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685 results on '"Esch, Hilde"'

2. PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework

Author

Dingemans, Alexander J. M., Hinne, Max, Truijen, Kim M. G., Goltstein, Lia, van Reeuwijk, Jeroen, de Leeuw, Nicole, Schuurs-Hoeijmakers, Janneke, Pfundt, Rolph, Diets, Illja J., den Hoed, Joery, de Boer, Elke, Coenen-van der Spek, Jet, Jansen, Sandra, van Bon, Bregje W., Jonis, Noraly, Ockeloen, Charlotte W., Vulto-van Silfhout, Anneke T., Kleefstra, Tjitske, Koolen, David A., Campeau, Philippe M., Palmer, Elizabeth E., Van Esch, Hilde, Lyon, Gholson J., Alkuraya, Fowzan S., Rauch, Anita, Marom, Ronit, Baralle, Diana, van der Sluijs, Pleuntje J., Santen, Gijs W. E., Kooy, R. Frank, van Gerven, Marcel A. J., Vissers, Lisenka E. L. M., and de Vries, Bert B. A.

Published
2023
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4. De novo MCM6 variants in neurodevelopmental disorders: a recognizable phenotype related to zinc binding residues

Author

Smits, Daphne J., Schot, Rachel, Popescu, Cristiana A., Dias, Kerith-Rae, Ades, Lesley, Briere, Lauren C., Sweetser, David A., Kushima, Itaru, Aleksic, Branko, Khan, Suliman, Karageorgou, Vasiliki, Ordonez, Natalia, Sleutels, Frank J. G. T., van der Kaay, Daniëlle C. M., Van Mol, Christine, Van Esch, Hilde, Bertoli-Avella, Aida M., Roscioli, Tony, and Mancini, Grazia M. S.

Published
2023
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5. The neurodevelopmental and facial phenotype in individuals with a TRIP12 variant

Author

Aerden, Mio, Denommé-Pichon, Anne-Sophie, Bonneau, Dominique, Bruel, Ange-Line, Delanne, Julian, Gérard, Bénédicte, Mazel, Benoît, Philippe, Christophe, Pinson, Lucile, Prouteau, Clément, Putoux, Audrey, Tran Mau-Them, Frédéric, Viora-Dupont, Éléonore, Vitobello, Antonio, Ziegler, Alban, Piton, Amélie, Isidor, Bertrand, Francannet, Christine, Maillard, Pierre-Yves, Julia, Sophie, Philippe, Anais, Schaefer, Elise, Koene, Saskia, Ruivenkamp, Claudia, Hoffer, Mariette, Legius, Eric, Theunis, Miel, Keren, Boris, Buratti, Julien, Charles, Perrine, Courtin, Thomas, Misra-Isrie, Mala, van Haelst, Mieke, Waisfisz, Quinten, Wieczorek, Dagmar, Schmetz, Ariane, Herget, Theresia, Kortüm, Fanny, Lisfeld, Jasmin, Debray, François-Guillaume, Bramswig, Nuria C., Atallah, Isis, Fodstad, Heidi, Jouret, Guillaume, Almoguera, Berta, Tahsin-Swafiri, Saoud, Santos-Simarro, Fernando, Palomares-Bralo, Maria, López-González, Vanesa, Kibaek, Maria, Tørring, Pernille M., Renieri, Alessandra, Bruno, Lucia Pia, Õunap, Katrin, Wojcik, Monica, Hsieh, Tzung-Chien, Krawitz, Peter, and Van Esch, Hilde

Published
2023
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7. Mutation update for the SATB2 gene.

Author

Zarate, Yuri, Bosanko, Katherine, Caffrey, Aisling, Bernstein, Jonathan, Martin, Donna, Williams, Marc, Berry-Kravis, Elizabeth, Mark, Paul, Manning, Melanie, Bhambhani, Vikas, Vargas, Marcelo, Seeley, Andrea, Estrada-Veras, Juvianee, van Dooren, Marieke, Schwab, Maria, Vanderver, Adeline, Melis, Daniela, Alsadah, Adnan, Sadler, Laurie, Van Esch, Hilde, Callewaert, Bert, Oostra, Ann, Maclean, Jane, Dentici, Maria, Orlando, Valeria, Lipson, Mark, Sparagana, Steven, Maarup, Timothy, Alsters, Suzanne, Brautbar, Ariel, Kovitch, Eliana, Naidu, Sakkubai, Lees, Melissa, Smith, Douglas, Turner, Lesley, Raggio, Víctor, Spangenberg, Lucía, Garcia-Miñaúr, Sixto, Roeder, Elizabeth, Littlejohn, Rebecca, Grange, Dorothy, Pfotenhauer, Jean, Jones, Marilyn, Balasubramanian, Meena, Martinez-Monseny, Antonio, Blok, Lot, Gavrilova, Ralitza, and Fish, Jennifer

Subjects
SATB2, SATB2-associated syndrome, genotype-phenotype correlation, pathogenic variants, whole exome sequencing, Adolescent, Animals, Child, Child, Preschool, Codon, Terminator, Disease Models, Animal, Female, Gene Rearrangement, Genetic Association Studies, Humans, Male, Matrix Attachment Region Binding Proteins, Mutation, Mutation, Missense, Neurodevelopmental Disorders, Polymorphism, Single Nucleotide, Transcription Factors
Abstract

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

Published
2019

8. Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

Author

Guissart, Claire, Latypova, Xenia, Rollier, Paul, Khan, Tahir N, Stamberger, Hannah, McWalter, Kirsty, Cho, Megan T, Kjaergaard, Susanne, Weckhuysen, Sarah, Lesca, Gaetan, Besnard, Thomas, Õunap, Katrin, Schema, Lynn, Chiocchetti, Andreas G, McDonald, Marie, de Bellescize, Julitta, Vincent, Marie, Van Esch, Hilde, Sattler, Shannon, Forghani, Irman, Thiffault, Isabelle, Freitag, Christine M, Barbouth, Deborah Sara, Cadieux-Dion, Maxime, Willaert, Rebecca, Sacoto, Maria J Guillen, Safina, Nicole P, Dubourg, Christèle, Grote, Lauren, Carré, Wilfrid, Saunders, Carol, Pajusalu, Sander, Farrow, Emily, Boland, Anne, Karlowicz, Danielle Hays, Deleuze, Jean-François, Wojcik, Monica H, Pressman, Rena, Isidor, Bertrand, Vogels, Annick, Van Paesschen, Wim, Al-Gazali, Lihadh, Shamsi, Aisha Mohamed Al, Claustres, Mireille, Pujol, Aurora, Sanders, Stephan J, Rivier, François, Leboucq, Nicolas, Cogné, Benjamin, Sasorith, Souphatta, Sanlaville, Damien, Retterer, Kyle, Odent, Sylvie, Katsanis, Nicholas, Bézieau, Stéphane, Koenig, Michel, Davis, Erica E, Pasquier, Laurent, and Küry, Sébastien

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Intellectual and Developmental Disabilities (IDD), Neurodegenerative, Neurosciences, Pediatric, Rare Diseases, Brain Disorders, Autism, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adolescent, Adult, Aged, 80 and over, Alleles, Animals, Autistic Disorder, Brain, Cerebellar Ataxia, Child, Child, Preschool, DNA Copy Number Variations, Disease Models, Animal, Female, Genes, Dominant, Genetic Complementation Test, Humans, Intellectual Disability, Larva, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Missense, Nuclear Receptor Subfamily 1, Group F, Member 1, Purkinje Cells, Syndrome, Zebrafish, RORA, autistic features, cerebellar ataxia, dual molecular effects, epilepsy, intellectual disability, neurodevelopmental disorder, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

Published
2018

10. Developmental epileptic encephalopathy in DLG4-related synaptopathy

Author

Kassabian, Benedetta, Levy, Amanda M., Gardella, Elena, Aledo-Serrano, Angel, Ananth, Amitha L., Brea-Fernández, Alejandro J., Caumes, Roseline, Chatron, Nicolas, Dainelli, Alice, De Wachter, Matthias, Denommé-Pichon, Anne-Sophie, Dye, Thomas J., Fazzi, Elisa, Felt, Roxanne, Fernández-Jaén, Alberto, Fernández-Prieto, Montse, Gantz, Emily, Gasperowicz, Piotr, Gil-Nagel, Antonio, Gómez-Andrés, David, Greiner, Hansel M., Guerrini, Renzo, Haanpää, Maria K., Helin, Minttu, Hoyer, Juliane, Hurst, Anna C. E., Kallish, Staci, Karkare, Shefali N., Khan, Amjad, Kleinendorst, Lotte, Koch, Johannes, Kothare, Sanjeev V., Koudijs, Suzanna M., Lagae, Lieven, Lakeman, Phillis, Leppig, Kathleen A., Lesca, Gaetan, Lopergolo, Diego, Lusk, Laina, Mackenzie, Alex, Mei, Davide, Møller, Rikke S., Pereira, Elaine M., Platzer, Konrad, Quelin, Chloe, Revah-Politi, Anya, Rheims, Sylvain, Rodríguez-Palmero, Agustí, Rossi, Andrea, Santorelli, Filippo, Seinfeld, Syndi, Sell, Erick, Stephenson, Donna, Szczaluba, Krzysztof, Trinka, Eugen, Umair, Muhammad, Van Esch, Hilde, van Haelst, Mieke M., Veenma, Danielle C. M., Weber, Sacha, Weckhuysen, Sarah, Zacher, Pia, Tümer, Zeynep, Rubboli, Guido, Kassabian, Benedetta, Levy, Amanda M., Gardella, Elena, Aledo-Serrano, Angel, Ananth, Amitha L., Brea-Fernández, Alejandro J., Caumes, Roseline, Chatron, Nicolas, Dainelli, Alice, De Wachter, Matthias, Denommé-Pichon, Anne-Sophie, Dye, Thomas J., Fazzi, Elisa, Felt, Roxanne, Fernández-Jaén, Alberto, Fernández-Prieto, Montse, Gantz, Emily, Gasperowicz, Piotr, Gil-Nagel, Antonio, Gómez-Andrés, David, Greiner, Hansel M., Guerrini, Renzo, Haanpää, Maria K., Helin, Minttu, Hoyer, Juliane, Hurst, Anna C. E., Kallish, Staci, Karkare, Shefali N., Khan, Amjad, Kleinendorst, Lotte, Koch, Johannes, Kothare, Sanjeev V., Koudijs, Suzanna M., Lagae, Lieven, Lakeman, Phillis, Leppig, Kathleen A., Lesca, Gaetan, Lopergolo, Diego, Lusk, Laina, Mackenzie, Alex, Mei, Davide, Møller, Rikke S., Pereira, Elaine M., Platzer, Konrad, Quelin, Chloe, Revah-Politi, Anya, Rheims, Sylvain, Rodríguez-Palmero, Agustí, Rossi, Andrea, Santorelli, Filippo, Seinfeld, Syndi, Sell, Erick, Stephenson, Donna, Szczaluba, Krzysztof, Trinka, Eugen, Umair, Muhammad, Van Esch, Hilde, van Haelst, Mieke M., Veenma, Danielle C. M., Weber, Sacha, Weckhuysen, Sarah, Zacher, Pia, Tümer, Zeynep, and Rubboli, Guido

Abstract

Objective: The postsynaptic density protein of excitatory neurons PSD-95 is encoded by discs large MAGUK scaffold protein 4 (DLG4), de novo pathogenic variants of which lead to DLG4-related synaptopathy. The major clinical features are developmental delay, intellectual disability (ID), hypotonia, sleep disturbances, movement disorders, and epilepsy. Even though epilepsy is present in 50% of the individuals, it has not been investigated in detail. We describe here the phenotypic spectrum of epilepsy and associated comorbidities in patients with DLG4-related synaptopathy. Methods: We included 35 individuals with a DLG4 variant and epilepsy as part of a multicenter study. The DLG4 variants were detected by the referring laboratories. The degree of ID, hypotonia, developmental delay, and motor disturbances were evaluated by the referring clinician. Data on awake and sleep electroencephalography (EEG) and/or video-polygraphy and brain magnetic resonance imaging were collected. Antiseizure medication response was retrospectively assessed by the referring clinician. Results: A large variety of seizure types was reported, although focal seizures were the most common. Encephalopathy related to status epilepticus during slow-wave sleep (ESES)/developmental epileptic encephalopathy with spike–wave activation during sleep (DEE-SWAS) was diagnosed in >25% of the individuals. All but one individual presented with neurodevelopmental delay. Regression in verbal and/or motor domains was observed in all individuals who suffered from ESES/DEE-SWAS, as well as some who did not. We could not identify a clear genotype–phenotype relationship even between individuals with the same DLG4 variants. Significance: Our study shows that a subgroup of individuals with DLG4-related synaptopathy have DEE, and approximately one fourth of them have ESES/DEE-SWAS. Our study confirms DEE as part of the DLG4-related phenotypic spectrum. Occurrence of ESES/DEE-SWAS in DLG4-related synaptopathy requi

Published
2024

11. Multiple paralogues and recombination mechanisms drive the high incidence of 22q11.2 Deletion Syndrome

Author

Vervoort, Lisanne, primary, Dierckxsens, Nicolas, additional, Sousa Santos, Marta, additional, Meynants, Senne, additional, Souche, Erika, additional, Cools, Ruben, additional, Heung, Tracy, additional, Devriendt, Koen, additional, Peeters, Hilde, additional, Mcdonald-mcginn, Donna, additional, Swillen, Ann, additional, Breckpot, Jeroen, additional, Emanuel, Beverly S., additional, Van Esch, Hilde, additional, Bassett, Anne S., additional, and Vermeesch, Joris R., additional

Published
2024
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12. Quaking promotes monocyte differentiation into pro-atherogenic macrophages by controlling pre-mRNA splicing and gene expression.

Author

de Bruin, Ruben G, Shiue, Lily, Prins, Jurriën, de Boer, Hetty C, Singh, Anjana, Fagg, W Samuel, van Gils, Janine M, Duijs, Jacques MGJ, Katzman, Sol, Kraaijeveld, Adriaan O, Böhringer, Stefan, Leung, Wai Y, Kielbasa, Szymon M, Donahue, John P, van der Zande, Patrick HJ, Sijbom, Rick, van Alem, Carla MA, Bot, Ilze, van Kooten, Cees, Jukema, J Wouter, Van Esch, Hilde, Rabelink, Ton J, Kazan, Hilal, Biessen, Erik AL, Ares, Manuel, van Zonneveld, Anton Jan, and van der Veer, Eric P

Subjects
Monocytes, Macrophages, Foam Cells, Animals, Humans, Mice, RNA-Binding Proteins, RNA, Messenger, Cell Differentiation, Gene Expression Regulation, RNA Splicing, Models, Biological, Models, Genetic, Atherosclerosis, Genetics, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, RNA, Messenger, Models, Biological, Genetic
Abstract

A hallmark of inflammatory diseases is the excessive recruitment and influx of monocytes to sites of tissue damage and their ensuing differentiation into macrophages. Numerous stimuli are known to induce transcriptional changes associated with macrophage phenotype, but posttranscriptional control of human macrophage differentiation is less well understood. Here we show that expression levels of the RNA-binding protein Quaking (QKI) are low in monocytes and early human atherosclerotic lesions, but are abundant in macrophages of advanced plaques. Depletion of QKI protein impairs monocyte adhesion, migration, differentiation into macrophages and foam cell formation in vitro and in vivo. RNA-seq and microarray analysis of human monocyte and macrophage transcriptomes, including those of a unique QKI haploinsufficient patient, reveal striking changes in QKI-dependent messenger RNA levels and splicing of RNA transcripts. The biological importance of these transcripts and requirement for QKI during differentiation illustrates a central role for QKI in posttranscriptionally guiding macrophage identity and function.

Published
2016

13. cGAS-mediated induction of type I interferon due to inborn errors of histone pre-mRNA processing

Author

Uggenti, Carolina, Lepelley, Alice, Depp, Marine, Badrock, Andrew P., Rodero, Mathieu P., El-Daher, Marie-Thérèse, Rice, Gillian I., Dhir, Somdutta, Wheeler, Ann P., Dhir, Ashish, Albawardi, Waad, Frémond, Marie-Louise, Seabra, Luis, Doig, Jennifer, Blair, Natalie, Martin-Niclos, Maria José, Della Mina, Erika, Rubio-Roldán, Alejandro, García-Pérez, Jose L., Sproul, Duncan, Rehwinkel, Jan, Hertzog, Jonny, Boland-Auge, Anne, Olaso, Robert, Deleuze, Jean-François, Baruteau, Julien, Brochard, Karine, Buckley, Jonathan, Cavallera, Vanessa, Cereda, Cristina, De Waele, Liesbeth M. H., Dobbie, Angus, Doummar, Diane, Elmslie, Frances, Koch-Hogrebe, Margarete, Kumar, Ram, Lamb, Kate, Livingston, John H., Majumdar, Anirban, Lorenço, Charles Marques, Orcesi, Simona, Peudenier, Sylviane, Rostasy, Kevin, Salmon, Caroline A., Scott, Christiaan, Tonduti, Davide, Touati, Guy, Valente, Marialuisa, van der Linden, Jr., Hélio, Van Esch, Hilde, Vermelle, Marie, Webb, Kate, Jackson, Andrew P., Reijns, Martin A. M., Gilbert, Nick, and Crow, Yanick J.

Published
2020
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14. Mutations in DDX3X Are a Common Cause of Unexplained Intellectual Disability with Gender-Specific Effects on Wnt Signaling

Author

Blok, Lot Snijders, Madsen, Erik, Juusola, Jane, Gilissen, Christian, Baralle, Diana, Reijnders, Margot RF, Venselaar, Hanka, Helsmoortel, Céline, Cho, Megan T, Hoischen, Alexander, Vissers, Lisenka ELM, Koemans, Tom S, Wissink-Lindhout, Willemijn, Eichler, Evan E, Romano, Corrado, Van Esch, Hilde, Stumpel, Connie, Vreeburg, Maaike, Smeets, Eric, Oberndorff, Karin, van Bon, Bregje WM, Shaw, Marie, Gecz, Jozef, Haan, Eric, Bienek, Melanie, Jensen, Corinna, Loeys, Bart L, Van Dijck, Anke, Innes, A Micheil, Racher, Hilary, Vermeer, Sascha, Di Donato, Nataliya, Rump, Andreas, Tatton-Brown, Katrina, Parker, Michael J, Henderson, Alex, Lynch, Sally A, Fryer, Alan, Ross, Alison, Vasudevan, Pradeep, Kini, Usha, Newbury-Ecob, Ruth, Chandler, Kate, Male, Alison, Study, the DDD, Dijkstra, Sybe, Schieving, Jolanda, Giltay, Jacques, van Gassen, Koen LI, Schuurs-Hoeijmakers, Janneke, Tan, Perciliz L, Pediaditakis, Igor, Haas, Stefan A, Retterer, Kyle, Reed, Patrick, Monaghan, Kristin G, Haverfield, Eden, Natowicz, Marvin, Myers, Angela, Kruer, Michael C, Stein, Quinn, Strauss, Kevin A, Brigatti, Karlla W, Keating, Katherine, Burton, Barbara K, Kim, Katherine H, Charrow, Joel, Norman, Jennifer, Foster-Barber, Audrey, Kline, Antonie D, Kimball, Amy, Zackai, Elaine, Harr, Margaret, Fox, Joyce, McLaughlin, Julie, Lindstrom, Kristin, Haude, Katrina M, van Roozendaal, Kees, Brunner, Han, Chung, Wendy K, Kooy, R Frank, Pfundt, Rolph, Kalscheuer, Vera, Mehta, Sarju G, Katsanis, Nicholas, and Kleefstra, Tjitske

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Intellectual and Developmental Disabilities (IDD), Human Genome, Clinical Research, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Amino Acid Substitution, Animals, Base Sequence, DEAD-box RNA Helicases, Embryo, Nonmammalian, Exome, Female, Gene Dosage, Humans, Intellectual Disability, Male, Molecular Sequence Data, Mutation, Missense, Phenotype, Sequence Analysis, DNA, Sex Characteristics, Wnt Signaling Pathway, Zebrafish, DDD Study, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Intellectual disability (ID) affects approximately 1%-3% of humans with a gender bias toward males. Previous studies have identified mutations in more than 100 genes on the X chromosome in males with ID, but there is less evidence for de novo mutations on the X chromosome causing ID in females. In this study we present 35 unique deleterious de novo mutations in DDX3X identified by whole exome sequencing in 38 females with ID and various other features including hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Based on our findings, mutations in DDX3X are one of the more common causes of ID, accounting for 1%-3% of unexplained ID in females. Although no de novo DDX3X mutations were identified in males, we present three families with segregating missense mutations in DDX3X, suggestive of an X-linked recessive inheritance pattern. In these families, all males with the DDX3X variant had ID, whereas carrier females were unaffected. To explore the pathogenic mechanisms accounting for the differences in disease transmission and phenotype between affected females and affected males with DDX3X missense variants, we used canonical Wnt defects in zebrafish as a surrogate measure of DDX3X function in vivo. We demonstrate a consistent loss-of-function effect of all tested de novo mutations on the Wnt pathway, and we further show a differential effect by gender. The differential activity possibly reflects a dose-dependent effect of DDX3X expression in the context of functional mosaic females versus one-copy males, which reflects the complex biological nature of DDX3X mutations.

Published
2015

15. Expanding the phenotypic spectrum of PORCN variants in two males with syndromic microphthalmia.

Author

Brady, Paul, Van Esch, Hilde, Fieremans, Nathalie, Froyen, Guy, Slavotinek, Anne, Deprest, Jan, Devriendt, Koenraad, and Vermeesch, Joris

Subjects
Acyltransferases, Female, Focal Dermal Hypoplasia, Genetic Variation, Genomics, Humans, Male, Membrane Proteins, Microarray Analysis, Microphthalmos, Pedigree, Phenotype, Sequence Analysis, DNA, X Chromosome Inactivation
Abstract

Variants in PORCN are a cause of Goltz-Gorlin syndrome or Focal Dermal Hypoplasia, an X-linked dominant disorder affecting heterozygous females and until now considered to be embryonic lethal in males. Exome sequencing was performed in a family in which two male siblings were characterized by microphthalmia and additional congenital anomalies including diaphragmatic hernia, spina bifida and cardiac defects. Surprisingly, we identified a maternally inherited variant in PORCN present in both males as well as in two female siblings. This represents the first finding of a PORCN variant in non-mosaic males affected with Goltz-Gorlin syndrome. The apparently asymptomatic mother showed extreme skewing of X-inactivation (90%), an asymptomatic female sibling showed skewing of 88%, and the second female sibling affected with cutis aplasia of the scalp showed X-inactivation considered within the normal range.

Published
2015

17. De novo CCND2 mutations leading to stabilization of cyclin D2 cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

Author

Mirzaa, Ghayda M, Parry, David A, Fry, Andrew E, Giamanco, Kristin A, Schwartzentruber, Jeremy, Vanstone, Megan, Logan, Clare V, Roberts, Nicola, Johnson, Colin A, Singh, Shawn, Kholmanskikh, Stanislav S, Adams, Carissa, Hodge, Rebecca D, Hevner, Robert F, Bonthron, David T, Braun, Kees PJ, Faivre, Laurence, Rivière, Jean-Baptiste, St-Onge, Judith, Gripp, Karen W, Mancini, Grazia MS, Pang, Ki, Sweeney, Elizabeth, van Esch, Hilde, Verbeek, Nienke, Wieczorek, Dagmar, Steinraths, Michelle, Majewski, Jacek, Boycott, Kym M, Pilz, Daniela T, Ross, M Elizabeth, Dobyns, William B, and Sheridan, Eamonn G

Subjects
Pediatric, 2.1 Biological and endogenous factors, Aetiology, Abnormalities, Multiple, Animals, Base Sequence, Blotting, Western, Bromodeoxyuridine, Cyclin D2, Electroporation, Exome, Female, HEK293 Cells, Humans, Hydrocephalus, Immunohistochemistry, Malformations of Cortical Development, Megalencephaly, Mice, Microscopy, Fluorescence, Molecular Sequence Data, Mutagenesis, Site-Directed, Polydactyly, Sequence Analysis, DNA, Syndrome, FORGE Canada Consortium, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Activating mutations in genes encoding phosphatidylinositol 3-kinase (PI3K)-AKT pathway components cause megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH, OMIM 603387). Here we report that individuals with MPPH lacking upstream PI3K-AKT pathway mutations carry de novo mutations in CCND2 (encoding cyclin D2) that are clustered around a residue that can be phosphorylated by glycogen synthase kinase 3β (GSK-3β). Mutant CCND2 was resistant to proteasomal degradation in vitro compared to wild-type CCND2. The PI3K-AKT pathway modulates GSK-3β activity, and cells from individuals with PIK3CA, PIK3R2 or AKT3 mutations showed similar CCND2 accumulation. CCND2 was expressed at higher levels in brains of mouse embryos expressing activated AKT3. In utero electroporation of mutant CCND2 into embryonic mouse brains produced more proliferating transfected progenitors and a smaller fraction of progenitors exiting the cell cycle compared to cells electroporated with wild-type CCND2. These observations suggest that cyclin D2 stabilization, caused by CCND2 mutation or PI3K-AKT activation, is a unifying mechanism in PI3K-AKT-related megalencephaly syndromes.

Published
2014

18. Developmental epileptic encephalopathy in DLG4‐related synaptopathy

Author

Kassabian, Benedetta, primary, Levy, Amanda M., additional, Gardella, Elena, additional, Aledo‐Serrano, Angel, additional, Ananth, Amitha L., additional, Brea‐Fernández, Alejandro J., additional, Caumes, Roseline, additional, Chatron, Nicolas, additional, Dainelli, Alice, additional, De Wachter, Matthias, additional, Denommé‐Pichon, Anne‐Sophie, additional, Dye, Thomas J., additional, Fazzi, Elisa, additional, Felt, Roxanne, additional, Fernández‐Jaén, Alberto, additional, Fernández‐Prieto, Montserrat, additional, Gantz, Emily, additional, Gasperowicz, Piotr, additional, Gil‐Nagel, Antonio, additional, Gómez‐Andrés, David, additional, Greiner, Hansel M., additional, Guerrini, Renzo, additional, Haanpää, Maria K., additional, Helin, Minttu, additional, Hoyer, Juliane, additional, Hurst, Anna C. E., additional, Kallish, Staci, additional, Karkare, Shefali N., additional, Khan, Amjad, additional, Kleinendorst, Lotte, additional, Koch, Johannes, additional, Kothare, Sanjeev V., additional, Koudijs, Suzanna V., additional, Lagae, Lieven, additional, Lakeman, Phillis, additional, Leppig, Kathleen A., additional, Lesca, Gaetan, additional, Lopergolo, Diego, additional, Lusk, Laina, additional, Mackenzie, Alex, additional, Mei, Davide, additional, Møller, Rikke S., additional, Pereira, Elaine M., additional, Platzer, Konrad, additional, Quelin, Chloe, additional, Revah‐Politi, Anya, additional, Rheims, Sylvain, additional, Rodríguez‐Palmero, Agustí, additional, Rossi, Andrea, additional, Santorelli, Filippo, additional, Seinfeld, Syndi, additional, Sell, Erick, additional, Stephenson, Donna, additional, Szczaluba, Krzysztof, additional, Trinka, Eugen, additional, Umair, Muhammad, additional, Van Esch, Hilde, additional, van Haelst, Mieke M., additional, Veenma, Danielle C. M., additional, Weber, Sacha, additional, Weckhuysen, Sarah, additional, Zacher, Pia, additional, Tümer, Zeynep, additional, and Rubboli, Guido, additional

Published
2023
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21. Clinical exome sequencing reveals locus heterogeneity and phenotypic variability of cohesinopathies

Author

Yuan, Bo, Neira, Juanita, Pehlivan, Davut, Santiago-Sim, Teresa, Song, Xiaofei, Rosenfeld, Jill, Posey, Jennifer E., Patel, Vipulkumar, Jin, Weihong, Adam, Margaret P., Baple, Emma L., Dean, John, Fong, Chin-To, Hickey, Scott E., Hudgins, Louanne, Leon, Eyby, Madan-Khetarpal, Suneeta, Rawlins, Lettie, Rustad, Cecilie F., Stray-Pedersen, Asbjørg, Tveten, Kristian, Wenger, Olivia, Diaz, Jullianne, Jenkins, Laura, Martin, Laura, McGuire, Marianne, Pietryga, Marguerite, Ramsdell, Linda, Slattery, Leah, DDD Study, Abid, Farida, Bertuch, Alison A., Grange, Dorothy, Immken, LaDonna, Schaaf, Christian P., Van Esch, Hilde, Bi, Weimin, Cheung, Sau Wai, Breman, Amy M., Smith, Janice L., Shaw, Chad, Crosby, Andrew H., Eng, Christine, Yang, Yaping, Lupski, James R., Xiao, Rui, and Liu, Pengfei

Published
2019
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22. Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders

Author

Maroofian, Reza, primary, Kaiyrzhanov, Rauan, additional, Cali, Elisa, additional, Zamani, Mina, additional, Zaki, Maha S, additional, Ferla, Matteo, additional, Tortora, Domenico, additional, Sadeghian, Saeid, additional, Saadi, Saadia Maryam, additional, Abdullah, Uzma, additional, Karimiani, Ehsan Ghayoor, additional, Efthymiou, Stephanie, additional, Yeşil, Gözde, additional, Alavi, Shahryar, additional, Al Shamsi, Aisha M, additional, Tajsharghi, Homa, additional, Abdel-Hamid, Mohamed S, additional, Saadi, Nebal Waill, additional, Al Mutairi, Fuad, additional, Alabdi, Lama, additional, Beetz, Christian, additional, Ali, Zafar, additional, Toosi, Mehran Beiraghi, additional, Rudnik-Schöneborn, Sabine, additional, Babaei, Meisam, additional, Isohanni, Pirjo, additional, Muhammad, Jameel, additional, Khan, Sheraz, additional, Al Shalan, Maha, additional, Hickey, Scott E, additional, Marom, Daphna, additional, Elhanan, Emil, additional, Kurian, Manju A, additional, Marafi, Dana, additional, Saberi, Alihossein, additional, Hamid, Mohammad, additional, Spaull, Robert, additional, Meng, Linyan, additional, Lalani, Seema, additional, Maqbool, Shazia, additional, Rahman, Fatima, additional, Seeger, Jürgen, additional, Palculict, Timothy Blake, additional, Lau, Tracy, additional, Murphy, David, additional, Mencacci, Niccolo Emanuele, additional, Steindl, Katharina, additional, Begemann, Anais, additional, Rauch, Anita, additional, Akbas, Sinan, additional, Aslanger, Ayça Dilruba, additional, Salpietro, Vincenzo, additional, Yousaf, Hammad, additional, Ben-Shachar, Shay, additional, Ejeskär, Katarina, additional, Al Aqeel, Aida I, additional, High, Frances A, additional, Armstrong-Javors, Amy E, additional, Zahraei, Seyed Mohammadsaleh, additional, Seifi, Tahereh, additional, Zeighami, Jawaher, additional, Shariati, Gholamreza, additional, Sedaghat, Alireza, additional, Asl, Samaneh Noroozi, additional, Shahrooei, Mohmmad, additional, Zifarelli, Giovanni, additional, Burglen, Lydie, additional, Ravelli, Claudia, additional, Zschocke, Johannes, additional, Schatz, Ulrich A, additional, Ghavideldarestani, Maryam, additional, Kamel, Walaa A, additional, Van Esch, Hilde, additional, Hackenberg, Annette, additional, Taylor, Jenny C, additional, Al-Gazali, Lihadh, additional, Bauer, Peter, additional, Gleeson, Joseph J, additional, Alkuraya, Fowzan Sami, additional, Lupski, James R, additional, Galehdari, Hamid, additional, Azizimalamiri, Reza, additional, Chung, Wendy K, additional, Baig, Shahid Mahmood, additional, Houlden, Henry, additional, and Severino, Mariasavina, additional

Published
2023
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23. Towards a 21st-century roadmap for biomedical research and drug discovery: consensus report and recommendations

Author

Langley, Gillian R., Adcock, Ian M., Busquet, François, Crofton, Kevin M., Csernok, Elena, Giese, Christoph, Heinonen, Tuula, Herrmann, Kathrin, Hofmann-Apitius, Martin, Landesmann, Brigitte, Marshall, Lindsay J., McIvor, Emily, Muotri, Alysson R., Noor, Fozia, Schutte, Katrin, Seidle, Troy, van de Stolpe, Anja, Van Esch, Hilde, Willett, Catherine, and Woszczek, Grzegorz

Published
2017
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24. A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency

Author

Jansen, Sandra, Hoischen, Alexander, Coe, Bradley P., Carvill, Gemma L., Van Esch, Hilde, Bosch, Daniëlle G. M., Andersen, Ulla A., Baker, Carl, Bauters, Marijke, Bernier, Raphael A., van Bon, Bregje W., Claahsen-van der Grinten, Hedi L., Gecz, Jozef, Gilissen, Christian, Grillo, Lucia, Hackett, Anna, Kleefstra, Tjitske, Koolen, David, Kvarnung, Malin, Larsen, Martin J., Marcelis, Carlo, McKenzie, Fiona, Monin, Marie-Lorraine, Nava, Caroline, Schuurs-Hoeijmakers, Janneke H., Pfundt, Rolph, Steehouwer, Marloes, Stevens, Servi J. C., Stumpel, Connie T., Vansenne, Fleur, Vinci, Mirella, van de Vorst, Maartje, Vries, Petra de, Witherspoon, Kali, Veltman, Joris A., Brunner, Han G., Mefford, Heather C., Romano, Corrado, Vissers, Lisenka E. L. M., Eichler, Evan E., and de Vries, Bert B. A.

Published
2018
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26. De novo MCM6 variants in neurodevelopmental disorders:a recognizable phenotype related to zinc binding residues

Author

Smits, Daphne J., Schot, Rachel, Popescu, Cristiana A., Dias, Kerith Rae, Ades, Lesley, Briere, Lauren C., Sweetser, David A., Kushima, Itaru, Aleksic, Branko, Khan, Suliman, Karageorgou, Vasiliki, Ordonez, Natalia, Sleutels, Frank J.G.T., van der Kaay, Daniëlle C.M., Van Mol, Christine, Van Esch, Hilde, Bertoli-Avella, Aida M., Roscioli, Tony, Mancini, Grazia M.S., Smits, Daphne J., Schot, Rachel, Popescu, Cristiana A., Dias, Kerith Rae, Ades, Lesley, Briere, Lauren C., Sweetser, David A., Kushima, Itaru, Aleksic, Branko, Khan, Suliman, Karageorgou, Vasiliki, Ordonez, Natalia, Sleutels, Frank J.G.T., van der Kaay, Daniëlle C.M., Van Mol, Christine, Van Esch, Hilde, Bertoli-Avella, Aida M., Roscioli, Tony, and Mancini, Grazia M.S.

Abstract

The minichromosome maintenance (MCM) complex acts as a DNA helicase during DNA replication, and thereby regulates cell cycle progression and proliferation. In addition, MCM-complex components localize to centrosomes and play an independent role in ciliogenesis. Pathogenic variants in genes coding for MCM components and other DNA replication factors have been linked to growth and developmental disorders as Meier–Gorlin syndrome and Seckel syndrome. Trio exome/genome sequencing identified the same de novo MCM6 missense variant p.(Cys158Tyr) in two unrelated individuals that presented with overlapping phenotypes consisting of intra-uterine growth retardation, short stature, congenital microcephaly, endocrine features, developmental delay and urogenital anomalies. The identified variant affects a zinc binding cysteine in the MCM6 zinc finger signature. This domain, and specifically cysteine residues, are essential for MCM-complex dimerization and the induction of helicase activity, suggesting a deleterious effect of this variant on DNA replication. Fibroblasts derived from the two affected individuals showed defects both in ciliogenesis and cell proliferation. We additionally traced three unrelated individuals with de novo MCM6 variants in the oligonucleotide binding (OB)-fold domain, presenting with variable (neuro)developmental features including autism spectrum disorder, developmental delay, and epilepsy. Taken together, our findings implicate de novo MCM6 variants in neurodevelopmental disorders. The clinical features and functional defects related to the zinc binding residue resemble those observed in syndromes related to other MCM components and DNA replication factors, while de novo OB-fold domain missense variants may be associated with more variable neurodevelopmental phenotypes. These data encourage consideration of MCM6 variants in the diagnostic arsenal of NDD.

Published
2023

27. Differences in Cerebral Glucose Metabolism in ALS Patients with and without C9orf72 and SOD1 Mutations

Author

De Vocht, Joke, primary, Van Weehaeghe, Donatienne, additional, Ombelet, Fouke, additional, Masrori, Pegah, additional, Lamaire, Nikita, additional, Devrome, Martijn, additional, Van Esch, Hilde, additional, Moisse, Mathieu, additional, Koole, Michel, additional, Dupont, Patrick, additional, Van Laere, Koen, additional, and Van Damme, Philip, additional

Published
2023
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33. Episignature Mapping of TRIP12 Provides Functional Insight into Clark–Baraitser Syndrome

Author

van der Laan, Liselot, primary, Rooney, Kathleen, additional, Alders, Mariëlle, additional, Relator, Raissa, additional, McConkey, Haley, additional, Kerkhof, Jennifer, additional, Levy, Michael A., additional, Lauffer, Peter, additional, Aerden, Mio, additional, Theunis, Miel, additional, Legius, Eric, additional, Tedder, Matthew L., additional, Vissers, Lisenka E. L. M., additional, Koene, Saskia, additional, Ruivenkamp, Claudia, additional, Hoffer, Mariette J. V., additional, Wieczorek, Dagmar, additional, Bramswig, Nuria C., additional, Herget, Theresia, additional, González, Vanesa López, additional, Santos-Simarro, Fernando, additional, Tørring, Pernille M., additional, Denomme-Pichon, Anne-Sophie, additional, Isidor, Bertrand, additional, Keren, Boris, additional, Julia, Sophie, additional, Schaefer, Elise, additional, Francannet, Christine, additional, Maillard, Pierre-Yves, additional, Misra-Isrie, Mala, additional, Van Esch, Hilde, additional, Mannens, Marcel M. A. M., additional, Sadikovic, Bekim, additional, van Haelst, Mieke M., additional, and Henneman, Peter, additional

Published
2022
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34. IRAK1 Duplication in MECP2 Duplication Syndrome Does Not Increase Canonical NF-κB–Induced Inflammation

Author

Gottschalk, Ilona, primary, Kölsch, Uwe, additional, Wagner, Dimitrios L., additional, Kath, Jonas, additional, Martini, Stefania, additional, Krüger, Renate, additional, Puel, Anne, additional, Casanova, Jean-Laurent, additional, Jezela-Stanek, Aleksandra, additional, Rossi, Rainer, additional, Chehadeh, Salima El, additional, Van Esch, Hilde, additional, and von Bernuth, Horst, additional

Published
2022
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35. PhenoScore: AI-based phenomics to quantify rare disease and genetic variation

Author

Dingemans, Alexander J M, primary, Hinne, Max, additional, Truijen, Kim M G, additional, Goltstein, Lia, additional, van Reeuwijk, Jeroen, additional, de Leeuw, Nicole, additional, Schuurs-Hoeijmakers, Janneke, additional, Pfundt, Rolph, additional, Diets, Illja J, additional, den Hoed, Joery, additional, de Boer, Elke, additional, Coenen-van der Spek, Jet, additional, Jansen, Sandra, additional, van Bon, Bregje W, additional, Jonis, Noraly, additional, Ockeloen, Charlotte, additional, Vulto-van Silfhout, Anneke T, additional, Kleefstra, Tjitske, additional, Koolen, David A, additional, Van Esch, Hilde, additional, Lyon, Gholson J, additional, Alkuraya, Fowzan S, additional, Rauch, Anita, additional, Marom, Ronit, additional, Baralle, Diana, additional, van der Sluijs, Pleuntje J, additional, Santen, Gijs W E, additional, Kooy, R Frank, additional, van Gerven, Marcel A J, additional, Vissers, Lisenka E L M, additional, and de Vries, Bert B A, additional

Published
2022
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42. Infectious and Immunologic Phenotype of MECP2 Duplication Syndrome

Author

Bauer, Michael, Kölsch, Uwe, Krüger, Renate, Unterwalder, Nadine, Hameister, Karin, Kaiser, Fabian Marc, Vignoli, Aglaia, Rossi, Rainer, Botella, Maria Pilar, Budisteanu, Magdalena, Rosello, Monica, Orellana, Carmen, Tejada, Maria Isabel, Papuc, Sorina Mihaela, Patat, Oliver, Julia, Sophie, Touraine, Renaud, Gomes, Thusari, Wenner, Kirsten, Xu, Xiu, Afenjar, Alexandra, Toutain, Annick, Philip, Nicole, Jezela-Stanek, Aleksandra, Gortner, Ludwig, Martinez, Francisco, Echenne, Bernard, Wahn, Volker, Meisel, Christian, Wieczorek, Dagmar, El-Chehadeh, Salima, Van Esch, Hilde, and von Bernuth, Horst

Published
2015
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46. Loss-of-function variants in exon 4 of TAB2 cause a recognizable multisystem disorder with cardiovascular, facial, cutaneous, and musculoskeletal involvement

Author

Micale, Lucia, primary, Morlino, Silvia, additional, Carbone, Annalucia, additional, Carissimo, Annamaria, additional, Nardella, Grazia, additional, Fusco, Carmela, additional, Palumbo, Orazio, additional, Schirizzi, Annalisa, additional, Russo, Federica, additional, Mazzoccoli, Gianluigi, additional, Breckpot, Jeroen, additional, De Luca, Chiara, additional, Ferraris, Alessandro, additional, Giunta, Cecilia, additional, Grammatico, Paola, additional, Haanpää, Maria K., additional, Mancano, Giorgia, additional, Forzano, Giulia, additional, Cacchiarelli, Davide, additional, Van Esch, Hilde, additional, Callewaert, Bert, additional, Rohrbach, Marianne, additional, and Castori, Marco, additional

Published
2022
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48. Navigating the uncertainties of next‐generation sequencing in the genetics clinic.

Author

Kuiper, Janneke M. L., Borry, Pascal, Vears, Danya F., Van Esch, Hilde, and Van Hoyweghen, Ine

Subjects
RESEARCH, MEETINGS, SEQUENCE analysis, GENETICS, NEGOTIATION, UNCERTAINTY, GENETIC testing, INTERVIEWING, FIELDWORK (Educational method), RESEARCH funding, HEALTH care teams, MEDICAL referrals, INTERPROFESSIONAL relations, GENOMICS, EMPIRICAL research, PATIENT-professional relations, THEMATIC analysis
Abstract

This study explores the different manifestations and navigations of uncertainty in the practice of diagnostic next‐generation sequencing (NGS) testing. Drawing upon multi‐sited fieldwork conducted at a large Centre for Human Genetics in Belgium, we analyse how uncertainty takes shape and is managed in the different steps of the diagnostic process: starting from the testing offer, to the analysis in the lab, the multidisciplinary team meetings (MDTs) and ending with the consultation with the patient. Building on interviews with genetic healthcare professionals and their patients and observations in consultations and MDTs, our empirical work underlines the duality of uncertainty as both burdensome and productive. Building on the existing literature on uncertainty in medicine and NGS, our analysis shows the ontological politics at play in the everyday uncertainty work in this CHG. We show how the, at times, contrasting ways of dealing with uncertainty lead to friction but also result in constructive negotiation and collaboration between actors, making use of multiple types of evidence and expertise. By not only minimising but also sustaining or inviting uncertainty, genetic healthcare professionals are able to advance the practices around NGS in a way that matches their multidisciplinary understandings, considerations and more normative stances. [ABSTRACT FROM AUTHOR]

Published
2023
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50. Increased STAG2 dosage defines a novel cohesinopathy with intellectual disability and behavioral problems

Author

Kumar, Raman, Corbett, Mark A., Van Bon, Bregje W.M., Gardner, Alison, Woenig, Joshua A., Jolly, Lachlan A., Douglas, Evelyn, Friend, Kathryn, Tan, Chuan, Van Esch, Hilde, Holvoet, Maureen, Raynaud, Martine, Field, Michael, Leffler, Melanie, Budny, Bartłomiej, Wisniewska, Marzena, Badura-Stronka, Magdalena, Latos-Bieleńska, Anna, Batanian, Jacqueline, Rosenfeld, Jill A., Basel-Vanagaite, Lina, Jensen, Corinna, Bienek, Melanie, Froyen, Guy, Ullmann, Reinhard, Hu, Hao, Love, Michael I., Haas, Stefan A., Stankiewicz, Pawel, Cheung, Sau Wai, Baxendale, Anne, Nicholl, Jillian, Thompson, Elizabeth M., Haan, Eric, Kalscheuer, Vera M., and Gecz, Jozef

Published
2015
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