5 results on '"Joost Kummeling"'
Search Results
2. GenIDA, a participatory patient registry for genetic forms of intellectual disability provides detailed caregiver reported information on 237 individuals with Koolen-de Vries syndrome
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Florent Colin, Pauline Burger, Timothée Mazzucotelli, Axelle Strehle, Joost Kummeling, Nicole Collot, Elyette Broly, Angela T. Morgan, Kenneth A. Myers, Agnès Bloch-Zupan, Charlotte W. Ockeloen, Bert B.A. de Vries, Tjitske Kleefstra, Pierre Parrend, David A. Koolen, and Jean-Louis Mandel
- Published
- 2023
3. Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth
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Damien Haye, Sandrine Vonwill, Rolph Pfundt, Annick Toutain, Stephan C. Collins, Joost Kummeling, Sylviane Marouillat, Marie-Pierre Moizard, Médéric Jeanne, Dévina C. Ung, Binnaz Yalcin, Frédéric Laumonnier, Nora Chelloug, Tjitske Kleefstra, Marie-Laure Vuillaume, Valerie E. Vancollie, and Christel Wagner
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0303 health sciences ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,biology ,030305 genetics & heredity ,Neurogenesis ,Hippocampus ,Hippocampal formation ,medicine.disease ,Phenotype ,Cell biology ,03 medical and health sciences ,Histone ,Neurodevelopmental disorder ,22q11 Deletion Syndrome ,Genetics ,biology.protein ,medicine ,Haploinsufficiency ,Genetics (clinical) ,030304 developmental biology - Abstract
Item does not contain fulltext The 22q11.2 deletion syndrome (22q11DS) is associated with a wide spectrum of cognitive and psychiatric symptoms. Despite the considerable work performed over the past 20 years, the genetic etiology of the neurodevelopmental phenotype remains speculative. Here, we report de novo heterozygous truncating variants in the HIRA (Histone cell cycle regulation defective, S. Cerevisiae, homolog of, A) gene associated with a neurodevelopmental disorder in two unrelated patients. HIRA is located within the commonly deleted region of the 22q11DS and encodes a histone chaperone that regulates neural progenitor proliferation and neurogenesis, and that belongs to the WD40 Repeat (WDR) protein family involved in brain development and neuronal connectivity. To address the specific impact of HIRA haploinsufficiency in the neurodevelopmental phenotype of 22q11DS, we combined Hira knock-down strategies in developing mouse primary hippocampal neurons, and the direct study of brains from heterozygous Hira(+/-) mice. Our in vitro analyses revealed that Hira gene is mostly expressed during neuritogenesis and early dendritogenesis stages in mouse total brain and in developing primary hippocampal neurons. Moreover, shRNA knock-down experiments showed that a twofold decrease of endogenous Hira expression level resulted in an impaired dendritic growth and branching in primary developing hippocampal neuronal cultures. In parallel, in vivo analyses demonstrated that Hira(+/-) mice displayed subtle neuroanatomical defects including a reduced size of the hippocampus, the fornix and the corpus callosum. Our results suggest that HIRA haploinsufficiency would likely contribute to the complex pathophysiology of the neurodevelopmental phenotype of 22q11DS by impairing key processes in neurogenesis and by causing neuroanatomical defects during cerebral development.
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- 2021
4. The impact of lockdown on young people with genetic neurodevelopmental disabilities: a study with the international participatory database GenIDA
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Romain Coutelle, Morgane Boedec, Karlijn Vermeulen, Joost Kummeling, David A. Koolen, Tjitske Kleefstra, Camille Fournier, Florent Colin, Axelle Strehle, David Geneviève, Pauline Burger, and Jean-Louis Mandel
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Adult ,Male ,Sleep Wake Disorders ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Adolescent ,Autism Spectrum Disorder ,COVID-19 ,Psychiatry and Mental health ,All institutes and research themes of the Radboud University Medical Center ,Intellectual Disability ,Communicable Disease Control ,Quality of Life ,Humans ,Female ,Child - Abstract
Background Previous publications suggested that lockdown is likely to impact daily living issues of individuals with intellectual disabilities. The authors notably suspected an intensification of behavioural, eating and sleep problems. Methods To test these hypotheses, we conducted an international online survey about the impact of COVID-19-associated first lockdown on people with genetic neurodevelopmental disorders. This survey was carried out using GenIDA, an international participatory database collecting medical information on genetic neurodevelopmental disorders. Patients’ relatives took part in this online survey from 30/04/2020 to 09/06/2020. This survey adapted from GenIDA standard questionnaire requested information on diagnosis, lifestyle and was based on yes/no answers to questions regarding behaviour, diet, and sleep, in the 6-months period before lockdown and during lockdown. We also asked relatives to evaluate the intensity of these problems by severity level. Finally, relatives could freely comment in open fields on the medical and/or quality of life problems they had encountered during lockdown. Results In total 199 participants—144 children and 45 adults—with neurodevelopmental disorders (intellectual disability (79.4%) and/or autism spectrum disorder (21.6%)) of various genetic origins, with near-equal male/female (96/103) contribution and originating mainly from Europe and Northern America, were included. The average lockdown duration at time of the survey was 57 days. We did not find differences in the frequency of behavioural, eating and sleep problems before and during lockdown. Moreover, there was no apparent difference in the intensity of eating and sleep disorders between both periods. However, for persons with behavioural problems at both periods, relatives reported an increase in aggressivity, self-aggressivity, depressiveness, stereotypies, and restricted interests during lockdown, all of which might be interpreted as consequences of a lack of stimulation or a reaction to unexpected changes in daily habits. Conclusions Our results support previous studies that suggest that the negative impact of lockdown does not depend on the intellectual disability per se but on the associated comorbidities such as behavioural disorders. This study addresses the need for prevention of behavioural disturbance in the vulnerable population with genetic neurodevelopmental disabilities.
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- 2021
5. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome
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Dirk Schubert, Pankaj B. Agrawal, Diante E Stremmelaar, Christian Gilissen, Koen L.I. van Gassen, Kirsty McWalter, Margot R.F. Reijnders, Rolph Pfundt, Alicia Casey, Jamie M Kramer, Tjitske Kleefstra, Olaf Bodamer, Eva Maria Christina Schwaibold, Annick Raas-Rothschild, Paulien A Terhal, Margje Sinnema, Nicholas Raun, Angela Bahr, Casie A. Genetti, Joost Kummeling, Trevor L Hoffman, James W. Wheless, Megan T. Cho, Martina Ruiterkamp-Versteeg, Velibor Tasic, Jasper J. van der Smagt, Katharina Steindl, Marleen Simon, Isabelle Thiffault, Pascal Joset, Elmar Keller, Marga Schepens, Marjolein H. Willemsen, Korbinian M. Riedhammer, David A. Koolen, Martin R. Higgs, Julia Hoefele, Nina Powell-Hamilton, Anita Rauch, Deniz Top, Dihong Zhou, Kendra Engleman, Calvin C O C O Man, MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
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0301 basic medicine ,Microcephaly ,Methyltransferase ,HISTONE H3K4 METHYLASES ,PROTEIN ,Haploinsufficiency ,OF-FUNCTION VARIANTS ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,Neurodevelopmental disorder ,Intellectual Disability ,SCHIZOPHRENIA ,medicine ,Animals ,Humans ,Global developmental delay ,Allele ,Child ,Molecular Biology ,030304 developmental biology ,Genetics ,0303 health sciences ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,biology ,COMPASS FAMILY ,GENETIC-VARIATION ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,Histone-Lysine N-Methyltransferase ,medicine.disease ,biology.organism_classification ,SELFISH SPERMATOGONIAL SELECTION ,Psychiatry and Mental health ,030104 developmental biology ,Drosophila melanogaster ,PATERNAL AGE ,DE-NOVO MUTATIONS ,Neurodevelopmental Disorders ,Histone methyltransferase ,Drosophila ,030217 neurology & neurosurgery - Abstract
Defects in histone methyltransferases (HMTs) are major contributing factors in neurodevelopmental disorders (NDDs). Heterozygous variants of SETD1A involved in histone H3 lysine 4 (H3K4) methylation were previously identified in individuals with schizophrenia. Here, we define the clinical features of the Mendelian syndrome associated with haploinsufficiency of SETD1A by investigating 15 predominantly pediatric individuals who all have de novo SETD1A variants. These individuals present with a core set of symptoms comprising global developmental delay and/or intellectual disability, subtle facial dysmorphisms, behavioral and psychiatric problems. We examined cellular phenotypes in three patient derived lymphoblastoid cell lines with three variants: p.Gly535Alafs*12, c.4582-2_4582delAG, and p.Tyr1499Asp. These patient cell lines displayed DNA damage repair defects that were comparable to previously observed RNAi-mediated depletion of SETD1A. This suggested that these variants, including the p.Tyr1499Asp in the catalytic SET domain, behave as Loss-of-Function (LoF) alleles. Previous studies demonstrated a role for SETD1A in cell cycle control and differentiation. However, individuals with SETD1A variants do not show major structural brain defects or severe microcephaly, suggesting that defective proliferation and differentiation of neural progenitors is unlikely the single underlying cause of the disorder. We show here that the Drosophila Melanogaster SETD1A orthologue is required in postmitotic neurons of the fly brain for normal memory, suggesting a role in post development neuronal function. Together, this study defines a neurodevelopmental disorder caused by dominant de novo LoF variants in SETD1A and further supports a role for H3K4 methyltransferases in the regulation of neuronal processes underlying normal cognitive functioning.
- Published
- 2019
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