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1. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Published
2023
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3. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Author

Helbig, Katherine L, Lauerer, Robert J, Bahr, Jacqueline C, Souza, Ivana A, Myers, Candace T, Uysal, Betül, Schwarz, Niklas, Gandini, Maria A, Huang, Sun, Keren, Boris, Mignot, Cyril, Afenjar, Alexandra, de Villemeur, Thierry Billette, Héron, Delphine, Nava, Caroline, Valence, Stéphanie, Buratti, Julien, Fagerberg, Christina R, Soerensen, Kristina P, Kibaek, Maria, Kamsteeg, Erik-Jan, Koolen, David A, Gunning, Boudewijn, Schelhaas, H Jurgen, Kruer, Michael C, Fox, Jordana, Bakhtiari, Somayeh, Jarrar, Randa, Padilla-Lopez, Sergio, Lindstrom, Kristin, Jin, Sheng Chih, Zeng, Xue, Bilguvar, Kaya, Papavasileiou, Antigone, Xing, Qinghe, Zhu, Changlian, Boysen, Katja, Vairo, Filippo, Lanpher, Brendan C, Klee, Eric W, Tillema, Jan-Mendelt, Payne, Eric T, Cousin, Margot A, Kruisselbrink, Teresa M, Wick, Myra J, Baker, Joshua, Haan, Eric, Smith, Nicholas, Sadeghpour, Azita, Davis, Erica E, Katsanis, Nicholas, Genomics, Task Force for Neonatal, Allori, Alexander, Angrist, Misha, Ashley, Patricia, Bidegain, Margarita, Boyd, Brita, Chambers, Eileen, Cope, Heidi, Cotten, C Michael, Curington, Theresa, Ellestad, Sarah, Fisher, Kimberley, French, Amanda, Gallentine, William, Goldberg, Ronald, Hill, Kevin, Kansagra, Sujay, Katsanis, Sara, Kurtzberg, Joanne, Marcus, Jeffrey, McDonald, Marie, Mikati, Mohammed, Miller, Stephen, Murtha, Amy, Perilla, Yezmin, Pizoli, Carolyn, Purves, Todd, Ross, Sherry, Smith, Edward, Wiener, John, Corbett, Mark A, MacLennan, Alastair H, Gecz, Jozef, Biskup, Saskia, Goldmann, Eva, Rodan, Lance H, Kichula, Elizabeth, Segal, Eric, Jackson, Kelly E, Asamoah, Alexander, Dimmock, David, McCarrier, Julie, Botto, Lorenzo D, Filloux, Francis, Tvrdik, Tatiana, and Cascino, Gregory D

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Neurodegenerative, Brain Disorders, Neurosciences, Epilepsy, Pediatric, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adolescent, Adult, Calcium Channels, R-Type, Cation Transport Proteins, Child, Child, Preschool, Contracture, Dyskinesias, Female, Genetic Variation, Humans, Infant, Male, Megalencephaly, Neurodevelopmental Disorders, Spasms, Infantile, Task Force for Neonatal Genomics, Deciphering Developmental Disorders Study, CACNA1E, ion channel, arthrogryposis, calcium channel, epilepsy, Biological Sciences, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

Published
2018

4. Phenotypic heterogeneity and mosaicism in Xia-Gibbs syndrome: Five Danish patients with novel variants in AHDC1

Author

Faergeman, Soren L., Bojesen, Anders B., Rasmussen, Maria, Becher, Naja, Andreasen, Lotte, Andersen, Brian N., Erbs, Emilie, Lildballe, Dorte L., Nielsen, Jens Erik K., Zilmer, Monica, Hammer, Trine Bjørg, Andersen, Mikkel Ø., Brasch-Andersen, Charlotte, Fagerberg, Christina R., Illum, Niels O., Thorup, Mette B., and Gregersen, Pernille A.

Published
2021
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5. Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author

Harris, Holly K., Nakayama, Tojo, Lai, Jenny, Zhao, Boxun, Argyrou, Nikoleta, Gubbels, Cynthia S., Soucy, Aubrie, Genetti, Casie A., Suslovitch, Victoria, Rodan, Lance H., Tiller, George E., Lesca, Gaetan, Gripp, Karen W., Asadollahi, Reza, Hamosh, Ada, Applegate, Carolyn D., Turnpenny, Peter D., Simon, Marleen E. H., Volker-Touw, Catharina M. L., Gassen, Koen L. I. van, Binsbergen, Ellen van, Pfundt, Rolph, Gardeitchik, Thatjana, Vries, Bert B. A. de, Immken, LaDonna L., Buchanan, Catherine, Willing, Marcia, Toler, Tomi L., Fassi, Emily, Baker, Laura, Vansenne, Fleur, Wang, Xiadong, Ambrus, Jr., Julian L., Fannemel, Madeleine, Posey, Jennifer E., Agolini, Emanuele, Novelli, Antonio, Rauch, Anita, Boonsawat, Paranchai, Fagerberg, Christina R., Larsen, Martin J., Kibaek, Maria, Labalme, Audrey, Poisson, Alice, Payne, Katelyn K., Walsh, Laurence E., Aldinger, Kimberly A., Balciuniene, Jorune, Skraban, Cara, Gray, Christopher, Murrell, Jill, Bupp, Caleb P., Pascolini, Giulia, Grammatico, Paola, Broly, Martin, Küry, Sébastien, Nizon, Mathilde, Rasool, Iqra Ghulam, Zahoor, Muhammad Yasir, Kraus, Cornelia, Reis, André, Iqbal, Muhammad, Uguen, Kevin, Audebert-Bellanger, Severine, Ferec, Claude, Redon, Sylvia, Baker, Janice, Wu, Yunhong, Zampino, Guiseppe, Syrbe, Steffan, Brosse, Ines, Jamra, Rami Abou, Dobyns, William B., Cohen, Lilian L., Blomhoff, Anne, Mignot, Cyril, Keren, Boris, Courtin, Thomas, Agrawal, Pankaj B., Beggs, Alan H., and Yu, Timothy W.

Published
2021
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6. Comprehensive Noninvasive Fetal Screening by Deep Trio-Exome Sequencing

Author

Miceikaitė, Ieva, primary, Hao, Qin, additional, Brasch-Andersen, Charlotte, additional, Fagerberg, Christina R., additional, Torring, Pernille M., additional, Kristiansen, Britta S., additional, Ousager, Lilian B., additional, Sperling, Lene, additional, Ibsen, Mette H., additional, Löser, Katrin, additional, and Larsen, Martin J., additional

Published
2023
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7. CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Author

Gehin, Charlotte, primary, Lone, Museer A., additional, Lee, Winston, additional, Capolupo, Laura, additional, Ho, Sylvia, additional, Adeyemi, Adekemi M., additional, Gerkes, Erica H., additional, Stegmann, Alexander P.A., additional, López-Martín, Estrella, additional, Bermejo-Sánchez, Eva, additional, Martínez-Delgado, Beatriz, additional, Zweier, Christiane, additional, Kraus, Cornelia, additional, Popp, Bernt, additional, Strehlow, Vincent, additional, Gräfe, Daniel, additional, Knerr, Ina, additional, Jones, Eppie R., additional, Zamuner, Stefano, additional, Abriata, Luciano A., additional, Kunnathully, Vidya, additional, Moeller, Brandon E., additional, Vocat, Anthony, additional, Rommelaere, Samuel, additional, Bocquete, Jean-Philippe, additional, Ruchti, Evelyne, additional, Limoni, Greta, additional, Van Campenhoudt, Marine, additional, Bourgeat, Samuel, additional, Henklein, Petra, additional, Gilissen, Christian, additional, van Bon, Bregje W., additional, Pfundt, Rolph, additional, Willemsen, Marjolein H., additional, Schieving, Jolanda H., additional, Leonardi, Emanuela, additional, Soli, Fiorenza, additional, Murgia, Alessandra, additional, Guo, Hui, additional, Zhang, Qiumeng, additional, Xia, Kun, additional, Fagerberg, Christina R., additional, Beier, Christoph P., additional, Larsen, Martin J., additional, Valenzuela, Irene, additional, Fernández-Álvarez, Paula, additional, Xiong, Shiyi, additional, Śmigiel, Robert, additional, López-González, Vanesa, additional, Armengol, Lluís, additional, Morleo, Manuela, additional, Selicorni, Angelo, additional, Torella, Annalaura, additional, Blyth, Moira, additional, Cooper, Nicola S., additional, Wilson, Valerie, additional, Oegema, Renske, additional, Herenger, Yvan, additional, Garde, Aurore, additional, Bruel, Ange-Line, additional, Tran Mau-Them, Frederic, additional, Maddocks, Alexis B.R., additional, Bain, Jennifer M., additional, Bhat, Musadiq A., additional, Costain, Gregory, additional, Kannu, Peter, additional, Marwaha, Ashish, additional, Champaigne, Neena L., additional, Friez, Michael J., additional, Richardson, Ellen B., additional, Gowda, Vykuntaraju K., additional, Srinivasan, Varunvenkat M., additional, Gupta, Yask, additional, Lim, Tze Y., additional, Sanna-Cherchi, Simone, additional, Lemaitre, Bruno, additional, Yamaji, Toshiyuki, additional, Hanada, Kentaro, additional, Burke, John E., additional, Jakšić, Ana Marjia, additional, McCabe, Brian D., additional, De Los Rios, Paolo, additional, Hornemann, Thorsten, additional, D’Angelo, Giovanni, additional, and Gennarino, Vincenzo A., additional

Published
2023
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8. CERT1 mutations perturb human development by disrupting sphingolipid homeostasis

Author

Genetica Klinische Genetica, Brain, Child Health, Gehin, Charlotte, Lone, Museer A, Lee, Winston, Capolupo, Laura, Ho, Sylvia, Adeyemi, Adekemi M, Gerkes, Erica H, Stegmann, Alexander Pa, López-Martín, Estrella, Bermejo-Sánchez, Eva, Martínez-Delgado, Beatriz, Zweier, Christiane, Kraus, Cornelia, Popp, Bernt, Strehlow, Vincent, Gräfe, Daniel, Knerr, Ina, Jones, Eppie R, Zamuner, Stefano, Abriata, Luciano A, Kunnathully, Vidya, Moeller, Brandon E, Vocat, Anthony, Rommelaere, Samuel, Bocquete, Jean-Philippe, Ruchti, Evelyne, Limoni, Greta, Van Campenhoudt, Marine, Bourgeat, Samuel, Henklein, Petra, Gilissen, Christian, van Bon, Bregje W, Pfundt, Rolph, Willemsen, Marjolein H, Schieving, Jolanda H, Leonardi, Emanuela, Soli, Fiorenza, Murgia, Alessandra, Guo, Hui, Zhang, Qiumeng, Xia, Kun, Fagerberg, Christina R, Beier, Christoph P, Larsen, Martin J, Valenzuela, Irene, Fernández-Álvarez, Paula, Xiong, Shiyi, Śmigiel, Robert, López-González, Vanesa, Armengol, Lluís, Morleo, Manuela, Selicorni, Angelo, Torella, Annalaura, Blyth, Moira, Cooper, Nicola S, Wilson, Valerie, Oegema, Renske, Herenger, Yvan, Garde, Aurore, Bruel, Ange-Line, Tran Mau-Them, Frederic, Maddocks, Alexis Br, Bain, Jennifer M, Bhat, Musadiq A, Costain, Gregory, Kannu, Peter, Marwaha, Ashish, Champaigne, Neena L, Friez, Michael J, Richardson, Ellen B, Gowda, Vykuntaraju K, Srinivasan, Varunvenkat M, Gupta, Yask, Lim, Tze Y, Sanna-Cherchi, Simone, Lemaitre, Bruno, Yamaji, Toshiyuki, Hanada, Kentaro, Burke, John E, Jakšić, Ana Marija, McCabe, Brian D, De Los Rios, Paolo, Hornemann, Thorsten, D'Angelo, Giovanni, Gennarino, Vincenzo A, Genetica Klinische Genetica, Brain, Child Health, Gehin, Charlotte, Lone, Museer A, Lee, Winston, Capolupo, Laura, Ho, Sylvia, Adeyemi, Adekemi M, Gerkes, Erica H, Stegmann, Alexander Pa, López-Martín, Estrella, Bermejo-Sánchez, Eva, Martínez-Delgado, Beatriz, Zweier, Christiane, Kraus, Cornelia, Popp, Bernt, Strehlow, Vincent, Gräfe, Daniel, Knerr, Ina, Jones, Eppie R, Zamuner, Stefano, Abriata, Luciano A, Kunnathully, Vidya, Moeller, Brandon E, Vocat, Anthony, Rommelaere, Samuel, Bocquete, Jean-Philippe, Ruchti, Evelyne, Limoni, Greta, Van Campenhoudt, Marine, Bourgeat, Samuel, Henklein, Petra, Gilissen, Christian, van Bon, Bregje W, Pfundt, Rolph, Willemsen, Marjolein H, Schieving, Jolanda H, Leonardi, Emanuela, Soli, Fiorenza, Murgia, Alessandra, Guo, Hui, Zhang, Qiumeng, Xia, Kun, Fagerberg, Christina R, Beier, Christoph P, Larsen, Martin J, Valenzuela, Irene, Fernández-Álvarez, Paula, Xiong, Shiyi, Śmigiel, Robert, López-González, Vanesa, Armengol, Lluís, Morleo, Manuela, Selicorni, Angelo, Torella, Annalaura, Blyth, Moira, Cooper, Nicola S, Wilson, Valerie, Oegema, Renske, Herenger, Yvan, Garde, Aurore, Bruel, Ange-Line, Tran Mau-Them, Frederic, Maddocks, Alexis Br, Bain, Jennifer M, Bhat, Musadiq A, Costain, Gregory, Kannu, Peter, Marwaha, Ashish, Champaigne, Neena L, Friez, Michael J, Richardson, Ellen B, Gowda, Vykuntaraju K, Srinivasan, Varunvenkat M, Gupta, Yask, Lim, Tze Y, Sanna-Cherchi, Simone, Lemaitre, Bruno, Yamaji, Toshiyuki, Hanada, Kentaro, Burke, John E, Jakšić, Ana Marija, McCabe, Brian D, De Los Rios, Paolo, Hornemann, Thorsten, D'Angelo, Giovanni, and Gennarino, Vincenzo A

Published
2023

9. CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology

Author

Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institutes of Health (US), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Hospital for Sick Children (Canada), University of Toronto, University of Southern Denmark, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A., Gurnett, Christina A., Jelsig, Anne Marie, Vineke, Susanne H., Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T., Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M., Semina, Elena V., Reuter, Miriam S., Scherer, Stephen W., Iascone, Maria, Weis, Denisa, Fagerberg, Christina R., Brasch-Andersen, Charlotte, Kjaersgaard Hansen, Lars, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B., Pavlidou, Despoina C., Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R., Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M., Lemke, Johannes R., Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Published
2023

10. CUX1-related neurodevelopmental disorder:deep insights into phenotype-genotype spectrum and underlying pathology

Author

Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, Platzer, Konrad, Oppermann, Henry, Marcos-Grañeda, Elia, Weiss, Linnea A, Gurnett, Christina A, Jelsig, Anne Marie, Vineke, Susanne H, Isidor, Bertrand, Mercier, Sandra, Magnussen, Kari, Zacher, Pia, Hashim, Mona, Pagnamenta, Alistair T, Race, Simone, Srivastava, Siddharth, Frazier, Zoë, Maiwald, Robert, Pergande, Matthias, Milani, Donatella, Rinelli, Martina, Levy, Jonathan, Krey, Ilona, Fontana, Paolo, Lonardo, Fortunato, Riley, Stephanie, Kretzer, Jasmine, Rankin, Julia, Reis, Linda M, Semina, Elena V, Reuter, Miriam S, Scherer, Stephen W, Iascone, Maria, Weis, Denisa, Fagerberg, Christina R, Brasch-Andersen, Charlotte, Hansen, Lars Kjaersgaard, Kuechler, Alma, Noble, Nathan, Gardham, Alice, Tenney, Jessica, Rathore, Geetanjali, Beck-Woedl, Stefanie, Haack, Tobias B, Pavlidou, Despoina C, Atallah, Isis, Vodopiutz, Julia, Janecke, Andreas R, Hsieh, Tzung-Chien, Lesmann, Hellen, Klinkhammer, Hannah, Krawitz, Peter M, Lemke, Johannes R, Jamra, Rami Abou, Nieto, Marta, Tümer, Zeynep, and Platzer, Konrad

Abstract

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/− mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/− mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/− mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/− brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course., Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1+/- mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1+/- mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1+/- mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1+/- brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

Published
2023

12. Carriers ofCOL3A1pathogenic variants in Denmark: Interfamilial variability in severity and outcome of elective surgical procedures

Author

Sølyst, Sofus, primary, Oksjoki, Riina, additional, Farholt, Stense, additional, Nielsen, Dorte Guldbrand, additional, Christensen, Alex H., additional, Fagerberg, Christina R., additional, Risom, Lotte, additional, Gregersen, Pernille Axél, additional, Christensen, Maria Bejerholm, additional, Rasmussen, Torsten Bloch, additional, and Diness, Birgitte Rode, additional

Published
2022
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15. Carriers of COL3A1 pathogenic variants in Denmark:Interfamilial variability in severity and outcome of elective surgical procedures

Author

Sølyst, Sofus, Oksjoki, Riina, Farholt, Stense, Nielsen, Dorte Guldbrand, Christensen, Alex H., Fagerberg, Christina R., Risom, Lotte, Gregersen, Pernille Axél, Christensen, Maria Bejerholm, Rasmussen, Torsten Bloch, Diness, Birgitte Rode, Sølyst, Sofus, Oksjoki, Riina, Farholt, Stense, Nielsen, Dorte Guldbrand, Christensen, Alex H., Fagerberg, Christina R., Risom, Lotte, Gregersen, Pernille Axél, Christensen, Maria Bejerholm, Rasmussen, Torsten Bloch, and Diness, Birgitte Rode

Abstract

The study describes all patients in Denmark with vascular Ehlers–Danlos syndrome (vEDS). Carriers of pathogenic or likely pathogenic COL3A1 variants were retrospectively identified through registries and specialized clinics. Medical records were reviewed for vascular- or organ ruptures and invasive procedures performed. Identified families were divided by variant type (null, splice, and missense) and familial phenotypes (severe or attenuated). Families in which at least one carrier has suffered a major event before the age of 30 were classified as severe, whereas families in which at least three carriers had reached the age of 40 without a major event were classified as attenuated. Eighty-seven persons (59 still alive) from 25 families were included with a mean observation time of 44 years. Sixty-seven percent of patients could be subclassified in a familial phenotype. Thirty-one major events were observed. Eleven complications in 172 invasive procedures were recorded. No fatal complications to elective surgery were observed. The type of COL3A1 variant did not reliably predict phenotype, but a pattern of intrafamilial consistency emerged with some families showing an attenuated form of vEDS. Elective medical procedures appear to be safer than previously thought, although data only allow for conclusions regarding individuals from families with the attenuated form of vEDS.

Published
2022

17. Carriers of COL3A1 pathogenic variants in Denmark: Interfamilial variability in severity and outcome of elective surgical procedures.

Author

Sølyst, Sofus, Oksjoki, Riina, Farholt, Stense, Nielsen, Dorte Guldbrand, Christensen, Alex H., Fagerberg, Christina R., Risom, Lotte, Gregersen, Pernille Axél, Christensen, Maria Bejerholm, Rasmussen, Torsten Bloch, and Diness, Birgitte Rode

Subjects
OPERATIVE surgery, EHLERS-Danlos syndrome, ORGAN rupture, SURGICAL complications, ELECTIVE surgery
Abstract

The study describes all patients in Denmark with vascular Ehlers–Danlos syndrome (vEDS). Carriers of pathogenic or likely pathogenic COL3A1 variants were retrospectively identified through registries and specialized clinics. Medical records were reviewed for vascular‐ or organ ruptures and invasive procedures performed. Identified families were divided by variant type (null, splice, and missense) and familial phenotypes (severe or attenuated). Families in which at least one carrier has suffered a major event before the age of 30 were classified as severe, whereas families in which at least three carriers had reached the age of 40 without a major event were classified as attenuated. Eighty‐seven persons (59 still alive) from 25 families were included with a mean observation time of 44 years. Sixty‐seven percent of patients could be subclassified in a familial phenotype. Thirty‐one major events were observed. Eleven complications in 172 invasive procedures were recorded. No fatal complications to elective surgery were observed. The type of COL3A1 variant did not reliably predict phenotype, but a pattern of intrafamilial consistency emerged with some families showing an attenuated form of vEDS. Elective medical procedures appear to be safer than previously thought, although data only allow for conclusions regarding individuals from families with the attenuated form of vEDS. [ABSTRACT FROM AUTHOR]

Published
2022
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18. Epileptic encephalopathy caused by ARV1 deficiency: Refinement of the genotype–phenotype spectrum and functional impact on GPI ‐anchored proteins

Author

Salian, Smrithi, primary, Scala, Marcello, additional, Nguyen, Thi Tuyet Mai, additional, Severino, Mariasavina, additional, Accogli, Andrea, additional, Amadori, Elisabetta, additional, Torella, Annalaura, additional, Pinelli, Michele, additional, Hudson, Beth, additional, Boothe, Megan, additional, Hurst, Anna, additional, Ben‐Omran, Tawfeg, additional, Larsen, Martin J., additional, Fagerberg, Christina R., additional, Sperling, Lene, additional, Miceikaite, Ieva, additional, Herissant, Lucas, additional, Doco‐Fenzy, Martine, additional, Jennesson, Mélanie, additional, Nigro, Vincenzo, additional, Striano, Pasquale, additional, Minetti, Carlo, additional, Sachdev, Rani K., additional, Palmer, Emma Elizabeth, additional, Capra, Valeria, additional, and Campeau, Philippe M., additional

Published
2021
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19. Phenotypic heterogeneity and mosaicism in Xia-Gibbs syndrome:Five Danish patients with novel variants in AHDC1

Author

Faergeman, Soren L., Bojesen, Anders B., Rasmussen, Maria, Becher, Naja, Andreasen, Lotte, Andersen, Brian N., Erbs, Emilie, Lildballe, Dorte L., Nielsen, Jens Erik K., Zilmer, Monica, Hammer, Trine Bjørg, Andersen, Mikkel, Brasch-Andersen, Charlotte, Fagerberg, Christina R., Illum, Niels O., Thorup, Mette B., Gregersen, Pernille A., Faergeman, Soren L., Bojesen, Anders B., Rasmussen, Maria, Becher, Naja, Andreasen, Lotte, Andersen, Brian N., Erbs, Emilie, Lildballe, Dorte L., Nielsen, Jens Erik K., Zilmer, Monica, Hammer, Trine Bjørg, Andersen, Mikkel, Brasch-Andersen, Charlotte, Fagerberg, Christina R., Illum, Niels O., Thorup, Mette B., and Gregersen, Pernille A.

Abstract

Xia-Gibbs syndrome (XGS) is a neurodevelopmental disorder characterized by intellectual disability, developmental delay, seizures, hypotonia, obstructive sleep apnoea and mild facial dysmorphism. Heterozygosity for loss-of-function variants in AHDC1, encoding the AT-hook DNA binding motif containing protein 1, were discovered in 2014 as the likely genetic cause of Xia-Gibbs syndrome. We present five patients with Xia-Gibbs syndrome caused by previously unreported variants in AHDC1. Two of the patients share a frameshift variant: c.2849del (p.(Pro950Argfs*192)) in AHDC1. Despite sharing this variant, the two patients show remarkable phenotypic differences underscoring the clinical heterogeneity of Xia-Gibbs syndrome. In addition, we present a case of Xia-Gibbs syndrome caused by mosaicism for an AHDC1 variant.

Published
2021

20. Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Harris, Holly K, Nakayama, Tojo, Lai, Jenny, Zhao, Boxun, Argyrou, Nikoleta, Gubbels, Cynthia S, Soucy, Aubrie, Genetti, Casie A, Suslovitch, Victoria, Rodan, Lance H, Tiller, George E, Lesca, Gaetan, Gripp, Karen W, Asadollahi, Reza, Hamosh, Ada, Applegate, Carolyn D, Turnpenny, Peter D, Simon, Marleen E H, Volker-Touw, Catharina M L, Gassen, Koen L I van, Binsbergen, Ellen van, Pfundt, Rolph, Gardeitchik, Thatjana, Vries, Bert B A de, Immken, LaDonna L, Buchanan, Catherine, Willing, Marcia, Toler, Tomi L, Fassi, Emily, Baker, Laura, Vansenne, Fleur, Wang, Xiadong, Ambrus, Julian L, Fannemel, Madeleine, Posey, Jennifer E, Agolini, Emanuele, Novelli, Antonio, Rauch, Anita, Boonsawat, Paranchai, Fagerberg, Christina R, Larsen, Martin J, Kibaek, Maria, Labalme, Audrey, Poisson, Alice, Payne, Katelyn K, Walsh, Laurence E, Aldinger, Kimberly A, Balciuniene, Jorune, Skraban, Cara, Gray, Christopher, Murrell, Jill, Bupp, Caleb P, Pascolini, Giulia, Grammatico, Paola, Broly, Martin, Küry, Sébastien, Nizon, Mathilde, Rasool, Iqra Ghulam, Zahoor, Muhammad Yasir, Kraus, Cornelia, Reis, André, Iqbal, Muhammad, Uguen, Kevin, Audebert-Bellanger, Severine, Ferec, Claude, Redon, Sylvia, Baker, Janice, Wu, Yunhong, Zampino, Guiseppe, Syrbe, Steffan, Brosse, Ines, Jamra, Rami Abou, Dobyns, William B, Cohen, Lilian L, Blomhoff, Anne, Mignot, Cyril, Keren, Boris, Courtin, Thomas, Agrawal, Pankaj B, Beggs, Alan H, Yu, Timothy W, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Harris, Holly K, Nakayama, Tojo, Lai, Jenny, Zhao, Boxun, Argyrou, Nikoleta, Gubbels, Cynthia S, Soucy, Aubrie, Genetti, Casie A, Suslovitch, Victoria, Rodan, Lance H, Tiller, George E, Lesca, Gaetan, Gripp, Karen W, Asadollahi, Reza, Hamosh, Ada, Applegate, Carolyn D, Turnpenny, Peter D, Simon, Marleen E H, Volker-Touw, Catharina M L, Gassen, Koen L I van, Binsbergen, Ellen van, Pfundt, Rolph, Gardeitchik, Thatjana, Vries, Bert B A de, Immken, LaDonna L, Buchanan, Catherine, Willing, Marcia, Toler, Tomi L, Fassi, Emily, Baker, Laura, Vansenne, Fleur, Wang, Xiadong, Ambrus, Julian L, Fannemel, Madeleine, Posey, Jennifer E, Agolini, Emanuele, Novelli, Antonio, Rauch, Anita, Boonsawat, Paranchai, Fagerberg, Christina R, Larsen, Martin J, Kibaek, Maria, Labalme, Audrey, Poisson, Alice, Payne, Katelyn K, Walsh, Laurence E, Aldinger, Kimberly A, Balciuniene, Jorune, Skraban, Cara, Gray, Christopher, Murrell, Jill, Bupp, Caleb P, Pascolini, Giulia, Grammatico, Paola, Broly, Martin, Küry, Sébastien, Nizon, Mathilde, Rasool, Iqra Ghulam, Zahoor, Muhammad Yasir, Kraus, Cornelia, Reis, André, Iqbal, Muhammad, Uguen, Kevin, Audebert-Bellanger, Severine, Ferec, Claude, Redon, Sylvia, Baker, Janice, Wu, Yunhong, Zampino, Guiseppe, Syrbe, Steffan, Brosse, Ines, Jamra, Rami Abou, Dobyns, William B, Cohen, Lilian L, Blomhoff, Anne, Mignot, Cyril, Keren, Boris, Courtin, Thomas, Agrawal, Pankaj B, Beggs, Alan H, and Yu, Timothy W

Published
2021

22. De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies

Author

Holt, Richard J., Young, Rodrigo M., Crespo, Berta, Ceroni, Fabiola, Curry, Cynthia J., Bellacchio, Emanuele, Bax, Dorine A., Ciolfi, Andrea, Simon, Marleen, Fagerberg, Christina R., van Binsbergen, Ellen, De Luca, Alessandro, Memo, Luigi, Dobyns, William B., Mohammed, Alaa Afif, Clokie, Samuel J.H., Zazo Seco, Celia, Jiang, Yong-Hui, Sørensen, Kristina P., Andersen, Helle, Sullivan, Jennifer, Powis, Zöe, Chassevent, Anna, Smith-Hicks, Constance, Petrovski, Slavé, Antoniadi, Thalia, Shashi, Vandana, Gelb, Bruce D., Wilson, Stephen W., Gerrelli, Dianne, Tartaglia, Marco, Chassaing, Nicolas, Calvas, Patrick, and Ragge, Nicola K.

Published
2019
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23. NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism

Author

Guo, Hui, primary, Zhang, Qiumeng, additional, Dai, Rujia, additional, Yu, Bin, additional, Hoekzema, Kendra, additional, Tan, Jieqiong, additional, Tan, Senwei, additional, Jia, Xiangbin, additional, Chung, Wendy K., additional, Hernan, Rebecca, additional, Alkuraya, Fowzan S., additional, Alsulaiman, Ahood, additional, Al-Muhaizea, Mohammad A., additional, Lesca, Gaetan, additional, Pons, Linda, additional, Labalme, Audrey, additional, Laux, Linda, additional, Bryant, Emily, additional, Brown, Natasha J., additional, Savva, Elena, additional, Ayres, Samantha, additional, Eratne, Dhamidhu, additional, Peeters, Hilde, additional, Bilan, Frédéric, additional, Letienne-Cejudo, Lucile, additional, Gilbert-Dussardier, Brigitte, additional, Ruiz-Arana, Inge-Lore, additional, Merlini, Jenny Meylan, additional, Boizot, Alexia, additional, Bartoloni, Lucia, additional, Santoni, Federico, additional, Karlowicz, Danielle, additional, McDonald, Marie, additional, Wu, Huidan, additional, Hu, Zhengmao, additional, Chen, Guodong, additional, Ou, Jianjun, additional, Brasch-Andersen, Charlotte, additional, Fagerberg, Christina R., additional, Dreyer, Inken, additional, chun-hui Tsai, Anne, additional, Slegesky, Valerie, additional, McGee, Rose B., additional, Daniels, Brina, additional, Sellars, Elizabeth A., additional, Carpenter, Lori A., additional, Schaefer, Bradley, additional, Sacoto, Maria J. Guillen, additional, Begtrup, Amber, additional, Schnur, Rhonda E., additional, Punj, Sumit, additional, Wentzensen, Ingrid M., additional, Rhodes, Lindsay, additional, Pan, Qian, additional, Bernier, Raphael A., additional, Chen, Chao, additional, Eichler, Evan E., additional, and Xia, Kun, additional

Published
2020
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24. Disruption of RFX family transcription factors causes autism, attention deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author

Harris, Holly K., primary, Nakayama, Tojo, additional, Lai, Jenny, additional, Zhao, Boxun, additional, Argyrou, Nikoleta, additional, Gubbels, Cynthia S., additional, Soucy, Aubrie, additional, Genetti, Casie A., additional, Rodan, Lance H., additional, Tiller, George E., additional, Lesca, Gaetan, additional, Gripp, Karen W., additional, Asadollahi, Reza, additional, Hamosh, Ada, additional, Applegate, Carolyn D., additional, Turnpenny, Peter D., additional, Simon, Marleen E.H., additional, Volker-Touw, Catharina (Nienke) M.L., additional, van Gassen, Koen L.I., additional, van Binsbergen, Ellen, additional, Pfundt, Rolph, additional, Gardeitchik, Thatjana, additional, de Vries, Bert B.A., additional, Imken, Ladonna L., additional, Buchanan, Catherine, additional, Willing, Marcia, additional, Toler, Tomi L., additional, Fassi, Emily, additional, Baker, Laura, additional, Vansenne, Fleur, additional, Wang, Xiadong, additional, Ambrus, Julian L., additional, Fannemel, Madeleine, additional, Posey, Jennifer E., additional, Agolini, Emanuele, additional, Novelli, Antonio, additional, Rauch, Anita, additional, Boonsawat, Paranchai, additional, Fagerberg, Christina R., additional, Larsen, Martin J., additional, Kibaek, Maria, additional, Labalme, Audrey, additional, Poisson, Alice, additional, Payne, Katelyn K., additional, Walsh, Laurence E., additional, Aldinger, Kimberly, additional, Balciuniene, Jorune, additional, Skraban, Cara, additional, Gray, Christopher, additional, Murrell, Jill, additional, Bupp, Caleb P., additional, Pascolini, Giulia, additional, Grammatico, Paola, additional, Broly, Martin, additional, Küry, Sébastien, additional, Nizon, Mathilde, additional, Rasool, Iqra Ghulam, additional, Zahoor, Muhammad Yasir, additional, Kraus, Cornelia, additional, Reis, André, additional, Iqbal, Muhammad, additional, Uguen, Kevin, additional, Audebert-Bellanger, Severine, additional, Ferec, Claude, additional, Redon, Sylvia, additional, Baker, Janice, additional, Wu, Yunhong, additional, Zampino, Guiseppe, additional, Syrbe, Steffan, additional, Brosse, Ines, additional, Jamra, Rami Abou, additional, Dobyns, William B., additional, Cohen, Lilian L., additional, Agrawal, Pankaj B., additional, Beggs, Alan, additional, and Yu, Timothy W., additional

Published
2020
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25. Bi-allelic Loss-of-Function Variants in NUP188 Cause a Recognizable Syndrome Characterized by Neurologic, Ocular, and Cardiac Abnormalities

Author

Muir, Alison M., primary, Cohen, Jennifer L., additional, Sheppard, Sarah E., additional, Guttipatti, Pavithran, additional, Lo, Tsz Y., additional, Weed, Natalie, additional, Doherty, Dan, additional, DeMarzo, Danielle, additional, Fagerberg, Christina R., additional, Kjærsgaard, Lars, additional, Larsen, Martin J., additional, Rump, Patrick, additional, Löhner, Katharina, additional, Hirsch, Yoel, additional, Zeevi, David A., additional, Zackai, Elaine H., additional, Bhoj, Elizabeth, additional, Song, Yuanquan, additional, and Mefford, Heather C., additional

Published
2020
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26. A new 1p36.13‐1p36.12 microdeletion syndrome characterized by learning disability, behavioral abnormalities, and ptosis

Author

Aagaard Nolting, Line, primary, Brasch‐Andersen, Charlotte, additional, Cox, Helen, additional, Kanani, Farah, additional, Parker, Michael, additional, Fry, Andrew E., additional, Loddo, Sara, additional, Novelli, Antonio, additional, Dentici, Maria Lisa, additional, Joss, Shelagh, additional, Jørgensen, Joan P., additional, and Fagerberg, Christina R., additional

Published
2020
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28. Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration

Author

Fagerberg, Christina R, primary, Taylor, Adrian, additional, Distelmaier, Felix, additional, Schrøder, Henrik D, additional, Kibæk, Maria, additional, Wieczorek, Dagmar, additional, Tarnopolsky, Mark, additional, Brady, Lauren, additional, Larsen, Martin J, additional, Jamra, Rami A, additional, Seibt, Annette, additional, Hejbøl, Eva Kildall, additional, Gade, Else, additional, Markovic, Ljubo, additional, Klee, Dirk, additional, Nagy, Peter, additional, Rouse, Nicholas, additional, Agarwal, Prasoon, additional, Dolinsky, Vernon W, additional, and Bakovic, Marica, additional

Published
2019
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29. Mono‐allelic loss of YTHDF3 and neurodevelopmental disorder: clinical features of four individuals with 8q12.3 deletions.

Author

Terkelsen, Thorkild, Brasch‐Andersen, Charlotte, Illum, Niels, Busa, Tiffany, Missirian, Chantal, Chandler, Kate, Holden, Simon T., Jensen, Uffe Birk, and Fagerberg, Christina R.

Subjects
INTELLECTUAL disabilities, DEVELOPMENTAL delay, NEURAL development, CENTRAL nervous system, CHILDREN with developmental disabilities, PEOPLE with disabilities, FRAGILE X syndrome
Abstract

The YTH domain family member 3 gene (YTHDF3) encodes a reader of the abundant N6‐methyladenosine (m6A) modification of eukaryotic mRNA, which plays an essential role in regulating mRNA stability and is necessary to achieve normal development of the central nervous system in animal models. YTHDF3 has not previously been implicated in Mendelian disease despite a high probability of loss of function intolerance and statistical evidence of enrichment for gene‐disruptive de novo variants in large‐scale studies of individuals with intellectual disability and/or developmental delay. We report four individuals with deletion of 8q12.3, deletion size 1.38–2.60 Mb, encompassing YTHDF3, three of them were de novo, and in one case, the inheritance was unknown. Common features of the individuals (age range, 4–22 years) were developmental delay and/or intellectual disability. Two individuals underwent squint surgery. We suggest that haploinsufficiency of YTHDF3 causes a neurodevelopmental disorder with developmental delay and intellectual disability of variable degree. [ABSTRACT FROM AUTHOR]

Published
2022
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30. ZTTK syndrome: Clinical and molecular findings of 15 cases and a review of the literature.

Author

Kushary, Sulagna Tina, Revah‐Politi, Anya, Barua, Subit, Ganapathi, Mythily, Accogli, Andrea, Aggarwal, Vimla, Brunetti‐Pierri, Nicola, Cappuccio, Gerarda, Capra, Valeria, Fagerberg, Christina R., Gazdagh, Gabriella, Guzman, Edwin, Hadonou, Medard, Harrison, Victoria, Havelund, Kathrine, Iancu, Daniela, Kraus, Alison, Lippa, Natalie C., Mansukhani, Mahesh, and McBrian, Danielle

Abstract

Zhu‐Tokita‐Takenouchi‐Kim (ZTTK) syndrome is caused by de novo loss‐of‐function variants in the SON gene (MIM #617140). This multisystemic disorder is characterized by intellectual disability, seizures, abnormal brain imaging, variable dysmorphic features, and various congenital anomalies. The wide application and increasing accessibility of whole exome sequencing (WES) has helped to identify new cases of ZTTK syndrome over the last few years. To date, there have been approximately 45 cases reported in the literature. Here, we describe 15 additional individuals with variants in the SON gene, including those with missense variants bringing the total number of known cases to 60. We have reviewed the clinical and molecular data of these new cases and all previously reported cases to further delineate the most common as well as emerging clinical findings related to this syndrome. Furthermore, we aim to delineate any genotype–phenotype correlations specifically for a recurring pathogenic four base pair deletion (c.5753_5756del) along with discussing the impact of missense variants seen in the SON gene. [ABSTRACT FROM AUTHOR]

Published
2021
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31. Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements

Author

Schönewolf-Greulich, Bitten, Bisgaard, Anne Marie, Dunø, Morten, Jespersgaard, Cathrine, Rokkjær, Mette, Hansen, Lars K., Tsoutsou, Eirini, Sofokleous, Christalena, Topcu, Meral, Kaur, Simran, Van Bergen, Nicole J., Brøndum-Nielsen, Karen, Larsen, Martin J., Sørensen, Kristina P., Christodoulou, John, Fagerberg, Christina R., Tümer, Zeynep, Schönewolf-Greulich, Bitten, Bisgaard, Anne Marie, Dunø, Morten, Jespersgaard, Cathrine, Rokkjær, Mette, Hansen, Lars K., Tsoutsou, Eirini, Sofokleous, Christalena, Topcu, Meral, Kaur, Simran, Van Bergen, Nicole J., Brøndum-Nielsen, Karen, Larsen, Martin J., Sørensen, Kristina P., Christodoulou, John, Fagerberg, Christina R., and Tümer, Zeynep

Abstract

Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS-based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield.

Published
2019

32. De Novo Missense Variants in FBXW11 Cause Diverse Developmental Phenotypes Including Brain, Eye, and Digit Anomalies

Author

Genetica, Genetica Klinische Genetica, Genetica Sectie Genoomdiagnostiek, Child Health, Holt, Richard J., Young, Rodrigo M., Crespo, Berta, Ceroni, Fabiola, Curry, Cynthia J., Bellacchio, Emanuele, Bax, Dorine A., Ciolfi, Andrea, Simon, Marleen, Fagerberg, Christina R., van Binsbergen, Ellen, De Luca, Alessandro, Memo, Luigi, Dobyns, William B., Mohammed, Alaa Afif, Clokie, Samuel J.H., Zazo Seco, Celia, Jiang, Yong Hui, Sørensen, Kristina P., Andersen, Helle, Sullivan, Jennifer, Powis, Zöe, Chassevent, Anna, Smith-Hicks, Constance, Petrovski, Slavé, Antoniadi, Thalia, Shashi, Vandana, Gelb, Bruce D., Wilson, Stephen W., Gerrelli, Dianne, Tartaglia, Marco, Chassaing, Nicolas, Calvas, Patrick, Ragge, Nicola K., Genetica, Genetica Klinische Genetica, Genetica Sectie Genoomdiagnostiek, Child Health, Holt, Richard J., Young, Rodrigo M., Crespo, Berta, Ceroni, Fabiola, Curry, Cynthia J., Bellacchio, Emanuele, Bax, Dorine A., Ciolfi, Andrea, Simon, Marleen, Fagerberg, Christina R., van Binsbergen, Ellen, De Luca, Alessandro, Memo, Luigi, Dobyns, William B., Mohammed, Alaa Afif, Clokie, Samuel J.H., Zazo Seco, Celia, Jiang, Yong Hui, Sørensen, Kristina P., Andersen, Helle, Sullivan, Jennifer, Powis, Zöe, Chassevent, Anna, Smith-Hicks, Constance, Petrovski, Slavé, Antoniadi, Thalia, Shashi, Vandana, Gelb, Bruce D., Wilson, Stephen W., Gerrelli, Dianne, Tartaglia, Marco, Chassaing, Nicolas, Calvas, Patrick, and Ragge, Nicola K.

Published
2019

33. De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

Author

Helbig, Katherine L., primary, Lauerer, Robert J., additional, Bahr, Jacqueline C., additional, Souza, Ivana A., additional, Myers, Candace T., additional, Uysal, Betül, additional, Schwarz, Niklas, additional, Gandini, Maria A., additional, Huang, Sun, additional, Keren, Boris, additional, Mignot, Cyril, additional, Afenjar, Alexandra, additional, Billette de Villemeur, Thierry, additional, Héron, Delphine, additional, Nava, Caroline, additional, Valence, Stéphanie, additional, Buratti, Julien, additional, Fagerberg, Christina R., additional, Soerensen, Kristina P., additional, Kibaek, Maria, additional, Kamsteeg, Erik-Jan, additional, Koolen, David A., additional, Gunning, Boudewijn, additional, Schelhaas, H. Jurgen, additional, Kruer, Michael C., additional, Fox, Jordana, additional, Bakhtiari, Somayeh, additional, Jarrar, Randa, additional, Padilla-Lopez, Sergio, additional, Lindstrom, Kristin, additional, Jin, Sheng Chih, additional, Zeng, Xue, additional, Bilguvar, Kaya, additional, Papavasileiou, Antigone, additional, Xing, Qinghe, additional, Zhu, Changlian, additional, Boysen, Katja, additional, Vairo, Filippo, additional, Lanpher, Brendan C., additional, Klee, Eric W., additional, Tillema, Jan-Mendelt, additional, Payne, Eric T., additional, Cousin, Margot A., additional, Kruisselbrink, Teresa M., additional, Wick, Myra J., additional, Baker, Joshua, additional, Haan, Eric, additional, Smith, Nicholas, additional, Sadeghpour, Azita, additional, Davis, Erica E., additional, Katsanis, Nicholas, additional, Corbett, Mark A., additional, MacLennan, Alastair H., additional, Gecz, Jozef, additional, Biskup, Saskia, additional, Goldmann, Eva, additional, Rodan, Lance H., additional, Kichula, Elizabeth, additional, Segal, Eric, additional, Jackson, Kelly E., additional, Asamoah, Alexander, additional, Dimmock, David, additional, McCarrier, Julie, additional, Botto, Lorenzo D., additional, Filloux, Francis, additional, Tvrdik, Tatiana, additional, Cascino, Gregory D., additional, Klingerman, Sherry, additional, Neumann, Catherine, additional, Wang, Raymond, additional, Jacobsen, Jessie C., additional, Nolan, Melinda A., additional, Snell, Russell G., additional, Lehnert, Klaus, additional, Sadleir, Lynette G., additional, Anderlid, Britt-Marie, additional, Kvarnung, Malin, additional, Guerrini, Renzo, additional, Friez, Michael J., additional, Lyons, Michael J., additional, Leonhard, Jennifer, additional, Kringlen, Gabriel, additional, Casas, Kari, additional, El Achkar, Christelle M., additional, Smith, Lacey A., additional, Rotenberg, Alexander, additional, Poduri, Annapurna, additional, Sanchis-Juan, Alba, additional, Carss, Keren J., additional, Rankin, Julia, additional, Zeman, Adam, additional, Raymond, F. Lucy, additional, Blyth, Moira, additional, Kerr, Bronwyn, additional, Ruiz, Karla, additional, Urquhart, Jill, additional, Hughes, Imelda, additional, Banka, Siddharth, additional, Hedrich, Ulrike B.S., additional, Scheffer, Ingrid E., additional, Helbig, Ingo, additional, Zamponi, Gerald W., additional, Lerche, Holger, additional, Mefford, Heather C., additional, Allori, Alexander, additional, Angrist, Misha, additional, Ashley, Patricia, additional, Bidegain, Margarita, additional, Boyd, Brita, additional, Chambers, Eileen, additional, Cope, Heidi, additional, Cotten, C. Michael, additional, Curington, Theresa, additional, Ellestad, Sarah, additional, Fisher, Kimberley, additional, French, Amanda, additional, Gallentine, William, additional, Goldberg, Ronald, additional, Hill, Kevin, additional, Kansagra, Sujay, additional, Katsanis, Sara, additional, Kurtzberg, Joanne, additional, Marcus, Jeffrey, additional, McDonald, Marie, additional, Mikati, Mohammed, additional, Miller, Stephen, additional, Murtha, Amy, additional, Perilla, Yezmin, additional, Pizoli, Carolyn, additional, Purves, Todd, additional, Ross, Sherry, additional, Smith, Edward, additional, and Wiener, John, additional

Published
2019
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34. Systemic epidermal nevus with involvement of the oral mucosa due to FGFR3 mutation

Author

Clemmensen Ole J, Fagerberg Christina R, Bygum Anette, Fiebig Britta, and Hafner Christian

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Epidermal nevi (EN) represent benign congenital skin lesions following the lines of Blaschko. They result from genetic mosaicism, and activating FGFR3 and PIK3CA mutations have been implicated. Case presentation We report a female patient with a systemic keratinocytic nevus also involving the oral mucosa. Molecular genetic analysis revealed a mosaicism of the FGFR3 hotspot mutation R248C in the EN lesions of the skin and of the oral mucosa. The detection of the R248C mutation in a proportion of blood leukocytes and a slight scoliosis suggest an EN syndrome. Conclusions Our results show that activating FGFR3 mutations can also affect the oral mucosa and that extracutaneous manifestations of EN syndrome can be subtle. We highlight the theoretical risk of the patient having an offspring with thanatophoric dysplasia as gonadal mosaicism for the R248C mutation cannot be excluded.

Published
2011
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35. Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements

Author

Schönewolf‐Greulich, Bitten, primary, Bisgaard, Anne‐Marie, additional, Dunø, Morten, additional, Jespersgaard, Cathrine, additional, Rokkjær, Mette, additional, Hansen, Lars K., additional, Tsoutsou, Eirini, additional, Sofokleous, Christalena, additional, Topcu, Meral, additional, Kaur, Simran, additional, Van Bergen, Nicole J., additional, Brøndum‐Nielsen, Karen, additional, Larsen, Martin J., additional, Sørensen, Kristina P., additional, Christodoulou, John, additional, Fagerberg, Christina R., additional, and Tümer, Zeynep, additional

Published
2018
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36. Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration.

Author

Fagerberg, Christina R, Taylor, Adrian, Distelmaier, Felix, Schrøder, Henrik D, Kibæk, Maria, Wieczorek, Dagmar, Tarnopolsky, Mark, Brady, Lauren, Larsen, Martin J, Jamra, Rami A, Seibt, Annette, Hejbøl, Eva Kildall, Gade, Else, Markovic, Ljubo, Klee, Dirk, Nagy, Peter, Rouse, Nicholas, Agarwal, Prasoon, Dolinsky, Vernon W, and Bakovic, Marica

Subjects
*CHOLINE, *MEMBRANE lipids, *GLOBUS pallidus, *SUBSTANTIA nigra, *FRAMESHIFT mutation
Abstract

Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance. [ABSTRACT FROM AUTHOR]

Published
2020
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38. Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements.

Author

Bisgaard, Anne‐Marie, Schönewolf‐Greulich, Bitten, Jespersgaard, Cathrine, Tümer, Zeynep, Dunø, Morten, Brøndum‐Nielsen, Karen, Rokkjær, Mette, Hansen, Lars K., Tsoutsou, Eirini, Sofokleous, Christalena, Topcu, Meral, Kaur, Simran, Van Bergen, Nicole J., Christodoulou, John, Larsen, Martin J., Sørensen, Kristina P., and Fagerberg, Christina R.

Subjects
MOSAICISM, METHYL-CpG-binding protein 2, RETT syndrome, NUCLEOTIDE sequencing, HAND, HUMAN mechanics
Abstract

Rett syndrome is rarely suspected in males because of the X‐linked dominant inheritance. In the literature, only six male patients have been reported with methyl‐CpG‐binding protein 2 (MECP2) mosaicism. Next‐generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS‐based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield. Even very low‐grade mosaicim in methyl‐CPG‐binding protein 2 (MECP2) can cause Rett syndrome in males. The c.1308dupT variant of a male patient was present in 4.2% in blood and 23.8% in muscle tissue (encircled). Analysis of MECP2 in males should be carried out with very high read depth and variant call threshold should be low. A negative finding blood should be repeated using other tissues. [ABSTRACT FROM AUTHOR]

Published
2019
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40. Prostaglandin E2‐EP3 receptor subtype gene deletion in mother and son impairs platelet aggregation.

Author

Goharian, Tina S., Fagerberg, Christina R., Jensen, Boye L., Graakjaer, Jesper, Brasch‐Andersen, Charlotte, and Nybo, Mads

Abstract

The article offers study which aimed to elucidate the physiological impact of a mono-allelic expression of null mutation of the gene encoding the EP3 receptor PTGER3 on platelet aggregation through Prostaglandin E2, an important inflammatory mediator produced by atherosclerotic plaques in healthy arterial walls. Topics include Array-comparative genomic hybridisation performed on two patients and reported a heterozygous deletion of PTGER3 in a mother and son with decreased platelet aggregation.

Published
2019
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41. Trisomy 14 mosaicism

Author

Fagerberg, Christina R., primary, Eriksen, Finn B., additional, Thormann, Jens, additional, and Østergaard, John R., additional

Published
2012
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44. Mosaic MECP2 variants in males with classical Rett syndrome features, including stereotypical hand movements.

Author

Schönewolf-Greulich B, Bisgaard AM, Dunø M, Jespersgaard C, Rokkjaer M, Hansen LK, Tsoutsou E, Sofokleous C, Topcu M, Kaur S, Van Bergen NJ, Brøndum-Nielsen K, Larsen MJ, Sørensen KP, Christodoulou J, Fagerberg CR, and Tümer Z

Subjects
Alleles, Biopsy, Child, Facies, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Humans, Male, Methyl-CpG-Binding Protein 2 genetics, Mosaicism, Mutation, Phenotype, Rett Syndrome diagnosis, Rett Syndrome genetics
Abstract

Rett syndrome is rarely suspected in males because of the X-linked dominant inheritance. In the literature, only six male patients have been reported with methyl-CpG-binding protein 2 (MECP2) mosaicism. Next-generation sequencing (NGS) methods have enabled better detection of somatic mosaicism compared to conventional Sanger sequencing; however, mosaics can still be difficult to detect. We present clinical and molecular findings in two males mosaic for a pathogenic MECP2 variant. Both have been reexamined using deep sequencing of DNA isolated from four different cell tissues (blood, muscle, fibroblasts and oral mucosa). Deep sequencing of the different tissues revealed that the variants were present in all tissues. In one patient, the molecular diagnosis could only be established by reexamination after a normal whole exome sequencing, and the other case is an example of reverse genetic diagnostics. Rett syndrome should be considered in males with neurodevelopmental delay and stereotypical hand movements. Subsequent to clinical diagnosis males should be investigated with NGS-based technologies of MECP2 with high read depth and a low threshold for variant calls. If the initial analysis on full blood derived DNA fails to confirm the suspicion, we recommend repeating the analysis on another tissue, preferentially fibroblasts to increase the diagnostic yield., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Published
2019
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45. Trisomy 14 mosaicism: clinical and cytogenetic findings in an adult.

Author

Fagerberg CR, Eriksen FB, Thormann J, and Østergaard JR

Subjects
Adult, Body Height genetics, Chromosomes, Human, Pair 14 genetics, Cytogenetic Analysis, Female, Humans, Karyotyping, Mosaicism, Phenotype, Skin Pigmentation genetics, Trisomy diagnosis, Trisomy genetics
Abstract

Trisomy 14 mosaicism is a well-known but rare chromosomal defect with most frequently reported features being growth retardation, psychomotor retardation, broad nose, dysplastic and/or apparently low set ears, micrognathia, short neck, congenital heart disease and, in males, micropenis and cryptorchidism. Other frequent findings are prominent forehead, hyperteleorism, narrow palpebral fissures, large mouth, cleft or highly arched palate, body asymmetry and abnormal skin-pigmentation (Fujimoto et al., 1992). To the best of our knowledge, only one adult patient with trisomy 14 mosaicism has been described so far (Fujimoto et al., 1992). We present the clinical findings in a 27-year-old woman to add to the knowledge of the adult phenotype of trisomy 14 mosaicism and to demonstrate the findings on fibroblast culture.

Published
2012
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