4 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
- Author
-
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
- Subjects
GenIDA ,Intellectual disability ,Koolen-de Vries syndrome ,Neurodevelopmental disorders ,Patient registry ,Genetics ,QH426-470 ,Medicine - Abstract
Purpose: GenIDA is an international patient registry for individuals diagnosed with intellectual disability, autism spectrum disorder, and/or epilepsy, which is based on an online questionnaire that is completed by parent caregivers. In this study, the GenIDA data on Koolen-de Vries syndrome (KdVS) was analyzed illustrating the value of GenIDA and patient/caregiver participation in rare genetic neurodevelopmental disorders (NDDs). Methods: Recruitment was done on the GenIDA website from November 2016 to February 2022. Clinical information on individuals with KdVS was extracted for in-depth analysis and for comparison with the GenIDA data of individuals diagnosed with other NDDs. Results: A total of 1417 patients/caregivers across 35 genetic conditions answered to the GenIDA questionnaire, including caregivers of 237 individuals with KdVS. GenIDA findings on KdVS were consistent with the existing literature, and there were no significant differences between individuals with a 17q21.31 microdeletion and those with a pathogenic variant in the KANSL1 gene. GenIDA provided detailed clinical information including features that are over-represented in KdVS compared with other NDDs (eg, laryngomalacia). Modeling of the natural history showed a positive development of speech and language over time and relatively good reading ability in KdVS. Valproate and oxcarbazepine were reported as effective antiepileptic drugs, and responses to open-ended questions indicated that childhood recurrent pneumonia and asthma are clinically relevant comorbidities that were not described in KdVS before. Conclusion: GenIDA is a powerful registry to collect and harness valuable data on rare NDDs. The study shows that caregiver-driven data collection is effective in terms of global recruitment and centralization of clinical data.
- Published
- 2023
- Full Text
- View/download PDF
3. Haploinsufficiency of the HIRA gene located in the 22q11 deletion syndrome region is associated with abnormal neurodevelopment and impaired dendritic outgrowth
- Author
-
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
- Subjects
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.
- Published
- 2021
4. Characterization of SETD1A haploinsufficiency in humans and Drosophila defines a novel neurodevelopmental syndrome
- Author
-
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
- Subjects
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
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.