura G., additional, Abdulrahman, Omar A., additional, Morrow, Eric, additional, McMillan, Clare, additional, Gerdts, Jennifer, additional, Peeden, Joseph, additional, Schrier Vergano, Samantha A., additional, Valentino, Caitlin, additional, Chung, Wendy K., additional, Ozmore, Jillian R., additional, Bedrosian-Sermone, Sandra, additional, Dennis, Anna, additional, Treat, Kayla, additional, Hughes, Susan Starling, additional, Safina, Nicole, additional, Le Pichon, Jean-Baptiste, additional, McGuire, Marianne, additional, Infante, Elena, additional, Madan-Khetarpal, Suneeta, additional, Desai, Sonal, additional, Benke, Paul, additional, Krokosky, Alyson, additional, Cristian, Ingrid, additional, Baker, Laura, additional, Gripp, Karen, additional, Stessman, Holly A., additional, Eichenberger, Jacob, additional, Jayakar, Parul, additional, Pizzino, Amy, additional, Manning, Melanie Ann, additional, and Slattery, Leah, additional

Published
2019
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48. CNV-WebStore: Online CNV Analysis, Storage and Interpretation

Author

Wuyts Wim, Reyniers Edwin, Vandeweyer Geert, Rooms Liesbeth, and Kooy R Frank

Subjects
Computer applications to medicine. Medical informatics, R858-859.7, Biology (General), QH301-705.5
Abstract

Abstract Background Microarray technology allows the analysis of genomic aberrations at an ever increasing resolution, making functional interpretation of these vast amounts of data the main bottleneck in routine implementation of high resolution array platforms, and emphasising the need for a centralised and easy to use CNV data management and interpretation system. Results We present CNV-WebStore, an online platform to streamline the processing and downstream interpretation of microarray data in a clinical context, tailored towards but not limited to the Illumina BeadArray platform. Provided analysis tools include CNV analsyis, parent of origin and uniparental disomy detection. Interpretation tools include data visualisation, gene prioritisation, automated PubMed searching, linking data to several genome browsers and annotation of CNVs based on several public databases. Finally a module is provided for uniform reporting of results. Conclusion CNV-WebStore is able to present copy number data in an intuitive way to both lab technicians and clinicians, making it a useful tool in daily clinical practice.

Published
2011
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49. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

Author

Schepers, Dorien, Tortora, Giada, Morisaki, Hiroko, MacCarrick, Gretchen, Lindsay, Mark, Liang, David, Mehta, Sarju G., Hague, Jennifer, Verhagen, Judith, van de Laar, Ingrid, Wessels, Marja, Detisch, Yvonne, van Haelst, Mieke, Baas, Annette, Lichtenbelt, Klaske, Braun, Kees, van der Linde, Denise, Roos-Hesselink, Jolien, McGillivray, George, Meester, Josephina, Maystadt, Isabelle, Coucke, Paul, El-Khoury, Elie, Parkash, Sandhya, Diness, Birgitte, Risom, Lotte, Scurr, Ingrid, Hilhorst-Hofstee, Yvonne, Morisaki, Takayuki, Richer, Julie, Désir, Julie, Kempers, Marlies, Rideout, Andrea L., Horne, Gabrielle, Bennett, Chris, Rahikkala, Elisa, Vandeweyer, Geert, Alaerts, Maaike, Verstraeten, Aline, Dietz, Hal, Van Laer, Lut, Loeys, Bart, Schepers, Dorien, Tortora, Giada, Morisaki, Hiroko, MacCarrick, Gretchen, Lindsay, Mark, Liang, David, Mehta, Sarju G., Hague, Jennifer, Verhagen, Judith, van de Laar, Ingrid, Wessels, Marja, Detisch, Yvonne, van Haelst, Mieke, Baas, Annette, Lichtenbelt, Klaske, Braun, Kees, van der Linde, Denise, Roos-Hesselink, Jolien, McGillivray, George, Meester, Josephina, Maystadt, Isabelle, Coucke, Paul, El-Khoury, Elie, Parkash, Sandhya, Diness, Birgitte, Risom, Lotte, Scurr, Ingrid, Hilhorst-Hofstee, Yvonne, Morisaki, Takayuki, Richer, Julie, Désir, Julie, Kempers, Marlies, Rideout, Andrea L., Horne, Gabrielle, Bennett, Chris, Rahikkala, Elisa, Vandeweyer, Geert, Alaerts, Maaike, Verstraeten, Aline, Dietz, Hal, Van Laer, Lut, and Loeys, Bart

Abstract

The Loeys–Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.

Published
2018

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