30 results on '"den Hoed J"'
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2. Denken in kansen. Het leerstuk verlies van een kans stevig verankerd
- Author
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den Hoed, J., primary
- Published
- 2021
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3. Mutation-specific pathophysiological mechanisms in a new SATB1-associated neurodevelopmental disorder
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den Hoed, J., De Boer, E., Voisin, N., Guex, N., Blok, L. Snijders, Chrast, J., Manwaring, L., Willing, M., Waheeb, A., Osmond, M., McWalter, K., Vitobello, A., Demurger, F., Lavillaureix, A., Odent, S., Mazel, B., Faivre, L., Thiffault, I., Schwager, C., Amudhavalli, S. M., Rosenfeld, J. A., Radtke, K., Preiksaitiene, E., Ranza, E., Depienne, C., Kuechler, A., Mohammed, S., Abedi, Y. Hamzavi, Bonagura, V. R., Zuccarelli, B., Horist, B., Krishnamurthy, V., Kattentidt-Mouravieva, A. A., Granger, L., Petersen, A., Jones, K. L., Sinnema, M., Stegmann, A. P. A., Newbury-Ecob, R., Kini, U., Newbury, D. F., Gilissen, C., Brunner, H., Kleefstra, T., Reymond, A., Vissers, L. E. L. M., Fisher, S. E., Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Université de Lausanne (UNIL), Washington University in Saint Louis (WUSTL), GeneDx [Gaithersburg, MD, USA], Université Bourgogne Franche-Comté [COMUE] (UBFC), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Groupe Hospitalier Bretagne Sud (GHBS), Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Ambry Genetics [Aliso Viejo, CA, USA], University of Kansas [Lawrence] (KU), Maastricht University [Maastricht], Radboud University [Nijmegen], Université de Lausanne = University of Lausanne (UNIL), and Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
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[SDV]Life Sciences [q-bio] ,ComputingMilieux_MISCELLANEOUS - Abstract
International audience
- Published
- 2020
4. Kansschade: een bewogen leerstuk
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den Hoed, J., primary
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- 2020
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5. Scheidslijnen tussen kansschade, proportionele aansprakelijkheid en de omkeringsregel
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den Hoed, J., primary
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- 2018
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6. Hallucinatory experiences during cataplexy in patients with narcolepsy
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W C Dement, Lucas Ea, and van den Hoed J
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Pediatrics ,medicine.medical_specialty ,Cataplexy ,Hallucinations ,business.industry ,Sleep, REM ,medicine.disease ,Dreams ,Psychiatry and Mental health ,medicine ,Humans ,In patient ,medicine.symptom ,business ,Narcolepsy - Published
- 1979
7. Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study
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Mm, Mitler, Wesley Seidel, van den Hoed J, Dj, Greenblatt, and Wc, Dement
- Subjects
Adult ,Flurazepam ,Male ,Time Factors ,Anti-Anxiety Agents ,Humans ,Female ,Triazolam ,Sleep Stages ,Middle Aged ,Sleep ,Substance Withdrawal Syndrome - Abstract
We studied sleep and daytime function in insomniac patients who took either flurazepam, 30 mg, triazolam, 0.5 mg, or placebo 30 minutes before bedtime. Subjects were 21 patients with either a primary or a secondary diagnosis of chronic psychophysiological insomnia or insomnia associated with personality disorder. Seven subjects were randomly assigned to each condition. The study used a three group by 9 week, double-blind design with three nocturnal sleep recordings each week. During week 1, subjects took no capsules; week 2, subjects took placebo; weeks 3 to 7, flurazepam, triazolam, or placebo; weeks 8 and 9, placebo. Daytime tests for alertness and performance were administered during weeks 1, 3, 5, 7, and 8. Flurazepam showed hypnotic efficacy for weeks 3 to 5. Triazolam showed hypnotic activity for weeks 3 to 7. Although not significant overall, discontinuation of flurazepam produced rebound insomnia in six of seven subjects sometime during the two withdrawal weeks. The relationship between plasma concentration of desalkylflurazepam, the principal active metabolite of flurazepam, and sleep disturbance suggested that the onset of the rebound insomnia depended on the rate of drug washout. Discontinuation of triazolam produced a significant rebound insomnia on the first and second nights of drug withdrawal. Placebo subjects showed improved sleep throughout weeks 2 to 9 of the study. Daytime testing revealed significantly decreased daytime alertness and decreased performance for flurazepam subjects during weeks 3 to 7, although these effects reverted toward baseline despite continued drug administration.
8. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
- Author
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den Hoed, J. and den Hoed, J.
- Abstract
Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
9. Posttraumatic excessive daytime sleepiness: A review of 20 patients
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Guilleminault, C., primary, Faull, K. F., additional, Miles, L., additional, and van den Hoed, J., additional
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- 1983
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10. PhenoScore quantifies phenotypic variation for rare genetic diseases by combining facial analysis with other clinical features using a machine-learning framework.
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Dingemans AJM, Hinne M, Truijen KMG, Goltstein L, van Reeuwijk J, de Leeuw N, Schuurs-Hoeijmakers J, Pfundt R, Diets IJ, den Hoed J, de Boer E, Coenen-van der Spek J, Jansen S, van Bon BW, Jonis N, Ockeloen CW, Vulto-van Silfhout AT, Kleefstra T, Koolen DA, Campeau PM, Palmer EE, Van Esch H, Lyon GJ, Alkuraya FS, Rauch A, Marom R, Baralle D, van der Sluijs PJ, Santen GWE, Kooy RF, van Gerven MAJ, Vissers LELM, and de Vries BBA
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- Humans, Phenotype, Algorithms, Machine Learning, Biological Variation, Population, DNA-Binding Proteins, Transcription Factors, Artificial Intelligence, Matrix Attachment Region Binding Proteins
- Abstract
Several molecular and phenotypic algorithms exist that establish genotype-phenotype correlations, including facial recognition tools. However, no unified framework that investigates both facial data and other phenotypic data directly from individuals exists. We developed PhenoScore: an open-source, artificial intelligence-based phenomics framework, combining facial recognition technology with Human Phenotype Ontology data analysis to quantify phenotypic similarity. Here we show PhenoScore's ability to recognize distinct phenotypic entities by establishing recognizable phenotypes for 37 of 40 investigated syndromes against clinical features observed in individuals with other neurodevelopmental disorders and show it is an improvement on existing approaches. PhenoScore provides predictions for individuals with variants of unknown significance and enables sophisticated genotype-phenotype studies by testing hypotheses on possible phenotypic (sub)groups. PhenoScore confirmed previously known phenotypic subgroups caused by variants in the same gene for SATB1, SETBP1 and DEAF1 and provides objective clinical evidence for two distinct ADNP-related phenotypes, already established functionally., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2023
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11. Characterization of the TBR1 interactome: variants associated with neurodevelopmental disorders disrupt novel protein interactions.
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Sollis E, den Hoed J, Quevedo M, Estruch SB, Vino A, Dekkers DHW, Demmers JAA, Poot R, Deriziotis P, and Fisher SE
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- Humans, Autism Spectrum Disorder genetics, Autism Spectrum Disorder metabolism, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism, Intellectual Disability genetics, Intellectual Disability metabolism, Protein Binding genetics, Protein Binding physiology, Proteins genetics, Proteins metabolism, Repressor Proteins genetics, Repressor Proteins metabolism, Transcription Factors genetics, Transcription Factors metabolism, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders metabolism, T-Box Domain Proteins genetics, T-Box Domain Proteins metabolism
- Abstract
TBR1 is a neuron-specific transcription factor involved in brain development and implicated in a neurodevelopmental disorder (NDD) combining features of autism spectrum disorder (ASD), intellectual disability (ID) and speech delay. TBR1 has been previously shown to interact with a small number of transcription factors and co-factors also involved in NDDs (including CASK, FOXP1/2/4 and BCL11A), suggesting that the wider TBR1 interactome may have a significant bearing on normal and abnormal brain development. Here, we have identified approximately 250 putative TBR1-interaction partners by affinity purification coupled to mass spectrometry. As well as known TBR1-interactors such as CASK, the identified partners include transcription factors and chromatin modifiers, along with ASD- and ID-related proteins. Five interaction candidates were independently validated using bioluminescence resonance energy transfer assays. We went on to test the interaction of these candidates with TBR1 protein variants implicated in cases of NDD. The assays uncovered disturbed interactions for NDD-associated variants and identified two distinct protein-binding domains of TBR1 that have essential roles in protein-protein interaction., (© The Author(s) 2022. Published by Oxford University Press.)
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- 2023
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12. A clustering of heterozygous missense variants in the crucial chromatin modifier WDR5 defines a new neurodevelopmental disorder.
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Snijders Blok L, Verseput J, Rots D, Venselaar H, Innes AM, Stumpel C, Õunap K, Reinson K, Seaby EG, McKee S, Burton B, Kim K, van Hagen JM, Waisfisz Q, Joset P, Steindl K, Rauch A, Li D, Zackai EH, Sheppard SE, Keena B, Hakonarson H, Roos A, Kohlschmidt N, Cereda A, Iascone M, Rebessi E, Kernohan KD, Campeau PM, Millan F, Taylor JA, Lochmüller H, Higgs MR, Goula A, Bernhard B, Velasco DJ, Schmanski AA, Stark Z, Gallacher L, Pais L, Marcogliese PC, Yamamoto S, Raun N, Jakub TE, Kramer JM, den Hoed J, Fisher SE, Brunner HG, and Kleefstra T
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- Animals, Humans, Drosophila melanogaster genetics, Cluster Analysis, Chromatin, Intracellular Signaling Peptides and Proteins genetics, Histone-Lysine N-Methyltransferase genetics, Autism Spectrum Disorder genetics, Neurodevelopmental Disorders genetics, Language Development Disorders, Drosophila Proteins genetics
- Abstract
WDR5 is a broadly studied, highly conserved key protein involved in a wide array of biological functions. Among these functions, WDR5 is a part of several protein complexes that affect gene regulation via post-translational modification of histones. We collected data from 11 unrelated individuals with six different rare de novo germline missense variants in WDR5 ; one identical variant was found in five individuals and another variant in two individuals. All individuals had neurodevelopmental disorders including speech/language delays (n = 11), intellectual disability (n = 9), epilepsy (n = 7), and autism spectrum disorder (n = 4). Additional phenotypic features included abnormal growth parameters (n = 7), heart anomalies (n = 2), and hearing loss (n = 2). Three-dimensional protein structures indicate that all the residues affected by these variants are located at the surface of one side of the WDR5 protein. It is predicted that five out of the six amino acid substitutions disrupt interactions of WDR5 with RbBP5 and/or KMT2A/C, as part of the COMPASS (complex proteins associated with Set1) family complexes. Our experimental approaches in Drosophila melanogaster and human cell lines show normal protein expression, localization, and protein-protein interactions for all tested variants. These results, together with the clustering of variants in a specific region of WDR5 and the absence of truncating variants so far, suggest that dominant-negative or gain-of-function mechanisms might be at play. All in all, we define a neurodevelopmental disorder associated with missense variants in WDR5 and a broad range of features. This finding highlights the important role of genes encoding COMPASS family proteins in neurodevelopmental disorders., Competing Interests: F.M. is a full-time employee at GeneDx, Inc. A.M.I. serves in a voluntary capacity as a member of the Human Genetics and Genomics Advances (HGG-A) Editorial board., (© 2022 The Authors.)
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- 2022
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13. Inherited variants in CHD3 show variable expressivity in Snijders Blok-Campeau syndrome.
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van der Spek J, den Hoed J, Snijders Blok L, Dingemans AJM, Schijven D, Nellaker C, Venselaar H, Astuti GDN, Barakat TS, Bebin EM, Beck-Wödl S, Beunders G, Brown NJ, Brunet T, Brunner HG, Campeau PM, Čuturilo G, Gilissen C, Haack TB, Hüning I, Husain RA, Kamien B, Lim SC, Lovrecic L, Magg J, Maver A, Miranda V, Monteil DC, Ockeloen CW, Pais LS, Plaiasu V, Raiti L, Richmond C, Rieß A, Schwaibold EMC, Simon MEH, Spranger S, Tan TY, Thompson ML, de Vries BBA, Wilkins EJ, Willemsen MH, Francks C, Vissers LELM, Fisher SE, and Kleefstra T
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- Heterozygote, Humans, Phenotype, Syndrome, DNA Helicases genetics, Mi-2 Nucleosome Remodeling and Deacetylase Complex genetics, Neurodevelopmental Disorders genetics
- Abstract
Purpose: Common diagnostic next-generation sequencing strategies are not optimized to identify inherited variants in genes associated with dominant neurodevelopmental disorders as causal when the transmitting parent is clinically unaffected, leaving a significant number of cases with neurodevelopmental disorders undiagnosed., Methods: We characterized 21 families with inherited heterozygous missense or protein-truncating variants in CHD3, a gene in which de novo variants cause Snijders Blok-Campeau syndrome., Results: Computational facial and Human Phenotype Ontology-based comparisons showed that the phenotype of probands with inherited CHD3 variants overlaps with the phenotype previously associated with de novo CHD3 variants, whereas heterozygote parents are mildly or not affected, suggesting variable expressivity. In addition, similarly reduced expression levels of CHD3 protein in cells of an affected proband and of healthy family members with a CHD3 protein-truncating variant suggested that compensation of expression from the wild-type allele is unlikely to be an underlying mechanism. Notably, most inherited CHD3 variants were maternally transmitted., Conclusion: Our results point to a significant role of inherited variation in Snijders Blok-Campeau syndrome, a finding that is critical for correct variant interpretation and genetic counseling and warrants further investigation toward understanding the broader contributions of such variation to the landscape of human disease., Competing Interests: Conflict of Interest M.L.T. is an employee of HudsonAlpha Institute for Biotechnology. For D.M., the following statements are applicable: “Research disclaimer: The views expressed in this article reflect the results of research conducted by the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government. Copyright statement: I am a military service member. This work was prepared as part of my official duties. Title 17 U.S.C. 105 provides that "Copyright protection under this title is not available for any work of the United States Government." Title 17 U.S.C. 101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.” All other authors declare no conflicts of interest., (Copyright © 2022 American College of Medical Genetics and Genomics. All rights reserved.)
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- 2022
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14. Molecular networks of the FOXP2 transcription factor in the brain.
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den Hoed J, Devaraju K, and Fisher SE
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- Gene Expression Regulation, Humans, Speech, Brain metabolism, Forkhead Transcription Factors genetics, Forkhead Transcription Factors metabolism
- Abstract
The discovery of the FOXP2 transcription factor, and its implication in a rare severe human speech and language disorder, has led to two decades of empirical studies focused on uncovering its roles in the brain using a range of in vitro and in vivo methods. Here, we discuss what we have learned about the regulation of FOXP2, its downstream effectors, and its modes of action as a transcription factor in brain development and function, providing an integrated overview of what is currently known about the critical molecular networks., (© 2021 The Authors. Published under the terms of the CC BY 4.0 license.)
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- 2021
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15. The Ncoa7 locus regulates V-ATPase formation and function, neurodevelopment and behaviour.
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Castroflorio E, den Hoed J, Svistunova D, Finelli MJ, Cebrian-Serrano A, Corrochano S, Bassett AR, Davies B, and Oliver PL
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- Animals, Endosomes metabolism, Female, Lysosomes metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurodevelopmental Disorders etiology, Neurodevelopmental Disorders metabolism, Neurons metabolism, Vacuolar Proton-Translocating ATPases genetics, Behavior, Animal, Disease Models, Animal, Neurodevelopmental Disorders pathology, Neurons pathology, Nuclear Receptor Coactivators physiology, Oxidative Stress, Vacuolar Proton-Translocating ATPases metabolism
- Abstract
Members of the Tre2/Bub2/Cdc16 (TBC), lysin motif (LysM), domain catalytic (TLDc) protein family are associated with multiple neurodevelopmental disorders, although their exact roles in disease remain unclear. For example, nuclear receptor coactivator 7 (NCOA7) has been associated with autism, although almost nothing is known regarding the mode-of-action of this TLDc protein in the nervous system. Here we investigated the molecular function of NCOA7 in neurons and generated a novel mouse model to determine the consequences of deleting this locus in vivo. We show that NCOA7 interacts with the cytoplasmic domain of the vacuolar (V)-ATPase in the brain and demonstrate that this protein is required for normal assembly and activity of this critical proton pump. Neurons lacking Ncoa7 exhibit altered development alongside defective lysosomal formation and function; accordingly, Ncoa7 deletion animals exhibited abnormal neuronal patterning defects and a reduced expression of lysosomal markers. Furthermore, behavioural assessment revealed anxiety and social defects in mice lacking Ncoa7. In summary, we demonstrate that NCOA7 is an important V-ATPase regulatory protein in the brain, modulating lysosomal function, neuronal connectivity and behaviour; thus our study reveals a molecular mechanism controlling endolysosomal homeostasis that is essential for neurodevelopment.
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- 2021
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16. Heterozygous variants that disturb the transcriptional repressor activity of FOXP4 cause a developmental disorder with speech/language delays and multiple congenital abnormalities.
- Author
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Snijders Blok L, Vino A, den Hoed J, Underhill HR, Monteil D, Li H, Reynoso Santos FJ, Chung WK, Amaral MD, Schnur RE, Santiago-Sim T, Si Y, Brunner HG, Kleefstra T, and Fisher SE
- Subjects
- Child, Developmental Disabilities genetics, Forkhead Transcription Factors genetics, Heterozygote, Humans, Mutation, Missense, Speech, Abnormalities, Multiple, Intellectual Disability, Language Development Disorders genetics
- Abstract
Purpose: Heterozygous pathogenic variants in various FOXP genes cause specific developmental disorders. The phenotype associated with heterozygous variants in FOXP4 has not been previously described., Methods: We assembled a cohort of eight individuals with heterozygous and mostly de novo variants in FOXP4: seven individuals with six different missense variants and one individual with a frameshift variant. We collected clinical data to delineate the phenotypic spectrum, and used in silico analyses and functional cell-based assays to assess pathogenicity of the variants., Results: We collected clinical data for six individuals: five individuals with a missense variant in the forkhead box DNA-binding domain of FOXP4, and one individual with a truncating variant. Overlapping features included speech and language delays, growth abnormalities, congenital diaphragmatic hernia, cervical spine abnormalities, and ptosis. Luciferase assays showed loss-of-function effects for all these variants, and aberrant subcellular localization patterns were seen in a subset. The remaining two missense variants were located outside the functional domains of FOXP4, and showed transcriptional repressor capacities and localization patterns similar to the wild-type protein., Conclusion: Collectively, our findings show that heterozygous loss-of-function variants in FOXP4 are associated with an autosomal dominant neurodevelopmental disorder with speech/language delays, growth defects, and variable congenital abnormalities.
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- 2021
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17. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction.
- Author
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den Hoed J, de Boer E, Voisin N, Dingemans AJM, Guex N, Wiel L, Nellaker C, Amudhavalli SM, Banka S, Bena FS, Ben-Zeev B, Bonagura VR, Bruel AL, Brunet T, Brunner HG, Chew HB, Chrast J, Cimbalistienė L, Coon H, Délot EC, Démurger F, Denommé-Pichon AS, Depienne C, Donnai D, Dyment DA, Elpeleg O, Faivre L, Gilissen C, Granger L, Haber B, Hachiya Y, Abedi YH, Hanebeck J, Hehir-Kwa JY, Horist B, Itai T, Jackson A, Jewell R, Jones KL, Joss S, Kashii H, Kato M, Kattentidt-Mouravieva AA, Kok F, Kotzaeridou U, Krishnamurthy V, Kučinskas V, Kuechler A, Lavillaureix A, Liu P, Manwaring L, Matsumoto N, Mazel B, McWalter K, Meiner V, Mikati MA, Miyatake S, Mizuguchi T, Moey LH, Mohammed S, Mor-Shaked H, Mountford H, Newbury-Ecob R, Odent S, Orec L, Osmond M, Palculict TB, Parker M, Petersen AK, Pfundt R, Preikšaitienė E, Radtke K, Ranza E, Rosenfeld JA, Santiago-Sim T, Schwager C, Sinnema M, Snijders Blok L, Spillmann RC, Stegmann APA, Thiffault I, Tran L, Vaknin-Dembinsky A, Vedovato-Dos-Santos JH, Schrier Vergano SA, Vilain E, Vitobello A, Wagner M, Waheeb A, Willing M, Zuccarelli B, Kini U, Newbury DF, Kleefstra T, Reymond A, Fisher SE, and Vissers LELM
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- Chromatin metabolism, Female, Genetic Association Studies, Haploinsufficiency, Humans, Male, Matrix Attachment Region Binding Proteins chemistry, Matrix Attachment Region Binding Proteins metabolism, Models, Molecular, Mutation, Missense, Protein Binding, Protein Domains, Transcription, Genetic, Matrix Attachment Region Binding Proteins genetics, Mutation, Neurodevelopmental Disorders genetics
- Abstract
Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability., (Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
- Full Text
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18. Genetic pathways involved in human speech disorders.
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den Hoed J and Fisher SE
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- Animals, High-Throughput Nucleotide Sequencing, Humans, Gene Expression Regulation, Genetic Markers, Genetic Predisposition to Disease, Genome, Human, Speech Disorders genetics, Speech Disorders pathology
- Abstract
Rare genetic variants that disrupt speech development provide entry points for deciphering the neurobiological foundations of key human capacities. The value of this approach is illustrated by FOXP2, a transcription factor gene that was implicated in speech apraxia, and subsequently investigated using human cell-based systems and animal models. Advances in next-generation sequencing, coupled to de novo paradigms, facilitated discovery of etiological variants in additional genes in speech disorder cohorts. As for other neurodevelopmental syndromes, gene-driven studies show blurring of boundaries between diagnostic categories, with some risk genes shared across speech disorders, intellectual disability and autism. Convergent evidence hints at involvement of regulatory genes co-expressed in early human brain development, suggesting that etiological pathways could be amenable for investigation in emerging neural models such as cerebral organoids., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2020
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19. Correction to 'Investigating genetic links between grapheme-colour synaesthesia and neuropsychiatric traits'.
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Tilot AK, Vino A, Kucera KS, Carmichael DA, van den Heuvel L, den Hoed J, Sidoroff-Dorso AV, Campbell A, Porteous DJ, St Pourcain B, van Leeuwen TM, Ward J, Rouw R, Simner J, and Fisher SE
- Published
- 2020
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20. Investigating genetic links between grapheme-colour synaesthesia and neuropsychiatric traits.
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Tilot AK, Vino A, Kucera KS, Carmichael DA, van den Heuvel L, den Hoed J, Sidoroff-Dorso AV, Campbell A, Porteous DJ, St Pourcain B, van Leeuwen TM, Ward J, Rouw R, Simner J, and Fisher SE
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- Adolescent, Autism Spectrum Disorder genetics, Autism Spectrum Disorder psychology, Child, Child, Preschool, Cohort Studies, Color Perception, Female, Humans, Imagination, Male, Memory, Multifactorial Inheritance, Neuropsychological Tests, Synesthesia genetics, Synesthesia psychology
- Abstract
Synaesthesia is a neurological phenomenon affecting perception, where triggering stimuli (e.g. letters and numbers) elicit unusual secondary sensory experiences (e.g. colours). Family-based studies point to a role for genetic factors in the development of this trait. However, the contributions of common genomic variation to synaesthesia have not yet been investigated. Here, we present the SynGenes cohort, the largest genotyped collection of unrelated people with grapheme-colour synaesthesia ( n = 723). Synaesthesia has been associated with a range of other neuropsychological traits, including enhanced memory and mental imagery, as well as greater sensory sensitivity. Motivated by the prior literature on putative trait overlaps, we investigated polygenic scores derived from published genome-wide scans of schizophrenia and autism spectrum disorder (ASD), comparing our SynGenes cohort to 2181 non-synaesthetic controls. We found a very slight association between schizophrenia polygenic scores and synaesthesia (Nagelkerke's R
2 = 0.0047, empirical p = 0.0027) and no significant association for scores related to ASD (Nagelkerke's R2 = 0.00092, empirical p = 0.54) or body mass index ( R2 = 0.00058, empirical p = 0.60), included as a negative control. As sample sizes for studying common genomic variation continue to increase, genetic investigations of the kind reported here may yield novel insights into the shared biology between synaesthesia and other traits, to complement findings from neuropsychology and brain imaging. This article is part of a discussion meeting issue 'Bridging senses: novel insights from synaesthesia'.- Published
- 2019
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21. Functional characterization of TBR1 variants in neurodevelopmental disorder.
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den Hoed J, Sollis E, Venselaar H, Estruch SB, Deriziotis P, and Fisher SE
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- Autism Spectrum Disorder physiopathology, Developmental Disabilities physiopathology, Exome genetics, Gene Expression Regulation genetics, High-Throughput Nucleotide Sequencing, Humans, Mutation, Missense genetics, Neurodevelopmental Disorders physiopathology, Protein Conformation, T-Box Domain Proteins chemistry, Exome Sequencing, Autism Spectrum Disorder genetics, Developmental Disabilities genetics, Neurodevelopmental Disorders genetics, T-Box Domain Proteins genetics
- Abstract
Recurrent de novo variants in the TBR1 transcription factor are implicated in the etiology of sporadic autism spectrum disorders (ASD). Disruptions include missense variants located in the T-box DNA-binding domain and previous work has demonstrated that they disrupt TBR1 protein function. Recent screens of thousands of simplex families with sporadic ASD cases uncovered additional T-box variants in TBR1 but their etiological relevance is unclear. We performed detailed functional analyses of de novo missense TBR1 variants found in the T-box of ASD cases, assessing many aspects of protein function, including subcellular localization, transcriptional activity and protein-interactions. Only two of the three tested variants severely disrupted TBR1 protein function, despite in silico predictions that all would be deleterious. Furthermore, we characterized a putative interaction with BCL11A, a transcription factor that was recently implicated in a neurodevelopmental syndrome involving developmental delay and language deficits. Our findings enhance understanding of molecular functions of TBR1, as well as highlighting the importance of functional testing of variants that emerge from next-generation sequencing, to decipher their contributions to neurodevelopmental disorders like ASD.
- Published
- 2018
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22. Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study.
- Author
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Mitler MM, Seidel WF, van den Hoed J, Greenblatt DJ, and Dement WC
- Subjects
- Adult, Female, Flurazepam adverse effects, Flurazepam analogs & derivatives, Flurazepam blood, Humans, Male, Middle Aged, Sleep Stages drug effects, Substance Withdrawal Syndrome, Time Factors, Anti-Anxiety Agents pharmacology, Flurazepam pharmacology, Sleep drug effects, Triazolam pharmacology
- Abstract
We studied sleep and daytime function in insomniac patients who took either flurazepam, 30 mg, triazolam, 0.5 mg, or placebo 30 minutes before bedtime. Subjects were 21 patients with either a primary or a secondary diagnosis of chronic psychophysiological insomnia or insomnia associated with personality disorder. Seven subjects were randomly assigned to each condition. The study used a three group by 9 week, double-blind design with three nocturnal sleep recordings each week. During week 1, subjects took no capsules; week 2, subjects took placebo; weeks 3 to 7, flurazepam, triazolam, or placebo; weeks 8 and 9, placebo. Daytime tests for alertness and performance were administered during weeks 1, 3, 5, 7, and 8. Flurazepam showed hypnotic efficacy for weeks 3 to 5. Triazolam showed hypnotic activity for weeks 3 to 7. Although not significant overall, discontinuation of flurazepam produced rebound insomnia in six of seven subjects sometime during the two withdrawal weeks. The relationship between plasma concentration of desalkylflurazepam, the principal active metabolite of flurazepam, and sleep disturbance suggested that the onset of the rebound insomnia depended on the rate of drug washout. Discontinuation of triazolam produced a significant rebound insomnia on the first and second nights of drug withdrawal. Placebo subjects showed improved sleep throughout weeks 2 to 9 of the study. Daytime testing revealed significantly decreased daytime alertness and decreased performance for flurazepam subjects during weeks 3 to 7, although these effects reverted toward baseline despite continued drug administration.
- Published
- 1984
23. Sleep-wake disorders in the elderly: polysomnographic analysis.
- Author
-
Coleman RM, Miles LE, Guilleminault CC, Zarcone VP Jr, van den Hoed J, and Dement WC
- Subjects
- Adolescent, Adult, Aged, Aging, Female, Humans, Leg, Male, Middle Aged, Myoclonus diagnosis, Psychophysiologic Disorders diagnosis, Sleep Apnea Syndromes diagnosis, Sleep Wake Disorders epidemiology, Sleep Wake Disorders psychology, Syndrome, United States, Sleep Wake Disorders diagnosis
- Abstract
The experience with 83 patients aged 60 or older from the Stanford Sleep-Wake Disorders Clinic is compared with that in 423 younger clinic patients seen during the same two-year period. Each patient received a medical, psychologic and polysomnographic evaluation. The final diagnoses were recorded according to the Diagnostic Classification System of the Association of Sleep Disorders Centers. The most common major diagnoses in the elderly group were sleep apnea syndrome (39 percent) and periodic movements-restless legs syndrome (18 percent). These syndromes showed a significantly greater prevalence in the older than in the younger patients (p less than .001), and were found in 68 percent of the elderly group. The elderly manifested more objective signs of sleep disturbance, including more wake time after sleep onset, and more frequent and longer awakenings; moreover, fewer of them experienced stage-4 sleep. The diagnostic findings seemed to indicate that complaints about sleep-wake functioning in many elderly patients may be a result of specific pathologic sleep disturbances.
- Published
- 1981
- Full Text
- View/download PDF
24. Excessive daytime sleepiness in man: multiple sleep latency measurement in narcoleptic and control subjects.
- Author
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Richardson GS, Carskadon MA, Flagg W, Van den Hoed J, Dement WC, and Mitler MM
- Subjects
- Adult, Diagnosis, Differential, Electroencephalography, Electromyography, Electrooculography, Female, Humans, Male, Middle Aged, Sleep, REM, Narcolepsy diagnosis, Sleep Stages
- Abstract
Excessive daytime sleepiness is a complaint characterizing many disorders of the wakefulness--sleep cycle. This paper addresses the complaint of sleepiness objectively by an attempt to differentiate a group of control subjects from a group of patients with unambiguous narcolepsy. Fourteen control and 27 narcoleptic subjects were evaluated by one of three protocols involving nocturnal recordings, detailed interviews, and 5 or more 20-min opportunities to sleep offered at 2-h intervals beginning at 10.00 o'clock, +/- 30 min. Each 20-min opportunity to sleep was given to subjects lying in a darkened quiet room and asked to try to fall asleep. Polysomnographic variables were monitored and sleep was scored in 30-sec epochs by standard criteria. The interval from the start of each test to the first epoch of NREM (including stage 1 sleep) or REM sleep was called sleep latency. In two of the protocols, the subjects were awakened immediately after sleep onset. In the third protocol, the subjects were awakened after 10 min of sleep. Narcoleptics consistently fell asleep much more readily than did control subjects. We conclude that the Multiple Sleep latency test, in addition to providing opportunities to clinically document sleep onset REM sleep periods, can demonstrate pathological sleepiness. Based on these data, we suggest that an average sleep latency less than 5 min be set as the minimum cutoff point for pathological sleepiness.
- Published
- 1978
- Full Text
- View/download PDF
25. Reduction of sleep apnea and bradycardia in preterm infants on oscillating water beds: a controlled polygraphic study.
- Author
-
Korner AF, Guilleminault C, Van den Hoed J, and Baldwin RB
- Subjects
- Apnea complications, Bradycardia complications, Humans, Infant, Newborn, Sleep Stages, Time Factors, Apnea prevention & control, Beds, Bradycardia prevention & control, Infant, Premature, Diseases, Sleep, Water
- Abstract
The sleep and respiratory patterns of eight apneic preterm infants were polygraphically recorded for 24 hours. This polygraphic study was designed to test and extend our previous finding that gently oscillating water beds reduce apnea in premature infants. The infants who ranged in gestational age from 27 to 32 weeks and in birth weight from 1,077 to 1,650 gm served as their own controls, off and on the water bed. The 24-hour recordings were divided into four time blocks with the infant being placed on the water bed during alternate six-hour periods. Apnea was significantly reduced while the infants were on the oscillating water beds, with the longest apneic periods and those associated with severe bradycardia being reduced the most. Reduction of apnea was most consistent during indeterminate sleep and most pronounced during quiet sleep. Short respiratory pauses and periodic breathing were not significantly reduced. Reductions of central, obstructive, and mixed apneas were approximately equal.
- Published
- 1978
26. Sleep and daytime sleepiness in the elderly.
- Author
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Carskadon MA, van den Hoed J, and Dement WC
- Subjects
- Aged, Circadian Rhythm, Electroencephalography, Female, Humans, Male, Myoclonus diagnosis, Respiration, Sleep Stages, Fatigue diagnosis, Sleep Initiation and Maintenance Disorders diagnosis, Sleep Wake Disorders diagnosis
- Published
- 1980
27. Disorders of excessive daytime somnolence: polygraphic and clinical data for 100 patients.
- Author
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van den Hoed J, Kraemer H, Guilleminault C, Zarcone VP Jr, Miles LE, Dement WC, and Mitler MM
- Subjects
- Adolescent, Adult, Aged, Analysis of Variance, Diagnosis, Differential, Electrocardiography, Electroencephalography, Electromyography, Electrooculography, Female, Humans, Male, Middle Aged, Myoclonus diagnosis, Narcolepsy diagnosis, Reaction Time, Sleep Wake Disorders diagnosis
- Abstract
A consecutive series of 100 sleep apnea free patients with the complaint of excessive daytime somnolence (EDS) were evaluated; data from medical histories, physical examination, personality inventories, and polysomnography [nocturnal polysomnography (NPSG) and daytime multiple sleep latency testing (MSLT)] were tabulated. Significant differences were found between narcoleptic and non-narcoleptic patients in a number of parameters, including EDS severity, mean sleep latency on MSLT, sleep latency on NPSG, latency to REM sleep at night, number of REM sleep at night, number of REM sleep segments throughout the night, the total number of nocturnal myoclonic jerks (as well as the number occurring per hour of NREM and REM sleep), and the number of arousals and wake periods preceded by a myoclonic jerk. Significant differences in sleep latency during MSLT and NPSG testing were found between different EDS diagnostic groups of non-narcoleptic patients. The majority of patients in the MSLT group with long sleep latencies were in the diagnostic groups of EDS associated with psychophysiological and/or psychiatric problems or with drug abuse; patients with a diagnosis of idiopathic central nervous system hypersomnia or EDS associated with disturbed nocturnal sleep formed the majority of the MSLT group with short sleep latencies. The non-narcoleptic patients in a MSLT group with short sleep latencies had significantly shorter sleep latencies at night, more sleep cycles, higher sleep efficiency, and earlier REM sleep than patients with long sleep latencies.
- Published
- 1981
- Full Text
- View/download PDF
28. Hallucinatory experiences during cataplexy in patients with narcolepsy.
- Author
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van den Hoed J, Lucas EA, and Dement WC
- Subjects
- Dreams, Humans, Sleep, REM, Cataplexy complications, Hallucinations etiology, Narcolepsy complications
- Published
- 1979
- Full Text
- View/download PDF
29. REM sleep episodes during the Multple Sleep Latency Test in narcoleptic patients.
- Author
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Mitler MM, Van den Hoed J, Carskadon MA, Richardson G, Park R, Guilleminault C, and Dement WC
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Narcolepsy diagnosis, Electroencephalography, Narcolepsy physiopathology, Reaction Time physiology, Sleep, REM physiology
- Abstract
Forty narcoleptic patients were given the Multiple Sleep Latency Test, consisting of 20 min opportunities to sleep offered at 10.00, 12.00, 14.00, 16.00 and 18.00 o'clock. Eleven patients had 2 episodes of REM sleep, 5 had 3, 11 had 4, and 13 had 5 before they were awakened. Fourteen control subjects given similar opportunities to sleep (reported in a companion article (Richardson et al. 1978)) had no REM sleep episodes. For the 10.00-18.00 o'clock opportunities respectively, there were 32, 29, 30, 28 and 27 REM sleep episodes. We conclude that this procedure can provide physicians with data useful in the diagnosis of narcolepsy.
- Published
- 1979
- Full Text
- View/download PDF
30. Acromegaly and narcolepsy.
- Author
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Guilleminault C and van den Hoed J
- Subjects
- Diagnosis, Differential, Humans, Sleep, Acromegaly diagnosis, Narcolepsy diagnosis
- Published
- 1979
- Full Text
- View/download PDF
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