32 results on '"van Gils, J."'
Search Results
2. SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients
- Author
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Mouillé, M., Rio, M., Breton, S., Piketty, M. L., Afenjar, A., Amiel, J., Capri, Y., Goldenberg, A., Francannet, C., Michot, C., Mignot, C., Perrin, L., Quelin, C., Van Gils, J., Barcia, G., Pingault, V., Maruani, G., Koumakis, E., and Cormier-Daire, V.
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- 2022
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3. Intriguing link between fetal intracranial hemorrhage and X‐linked recessive chondrodysplasia punctata
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Létard, P., primary, Wintjens, R., additional, Van‐Gils, J., additional, Martinovic, J., additional, Laffargue, F., additional, Dufernez, F., additional, and Egloff, M., additional
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- 2024
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4. The mesencephalic astrocyte-derived neurotrophic factor (MANF) as a novel regulator of post-infarction cardiac sympathetic hyperinnervation
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Blok, M, primary, Van Gils, J M, additional, Boukens, B J D, additional, Kielbasa, S M, additional, Van Schendel, B W, additional, Schoones, J W, additional, Smits, A M, additional, Goumans, M J T H, additional, De Ruiter, M C, additional, and Jongbloed, M R M, additional
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- 2023
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5. Cost of exome analysis in patients with intellectual disability: a micro-costing study in a French setting
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Soilly, Al, Robert-Viard, C, Besse, C, Bruel, Al, Gerard, B, Boland, A, Piton, A, Duffourd, Y, Muller, J, Poë, C, Jouan, T, El Doueiri, S, Faivre, L, Bacq-Daian, D, Isidor, B, Genevieve, D, Odent, S, Philip, N, Doco-Fenzy, M, Lacombe, D, Asensio, Ml, Deleuze, Jf, Binquet, C, Thauvin-Robinet, C, Lejeune, C, Arpin, S, Blanchet, P, Blesson, S, Boute-Benejean, O, Busa, T, Colin, E, Coubes, C, Devillard, F, Edery, P, El Chehadeh, S, Fradin, M, Goldenberg, A, Guerrot, A-M, Herenger, Y, Houcinat, N, Jean-Marcais, N, Jouk, P., Lambert, L, Lavillaureix, A, Legendre, M, Leheup, B, Manouvrier, S, Mercier, S, Moutton, S, Nizon, M, Pasquier, L, Petit, F, Pinson, L, Poirsier, C, Pons, L, Putoux, A, Quelin, C, Renaud, M, Rossi, M, Sorlin, A, Spodenkiewicz, M, Thevenon, J, Toutain, A, Van-Gils, J, Vanlerberghe, C, Verloes, A, Vincent, M, Vincent-Delorme, C, Willems, M, Ziegler, A, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'Investigation Clinique 1432 (Dijon) - Epidemiologie Clinique/Essais Cliniques (CIC-EC), Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre National de Recherche en Génomique Humaine (CNRGH), Laboratoire de Diagnostic Génétique [CHU Strasbourg], Université de Strasbourg (UNISTRA)-CHU Strasbourg, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre hospitalier universitaire de Nantes (CHU Nantes), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Institut de Génétique et Développement de Rennes (IGDR), 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 ), CHU Pontchaillou [Rennes], Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), FHU TRANSLAD (CHU de Dijon), and This study was funded by the French Ministry of Health as part of the 2015 Medico-Economic Research Program.
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Exome sequencing ,MESH: France ,MESH: Exome ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,MESH: Humans ,Cost analysis ,Intellectual disability ,Micro-costing ,MESH: Intellectual Disability - Abstract
Background: With the development of next generation sequencing technologies in France, exome sequencing (ES) has recently emerged as an opportunity to improve the diagnosis rate of patients presenting an intellectual disability (ID). To help French policy makers determine an adequate tariff for ES, we aimed to assess the unit cost per ES diagnostic test for ID from the preparation of the pre-analytical step until the report writing step and to identify its main cost drivers.Methods: A micro-costing bottom-up approach was conducted for the year 2018 in a French setting as part of the DISSEQ study, a cost-effectiveness study funded by the Ministry of Health and performed in collaboration with the GAD (Génétique des Anomalies du Développement), a genetic team from the Dijon University Hospital, and a public sequencing platform, the Centre National de Recherche en Génomique Humaine (CNRGH). The analysis was conducted from the point of view of these two ES stakeholders. All of the resources (labor, equipment, disposables and reagents, reusable material) required to analyze blood samples were identified, collected and valued. Several sensitivity analyses were performed.Results: The unit nominal cost per ES diagnostic test for ID was estimated to be €2,019.39. Labor represented 50.7% of the total cost. The analytical step (from the preparation of libraries to the analysis of sequences) represented 88% of the total cost. Sensitivity analyses suggested that a simultaneous price decrease of 20% for the capture kit and 50% for the sequencing support kit led to an estimation of €1,769 per ES diagnostic test for ID.Conclusion: This is the first estimation of ES cost to be done in the French setting of ID diagnosis. The estimation is especially influenced by the price of equipment kits, but more generally by the organization of the centers involved in the different steps of the analysis and the time period in which the study was conducted. This information can now be used to define an adequate tariff and assess the efficiency of ES.Trial registration: ClinicalTrials.gov identifier NCT03287206 on September 19, 2017.
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- 2023
6. Management of trace contaminants in the Danube river basin
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Zoboli, O., primary, Kovacs, A., additional, Kittlaus, S., additional, Clement, A., additional, Kardos, M. K., additional, Jolánkai, Z., additional, Kaps, R., additional, Gabriel, O., additional, Broer, M., additional, van Gils, J., additional, Loos, S., additional, Weber, N., additional, Milacic, R., additional, Dimova, G., additional, Tonev, R., additional, Nedelea, I., additional, Marchidan, E., additional, and Zessner, M., additional
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- 2023
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7. Additional file 2 of SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients
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Mouill��, M., Rio, M., Breton, S., Piketty, M. L., Afenjar, A., Amiel, J., Capri, Y., Goldenberg, A., Francannet, C., Michot, C., Mignot, C., Perrin, L., Quelin, C., Van Gils, J., Barcia, G., Pingault, V., Maruani, G., Koumakis, E., and Cormier-Daire, V.
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musculoskeletal diseases ,musculoskeletal, neural, and ocular physiology ,education ,musculoskeletal system - Abstract
Additional file 2. Raw data and ULM values for P1NP and Osteocalcin in the 19 patients.
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- 2022
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8. Additional file 1 of SATB2-associated syndrome: characterization of skeletal features and of bone fragility in a prospective cohort of 19 patients
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Mouill��, M., Rio, M., Breton, S., Piketty, M. L., Afenjar, A., Amiel, J., Capri, Y., Goldenberg, A., Francannet, C., Michot, C., Mignot, C., Perrin, L., Quelin, C., Van Gils, J., Barcia, G., Pingault, V., Maruani, G., Koumakis, E., and Cormier-Daire, V.
- Abstract
Additional file 1. References for normal biological values for children and adults.
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- 2022
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9. PURA-Related Developmental and Epileptic Encephalopathy
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Johannesen, K.M., Gardella, E., Gjerulfsen, C.E., Bayat, A., Rouhl, R.P.W., Reijnders, M., Whalen, S., Keren, B., Buratti, J., Courtin, T., Wierenga, K.J., Isidor, B., Piton, A., Faivre, L., Garde, A., Moutton, S., Tran-Mau-Them, F., Denomme-Pichon, A.S., Coubes, C., Larson, A., Esser, M.J., Appendino, J.P., Al-Hertani, W., Gamboni, B., Mampel, A., Mayorga, L., Orsini, A., Bonuccelli, A., Suppiej, A., Van-Gils, J., Vogt, J., Damioli, S., Giordano, L., Moortgat, S., Wirrell, E., Hicks, S., Kini, U., Noble, N., Stewart, H., Asakar, S., Cohen, J.S., Naidu, S.R., Collier, A., Brilstra, E.H., Li, M.H., Brew, C., Bigoni, S., Ognibene, D., Ballardini, E., Ruivenkamp, C., RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), and MUMC+: DA KG Polikliniek (9)
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ALPHA ,DELINEATION ,EPILEPSIES ,DE-NOVO MUTATIONS ,MORTALITY ,FEATURES ,PHENOTYPE ,CLASSIFICATION ,POSTNATAL BRAIN-DEVELOPMENT - Abstract
Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-alpha, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.
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- 2021
10. Variants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behaviors.
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Willim J, Woike D, Greene D, Das S, Pfeifer K, Yuan W, Lindsey A, Itani O, Böhme AL, Tibbe D, Hönck HH, Hassani Nia F, Zech M, Brunet T, Faivre L, Sorlin A, Vitobello A, Smol T, Colson C, Baranano K, Schatz K, Bayat A, Schoch K, Spillmann R, Davis EE, Conboy E, Vetrini F, Platzer K, Neuser S, Gburek-Augustat J, Grace AN, Mitchell B, Stegmann A, Sinnema M, Meeks N, Saunders C, Cadieux-Dion M, Hoyer J, Van-Gils J, de Sainte-Agathe JM, Thompson ML, Bebin EM, Weisz-Hubshman M, Tabet AC, Verloes A, Levy J, Latypova X, Harder S, Silverman GA, Pak SC, Schedl T, Freson K, Mumford A, Turro E, Schlein C, Shashi V, and Kreienkamp HJ
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- Humans, Male, Female, Child, HEK293 Cells, Neurons metabolism, Adolescent, Membrane Proteins genetics, Membrane Proteins metabolism, Adult, Animals, Child, Preschool, Nerve Tissue Proteins genetics, Nerve Tissue Proteins metabolism, Young Adult, Synapses metabolism, PDZ Domains genetics, Intellectual Disability genetics, Autistic Disorder genetics, Autistic Disorder metabolism, Aggression physiology
- Abstract
Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca
2+ /calmodulin-dependent protein kinase II. We have previously observed an association between high impact variants in LRRC7 and Intellectual Disability; also three individual cases with variants in LRRC7 had been described. We identify here 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in LRRC7. The clinical spectrum involves intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. A PDZ domain variant interferes with synaptic targeting of Densin-180 in primary cultured neurons. Using in vitro systems (two hybrid, BioID, coimmunoprecipitation of tagged proteins from 293T cells) we identified new candidate interaction partners for the LRR domain, including protein phosphatase 1 (PP1), and observed that variants in the LRR reduced binding to these proteins. We conclude that LRRC7 encodes a major determinant of intellectual development and behaviour., (© 2024. The Author(s).)- Published
- 2024
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11. Menke-Hennekam syndrome; delineation of domain-specific subtypes with distinct clinical and DNA methylation profiles.
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Haghshenas S, Bout HJ, Schijns JM, Levy MA, Kerkhof J, Bhai P, McConkey H, Jenkins ZA, Williams EM, Halliday BJ, Huisman SA, Lauffer P, de Waard V, Witteveen L, Banka S, Brady AF, Galazzi E, van Gils J, Hurst ACE, Kaiser FJ, Lacombe D, Martinez-Monseny AF, Fergelot P, Monteiro FP, Parenti I, Persani L, Santos-Simarro F, Simpson BN, Alders M, Robertson SP, Sadikovic B, and Menke LA
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- Humans, Male, Female, Child, Adolescent, Child, Preschool, Adult, Phenotype, Young Adult, Rubinstein-Taybi Syndrome genetics, Mutation, Protein Domains genetics, DNA Methylation genetics, CREB-Binding Protein genetics, E1A-Associated p300 Protein genetics
- Abstract
CREB-binding protein (CBP, encoded by CREBBP) and its paralog E1A-associated protein (p300, encoded by EP300) are involved in histone acetylation and transcriptional regulation. Variants that produce a null allele or disrupt the catalytic domain of either protein cause Rubinstein-Taybi syndrome (RSTS), while pathogenic missense and in-frame indel variants in parts of exons 30 and 31 cause phenotypes recently described as Menke-Hennekam syndrome (MKHK). To distinguish MKHK subtypes and define their characteristics, molecular and extended clinical data on 82 individuals (54 unpublished) with variants affecting CBP (n = 71) or p300 (n = 11) (NP_004371.2 residues 1,705-1,875 and NP_001420.2 residues 1,668-1,833, respectively) were summarized. Additionally, genome-wide DNA methylation profiles were assessed in DNA extracted from whole peripheral blood from 54 individuals. Most variants clustered closely around the zinc-binding residues of two zinc-finger domains (ZZ and TAZ2) and within the first α helix of the fourth intrinsically disordered linker (ID4) of CBP/p300. Domain-specific methylation profiles were discerned for the ZZ domain in CBP/p300 (found in nine out of 10 tested individuals) and TAZ2 domain in CBP (in 14 out of 20), while a domain-specific diagnostic episignature was refined for the ID4 domain in CBP/p300 (in 21 out of 21). Phenotypes including intellectual disability of varying degree and distinct physical features were defined for each of the regions. These findings demonstrate existence of at least three MKHK subtypes, which are domain specific (MKHK-ZZ, MKHK-TAZ2, and MKHK-ID4) rather than gene specific (CREBBP/EP300). DNA methylation episignatures enable stratification of molecular pathophysiologic entities within a gene or across a family of paralogous genes., Competing Interests: Declaration of interests B.S. is a shareholder in EpiSign Inc., a biotech firm involved in commercial application of EpiSign technology., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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12. Care pathways in childhood neurodevelopmental disorders: Toward greater awareness of KBG syndrome among pediatricians.
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Adamo-Croux M, Auger-Gilli A, Guyader GL, Aubin-Courjault J, Margot H, Bar C, Lacombe D, Van-Gils J, Legendre M, Binet A, and Horn XLG
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- Humans, Retrospective Studies, Female, Male, Child, Child, Preschool, Referral and Consultation statistics & numerical data, Intellectual Disability genetics, Intellectual Disability diagnosis, Adolescent, Infant, Pediatricians psychology, Abnormalities, Multiple genetics, Abnormalities, Multiple diagnosis, Abnormalities, Multiple psychology, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics
- Abstract
Introduction: KBG syndrome is an autosomal dominant, polymalformative genetic syndrome that is mainly associated with neurodevelopmental and learning disorders, intellectual disability, behavioral disorders, and epilepsy as well as characteristic dysmorphic features, short stature, and ENT (ear, nose, and throat) abnormalities. However, the diagnostic pathway of these individuals is an element that has not been broadly evaluated. The main aim of this study was therefore to characterize the diagnostic pathway for these individuals, by assessing the different healthcare professionals involved and the main referral elements., Method: This was a multicenter, retrospective, descriptive study. A cohort of 30 individuals with KBG syndrome who were followed up at Poitiers University Hospital and Bordeaux University Hospital we recruited., Results: Pediatricians were the main healthcare professionals who referred individuals for genetic consultation, and the main reason for referral was an assessment of learning delays or intellectual disability, in association with other abnormalities., Conclusion: Pediatricians play a crucial role in the diagnostic guidance of individuals with KBG syndrome, and the main reason for referral remains the assessment of a learning delay or intellectual disability. Healthcare professionals must therefore remain attentive to the child's development and the various anomalies associated with it, in particular characteristic dysmorphic features, behavioral disorders, and statural growth., Competing Interests: Declaration of competing interest None., (Copyright © 2024 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.)
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- 2024
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13. Clinical spectrum of rare bone fragility disorders and response to bisphosphonate treatment: a retrospective study.
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Charpié M, Brunelle P, Baujat G, Michot C, Van Gils J, Leheup B, Schaefer É, Koumakis E, Pejin Z, Pinto G, Monnot S, and Cormier-Daire V
- Abstract
Osteogenesis Imperfecta (OI) is a clinically and genetically heterogeneous group of diseases characterized by brittle bones. Though genetic mutations in COL1A1 and COL1A2 account for approximately 85-90% of OI cases, there are now more than twenty genes described, responsible for rare forms of OI. Treatment is based on the use of bisphosphonates and though it is well established that they increase lumbar spine (LS) bone mineral density (BMD), the clinical impact on fracture reduction is still debated.In this study, we investigated the clinical characteristics of 38 patients with a bone fragility disorder that had variants in non-COL1A1/COL1A2 genes in order to study genotype-phenotype correlations, as the natural history of these rare forms is still not well known. We then studied the usefulness of bisphosphonate treatment by evaluating the effects on LS BMD, annual non-vertebral fracture rate, bone turnover markers and height. This study enabled us to better define the natural history of patients with non-COL1 pathogenic variants. Patients with CRTAP and TMEM38B variants consistently had a prenatal presentation with a short (<3
rd p) and bowed femur. Importantly, this prenatal involvement does not predict the postnatal severity of the disease. Regarding treatment by bisphosphonates, all patients showed a significant increase in LS BMD while treated and this increase was dependent on the dose received. The increase in LS BMD also translated in a reduction of fracture rate during treatment. Finally, our study showed that the earlier bisphosphonates are initiated, the greater the fracture rate is reduced., (© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)- Published
- 2024
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14. Diagnosis and management in Rubinstein-Taybi syndrome: first international consensus statement.
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Lacombe D, Bloch-Zupan A, Bredrup C, Cooper EB, Houge SD, García-Miñaúr S, Kayserili H, Larizza L, Lopez Gonzalez V, Menke LA, Milani D, Saettini F, Stevens CA, Tooke L, Van der Zee JA, Van Genderen MM, Van-Gils J, Waite J, Adrien JL, Bartsch O, Bitoun P, Bouts AHM, Cueto-González AM, Dominguez-Garrido E, Duijkers FA, Fergelot P, Halstead E, Huisman SA, Meossi C, Mullins J, Nikkel SM, Oliver C, Prada E, Rei A, Riddle I, Rodriguez-Fonseca C, Rodríguez Pena R, Russell J, Saba A, Santos-Simarro F, Simpson BN, Smith DF, Stevens MF, Szakszon K, Taupiac E, Totaro N, Valenzuena Palafoll I, Van Der Kaay DCM, Van Wijk MP, Vyshka K, Wiley S, and Hennekam RC
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- Humans, Consensus, Disease Management, Mutation, Rubinstein-Taybi Syndrome genetics, Rubinstein-Taybi Syndrome diagnosis, Rubinstein-Taybi Syndrome therapy, CREB-Binding Protein genetics, E1A-Associated p300 Protein genetics
- Abstract
Rubinstein-Taybi syndrome (RTS) is an archetypical genetic syndrome that is characterised by intellectual disability, well-defined facial features, distal limb anomalies and atypical growth, among numerous other signs and symptoms. It is caused by variants in either of two genes ( CREBBP , EP300 ) which encode for the proteins CBP and p300, which both have a function in transcription regulation and histone acetylation. As a group of international experts and national support groups dedicated to the syndrome, we realised that marked heterogeneity currently exists in clinical and molecular diagnostic approaches and care practices in various parts of the world. Here, we outline a series of recommendations that document the consensus of a group of international experts on clinical diagnostic criteria for types of RTS (RTS1: CREBBP ; RTS2: EP300 ), molecular investigations, long-term management of various particular physical and behavioural issues and care planning. The recommendations as presented here will need to be evaluated for improvements to allow for continued optimisation of diagnostics and care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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15. Autoimmune cytopenia and Kabuki syndrome in paediatrics: Insights in 11 patients.
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Bianchi C, Margot H, Fernandes H, Pasquet M, Priqueler L, Roy-Peaud F, Bauduer F, Bayart S, Garnier N, Fain O, Van Gils J, Joly SB, Rialland F, Paillard C, Deparis M, Lambilliotte A, Leblanc T, Fahd M, Leverger G, Héritier S, Geneviève D, Rieux-Laucat F, Picard C, Neyraud C, and Aladjidi N
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- Humans, Child, Female, Male, Child, Preschool, Adolescent, Purpura, Thrombocytopenic, Idiopathic genetics, Purpura, Thrombocytopenic, Idiopathic therapy, Purpura, Thrombocytopenic, Idiopathic diagnosis, Infant, Thrombocytopenia genetics, Thrombocytopenia diagnosis, Thrombocytopenia etiology, Thrombocytopenia therapy, Anemia, Hemolytic, Autoimmune genetics, Anemia, Hemolytic, Autoimmune diagnosis, Anemia, Hemolytic, Autoimmune therapy, Autoimmune Diseases genetics, Autoimmune Diseases diagnosis, Rituximab therapeutic use, Mutation, Cytopenia, Vestibular Diseases genetics, Vestibular Diseases diagnosis, Face abnormalities, Abnormalities, Multiple genetics, Histone Demethylases genetics, Neoplasm Proteins genetics, Hematologic Diseases genetics, DNA-Binding Proteins genetics
- Abstract
Kabuki syndrome (KS) is now listed in the Human Inborn Errors of Immunity (IEI) Classification. It is a rare disease caused by KMT2D and KDM6A variants, dominated by intellectual disability and characteristic facial features. Recurrently, pathogenic variants are identified in those genes in patients examined for autoimmune cytopenia (AIC), but interpretation remains challenging. This study aims to describe the genetic diagnosis and the clinical management of patients with paediatric-onset AIC and KS. Among 11 patients with AIC and KS, all had chronic immune thrombocytopenic purpura, and seven had Evans syndrome. All had other associated immunopathological manifestations, mainly symptomatic hypogammaglobinaemia. They had a median of 8 (5-10) KS-associated manifestations. Pathogenic variants were detected in KMT2D gene without clustering, during the immunological work-up of AIC in three cases, and the clinical strategy to validate them is emphasized. Eight patients received second-line treatments, mainly rituximab and mycophenolate mofetil. With a median follow-up of 17 (2-31) years, 8/10 alive patients still needed treatment for AIC. First-line paediatricians should be able to recognize and confirm KS in children with ITP or multiple AIC, to provide early appropriate clinical management and specific long-term follow-up. The epigenetic immune dysregulation in KS opens exciting new perspectives., (© 2024 British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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16. Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders.
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Husson T, Lecoquierre F, Nicolas G, Richard AC, Afenjar A, Audebert-Bellanger S, Badens C, Bilan F, Bizaoui V, Boland A, Bonnet-Dupeyron MN, Brischoux-Boucher E, Bonnet C, Bournez M, Boute O, Brunelle P, Caumes R, Charles P, Chassaing N, Chatron N, Cogné B, Colin E, Cormier-Daire V, Dard R, Dauriat B, Delanne J, Deleuze JF, Demurger F, Denommé-Pichon AS, Depienne C, Dieux A, Dubourg C, Edery P, El Chehadeh S, Faivre L, Fergelot P, Fradin M, Garde A, Geneviève D, Gilbert-Dussardier B, Goizet C, Goldenberg A, Gouy E, Guerrot AM, Guimier A, Harzalla I, Héron D, Isidor B, Lacombe D, Le Guillou Horn X, Keren B, Kuechler A, Lacaze E, Lavillaureix A, Lehalle D, Lesca G, Lespinasse J, Levy J, Lyonnet S, Morel G, Jean-Marçais N, Marlin S, Marsili L, Mignot C, Nambot S, Nizon M, Olaso R, Pasquier L, Perrin L, Petit F, Pingault V, Piton A, Prieur F, Putoux A, Planes M, Odent S, Quélin C, Quemener-Redon S, Rama M, Rio M, Rossi M, Schaefer E, Rondeau S, Saugier-Veber P, Smol T, Sigaudy S, Touraine R, Mau-Them FT, Trimouille A, Van Gils J, Vanlerberghe C, Vantalon V, Vera G, Vincent M, Ziegler A, Guillin O, Campion D, and Charbonnier C
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- Humans, DNA Methylation, Biomarkers, Pathology, Molecular, Neurodevelopmental Disorders diagnosis, Neurodevelopmental Disorders genetics
- Abstract
Variants of uncertain significance (VUS) are a significant issue for the molecular diagnosis of rare diseases. The publication of episignatures as effective biomarkers of certain Mendelian neurodevelopmental disorders has raised hopes to help classify VUS. However, prediction abilities of most published episignatures have not been independently investigated yet, which is a prerequisite for an informed and rigorous use in a diagnostic setting. We generated DNA methylation data from 101 carriers of (likely) pathogenic variants in ten different genes, 57 VUS carriers, and 25 healthy controls. Combining published episignature information and new validation data with a k-nearest-neighbour classifier within a leave-one-out scheme, we provide unbiased specificity and sensitivity estimates for each of the signatures. Our procedure reached 100% specificity, but the sensitivities unexpectedly spanned a very large spectrum. While ATRX, DNMT3A, KMT2D, and NSD1 signatures displayed a 100% sensitivity, CREBBP-RSTS and one of the CHD8 signatures reached <40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70-100% sensitivity at best with unstable performances, suffering from heterogeneous methylation profiles among cases and rare discordant samples. Our results call for cautiousness and demonstrate that episignatures do not perform equally well. Some signatures are ready for confident use in a diagnostic setting. Yet, it is imperative to characterise the actual validity perimeter and interpretation of each episignature with the help of larger validation sample sizes and in a broader set of episignatures., (© 2023. The Author(s).)
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- 2024
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17. Weill-Marchesani syndrome: natural history and genotype-phenotype correlations from 18 news cases and review of literature.
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Marzin P, Rondeau S, Alessandri JL, Dieterich K, le Goff C, Mahaut C, Mercier S, Michot C, Moldovan O, Miolo G, Rossi M, Van-Gils J, Francannet C, Robert MP, Jaïs JP, Huber C, and Cormier-Daire V
- Subjects
- Humans, Phenotype, Genetic Association Studies, Fibrillin-1 genetics, Latent TGF-beta Binding Proteins genetics, Multicenter Studies as Topic, Weill-Marchesani Syndrome genetics, Weill-Marchesani Syndrome diagnosis, Weill-Marchesani Syndrome pathology, Dwarfism genetics, Eye Abnormalities
- Abstract
Background: Weill-Marchesani syndrome (WMS) belongs to the group of acromelic dysplasias, defined by short stature, brachydactyly and joint limitations. WMS is characterised by specific ophthalmological abnormalities, although cardiovascular defects have also been reported. Monoallelic variations in FBN1 are associated with a dominant form of WMS, while biallelic variations in ADAMTS10 , ADAMTS17 and LTBP2 are responsible for a recessive form of WMS., Objective: Natural history description of WMS and genotype-phenotype correlation establishment., Materials and Methods: Retrospective multicentre study and literature review., Inclusion Criteria: clinical diagnosis of WMS with identified pathogenic variants., Results: 61 patients were included: 18 individuals from our cohort and 43 patients from literature. 21 had variants in ADAMTS17 , 19 in FBN1 , 19 in ADAMTS10 and 2 in LTBP2 . All individuals presented with eye anomalies, mainly spherophakia (42/61) and ectopia lentis (39/61). Short stature was present in 73% (from -2.2 to -5.5 SD), 10/61 individuals had valvulopathy. Regarding FBN1 variants, patients with a variant located in transforming growth factor (TGF)-β-binding protein-like domain 5 (TB5) domain were significantly smaller than patients with FBN1 variant outside TB5 domain (p=0.0040)., Conclusion: Apart from the ophthalmological findings, which are mandatory for the diagnosis, the phenotype of WMS seems to be more variable than initially described, partially explained by genotype-phenotype correlation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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18. TRAPPC6B biallelic variants cause a neurodevelopmental disorder with TRAPP II and trafficking disruptions.
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Almousa H, Lewis SA, Bakhtiari S, Nordlie SH, Pagnozzi A, Magee H, Efthymiou S, Heim JA, Cornejo P, Zaki MS, Anwar N, Maqbool S, Rahman F, Neilson DE, Vemuri A, Jin SC, Yang XR, Heidari A, van Gassen K, Trimouille A, Thauvin-Robinet C, Liu J, Bruel AL, Tomoum H, Shata MO, Hashem MO, Toosi MB, Karimiani EG, Yeşil G, Lingappa L, Baruah D, Ebrahimzadeh F, Van-Gils J, Faivre L, Zamani M, Galehdari H, Sadeghian S, Shariati G, Mohammad R, van der Smagt J, Qari A, Vincent JB, Innes AM, Dursun A, Özgül RK, Akar HT, Bilguvar K, Mignot C, Keren B, Raveli C, Burglen L, Afenjar A, Kaat LD, van Slegtenhorst M, Alkuraya F, Houlden H, Padilla-Lopez S, Maroofian R, Sacher M, and Kruer MC
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- Animals, Humans, Vesicular Transport Proteins genetics, Microcephaly genetics, Intellectual Disability genetics, Dystonia, Neurodevelopmental Disorders genetics, Epilepsy genetics
- Abstract
Highly conserved transport protein particle (TRAPP) complexes regulate subcellular trafficking pathways. Accurate protein trafficking has been increasingly recognized to be critically important for normal development, particularly in the nervous system. Variants in most TRAPP complex subunits have been found to lead to neurodevelopmental disorders with diverse but overlapping phenotypes. We expand on limited prior reports on TRAPPC6B with detailed clinical and neuroradiologic assessments, and studies on mechanisms of disease, and new types of variants. We describe 29 additional patients from 18 independent families with biallelic variants in TRAPPC6B. We identified seven homozygous nonsense (n = 12 patients) and eight canonical splice-site variants (n = 17 patients). In addition, we identified one patient with compound heterozygous splice-site/missense variants with a milder phenotype and one patient with homozygous missense variants. Patients displayed non-progressive microcephaly, global developmental delay/intellectual disability, epilepsy and absent expressive language. Movement disorders including stereotypies, spasticity and dystonia were also observed. Brain imaging revealed reductions in cortex, cerebellum and corpus callosum size with frequent white matter hyperintensity. Volumetric measurements indicated globally diminished volume rather than specific regional losses. We identified a reduced rate of trafficking into the Golgi apparatus and Golgi fragmentation in patient-derived fibroblasts that was rescued by wild-type TRAPPC6B. Molecular studies revealed a weakened interaction between mutant TRAPPC6B (c.454C>T, p.Q152*) and its TRAPP binding partner TRAPPC3. Patient-derived fibroblasts from the TRAPPC6B (c.454C>T, p.Q152*) variant displayed reduced levels of TRAPPC6B as well as other TRAPP II complex-specific members (TRAPPC9 and TRAPPC10). Interestingly, the levels of the TRAPPC6B homologue TRAPPC6A were found to be elevated. Moreover, co-immunoprecipitation experiments showed that TRAPPC6A co-precipitates equally with TRAPP II and TRAPP III, while TRAPPC6B co-precipitates significantly more with TRAPP II, suggesting enrichment of the protein in the TRAPP II complex. This implies that variants in TRAPPC6B may preferentially affect TRAPP II functions compared to TRAPP III functions. Finally, we assessed phenotypes in a Drosophila TRAPPC6B-deficiency model. Neuronal TRAPPC6B knockdown impaired locomotion and led to wing posture defects, supporting a role for TRAPPC6B in neuromotor function. Our findings confirm the association of damaging biallelic TRAPPC6B variants with microcephaly, intellectual disability, language impairments, and epilepsy. A subset of patients also exhibited dystonia and/or spasticity with impaired ambulation. These features overlap with disorders arising from pathogenic variants in other TRAPP subunits, particularly components of the TRAPP II complex. These findings suggest that TRAPPC6B is essential for brain development and function, and TRAPP II complex activity may be particularly relevant for mediating this function., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2024
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19. Clinico-biological refinement of BCL11B-related disorder and identification of an episignature: A series of 20 unreported individuals.
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Sabbagh Q, Haghshenas S, Piard J, Trouvé C, Amiel J, Attié-Bitach T, Balci T, Barat-Houari M, Belonis A, Boute O, Brightman DS, Bruel AL, Caraffi SG, Chatron N, Collet C, Dufour W, Edery P, Fong CT, Fusco C, Gatinois V, Gouy E, Guerrot AM, Heide S, Joshi A, Karp N, Keren B, Lesieur-Sebellin M, Levy J, Levy MA, Lozano C, Lyonnet S, Margot H, Marzin P, McConkey H, Michaud V, Nicolas G, Nizard M, Paulet A, Peluso F, Pernin V, Perrin L, Philippe C, Prasad C, Prasad M, Relator R, Rio M, Rondeau S, Ruault V, Ruiz-Pallares N, Sanchez E, Shears D, Siu VM, Sorlin A, Tedder M, Tharreau M, Mau-Them FT, van der Laan L, Van Gils J, Verloes A, Whalen S, Willems M, Yauy K, Zuntini R, Kerkhof J, Sadikovic B, and Geneviève D
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- Humans, CD8-Positive T-Lymphocytes metabolism, Transcription Factors genetics, DNA Methylation genetics, Tumor Suppressor Proteins genetics, Repressor Proteins genetics, Repressor Proteins metabolism, Neurodevelopmental Disorders genetics, Intellectual Disability genetics
- Abstract
Purpose: BCL11B-related disorder (BCL11B-RD) arises from rare genetic variants within the BCL11B gene, resulting in a distinctive clinical spectrum encompassing syndromic neurodevelopmental disorder, with or without intellectual disability, associated with facial features and impaired immune function. This study presents an in-depth clinico-biological analysis of 20 newly reported individuals with BCL11B-RD, coupled with a characterization of genome-wide DNA methylation patterns of this genetic condition., Methods: Through an international collaboration, clinical and molecular data from 20 individuals were systematically gathered, and a comparative analysis was conducted between this series and existing literature. We further scrutinized peripheral blood DNA methylation profile of individuals with BCL11B-RD, contrasting them with healthy controls and other neurodevelopmental disorders marked by established episignature., Results: Our findings unveil rarely documented clinical manifestations, notably including Rubinstein-Taybi-like facial features, craniosynostosis, and autoimmune disorders, all manifesting within the realm of BCL11B-RD. We refine the intricacies of T cell compartment alterations of BCL11B-RD, revealing decreased levels naive CD4
+ T cells and recent thymic emigrants while concurrently observing an elevated proportion of effector-memory expressing CD45RA CD8+ T cells (TEMRA). Finally, a distinct DNA methylation episignature exclusive to BCL11B-RD is unveiled., Conclusion: This study serves to enrich our comprehension of the clinico-biological landscape of BCL11B-RD, potentially furnishing a more precise framework for diagnosis and follow-up of individuals carrying pathogenic BCL11B variant. Moreover, the identification of a unique DNA methylation episignature offers a valuable diagnosis tool for BCL11B-RD, thereby facilitating routine clinical practice by empowering physicians to reevaluate variants of uncertain significance within the BCL11B gene., Competing Interests: Conflict of Interest The authors declare no conflicts of interest., (Copyright © 2023 American College of Medical Genetics and Genomics. All rights reserved.)- Published
- 2024
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20. Combining globally search for a regular expression and print matching lines with bibliographic monitoring of genomic database improves diagnosis.
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Tran Mau-Them F, Overs A, Bruel AL, Duquet R, Thareau M, Denommé-Pichon AS, Vitobello A, Sorlin A, Safraou H, Nambot S, Delanne J, Moutton S, Racine C, Engel C, De Giraud d'Agay M, Lehalle D, Goldenberg A, Willems M, Coubes C, Genevieve D, Verloes A, Capri Y, Perrin L, Jacquemont ML, Lambert L, Lacaze E, Thevenon J, Hana N, Van-Gils J, Dubucs C, Bizaoui V, Gerard-Blanluet M, Lespinasse J, Mercier S, Guerrot AM, Maystadt I, Tisserant E, Faivre L, Philippe C, Duffourd Y, and Thauvin-Robinet C
- Abstract
Introduction: Exome sequencing has a diagnostic yield ranging from 25% to 70% in rare diseases and regularly implicates genes in novel disorders. Retrospective data reanalysis has demonstrated strong efficacy in improving diagnosis, but poses organizational difficulties for clinical laboratories. Patients and methods: We applied a reanalysis strategy based on intensive prospective bibliographic monitoring along with direct application of the GREP command-line tool (to "globally search for a regular expression and print matching lines") in a large ES database. For 18 months, we submitted the same five keywords of interest [( intellectual disability , ( neuro ) developmental delay , and ( neuro ) developmental disorder )] to PubMed on a daily basis to identify recently published novel disease-gene associations or new phenotypes in genes already implicated in human pathology. We used the Linux GREP tool and an in-house script to collect all variants of these genes from our 5,459 exome database. Results: After GREP queries and variant filtration, we identified 128 genes of interest and collected 56 candidate variants from 53 individuals. We confirmed causal diagnosis for 19/128 genes (15%) in 21 individuals and identified variants of unknown significance for 19/128 genes (15%) in 23 individuals. Altogether, GREP queries for only 128 genes over a period of 18 months permitted a causal diagnosis to be established in 21/2875 undiagnosed affected probands (0.7%). Conclusion: The GREP query strategy is efficient and less tedious than complete periodic reanalysis. It is an interesting reanalysis strategy to improve diagnosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tran Mau-Them, Overs, Bruel, Duquet, Thareau, Denommé-Pichon, Vitobello, Sorlin, Safraou, Nambot, Delanne, Moutton, Racine, Engel, De Giraud d’Agay, Lehalle, Goldenberg, Willems, Coubes, Genevieve, Verloes, Capri, Perrin, Jacquemont, Lambert, Lacaze, Thevenon, Hana, Van-Gils, Dubucs, Bizaoui, Gerard-Blanluet, Lespinasse, Mercier, Guerrot, Maystadt, Tisserant, Faivre, Philippe, Duffourd and Thauvin-Robinet.)
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- 2023
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21. Hindcasting harmful algal bloom risk due to land-based nutrient pollution in the Eastern Chinese coastal seas.
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Wang H, Bouwman AF, Van Gils J, Vilmin L, Beusen AHW, Wang J, Liu X, Yu Z, and Ran X
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- Humans, Harmful Algal Bloom, East Asian People, Nutrients, Nitrogen analysis, Oceans and Seas, Dinoflagellida, Diatoms
- Abstract
Harmful algal blooms (HABs) have been increasing in frequency, areal extent and duration due to the large increase in nutrient inputs from land-based sources to coastal seas, and cause significant economic losses. In this study, we used the "watershed-coast-continuum" concept to explore the effects of land-based nutrient pollution on HAB development in the Eastern Chinese coastal seas (ECCS). Results from the coupling of a watershed nutrient model and a coast hydrodynamic-biogeochemical model show that between the 1980s and 2000s, the risk of diatom blooms and dinoflagellate blooms increased by 158% and 127%, respectively. The spatial expansion of HAB risk caused by dinoflagellates is larger than that of diatoms. The simulated suitability of the habitat for bloom of Aureococcus anophagefferens, a pico-plankton of non-diatom or dinoflagellate, in the Bohai Sea is consistent with observations spatially and temporally. To halt further nutrient accumulation in the ECCS, reductions of dissolved inorganic nitrogen (DIN) (16%) and dissolved inorganic phosphorus (DIP) (33%) loading are required. To improve the situation of distorted DIN:DIP ratios, even larger reductions of DIN are required, especially in the Bohai Sea. Our approach is a feasible way to predict the risk of HABs under the pressure of increasing anthropogenic nutrient pollution in coastal waters., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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22. Habitat suitability modelling to improve understanding of seagrass loss and recovery and to guide decisions in relation to coastal discharge.
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Erftemeijer PLA, van Gils J, Fernandes MB, Daly R, van der Heijden L, and Herman PMJ
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- South Australia, Ecosystem
- Abstract
Habitat suitability modelling was used to test the relationship between coastal discharges and seagrass occurrence based on data from Adelaide (South Australia). Seven variables (benthic light including epiphyte shading, temperature, salinity, substrate, wave exposure, currents and tidal exposure) were simulated using a coupled hydrodynamic-biogeochemical model and interrogated against literature-derived thresholds for nine local seagrass species. Light availability was the most critical driver across the study area but wave exposure played a key role in shallow nearshore areas. Model validation against seagrass mapping data showed 86 % goodness-of-fit. Comparison against later mapping data suggested that modelling could predict ~745 ha of seagrass recovery in areas previously classified as 'false positives'. These results suggest that habitat suitability modelling is reliable to test scenarios and predict seagrass response to reduction of land-based loads, providing a useful tool to guide (investment) decisions to prevent loss and promote recovery of seagrasses., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paul Erftemeijer reports financial support was provided by South Australian Water Corporation. Jos van Gils reports financial support was provided by South Australian Water Corporation., (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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- 2023
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23. Coupling a pathway-oriented approach with tailor-made monitoring as key to well-performing regionalized modelling of PFAS emissions and river concentrations.
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Kittlaus S, Clara M, van Gils J, Gabriel O, Broer MB, Hochedlinger G, Trautvetter H, Hepp G, Krampe J, Zessner M, and Zoboli O
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- Caprylates, Rivers, Alkanesulfonic Acids, Fluorocarbons analysis, Water Pollutants, Chemical analysis
- Abstract
Surface water pollution with poly- and perfluorinated compounds (PFAS) is a well-recognized problem, but knowledge about contribution of different emission pathways, especially diffuse ones, is very limited. This study investigates the potential of the pathway oriented MoRE model in shedding light on the relevance of different emission pathways on regional scale and in predicting concentrations and loads in unmonitored rivers. Modelling was supported with a tailor-made monitoring programme aimed to fill gaps on PFAS concentration in different environmental compartments. The study area covers the whole Austrian territory including some additional transboundary catchments and it focuses on perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS). These two PFAS are regulated and therefore their production and use in Europe are currently decreasing. Nevertheless, these compounds are still emitted into the environment via legacy pollution and as transformation products from other PFAS. These two compounds were selected for this study in view of the larger information availability compared to other PFAS. Despite considerable uncertainties in the input data, model validations show that this approach performs significantly better than previous modelling frameworks based on population-specific emission factors, population density and wastewater treatment plant information. The study reveals the predominance of emissions via municipal wastewater treatment plants for PFOS and a relevant role of diffuse emission pathways for PFOA. Results suggest that unpaved areas contribute the biggest share to total diffuse emissions, but the estimation of these pathways is affected by the highest uncertainty in the input data and requires better input data from monitoring. Once the currently growing substance-specific data sets on the concentration of PFAS, others than PFOS and PFOA, in different environmental compartments, will reach an adequate quality, the model presented here will be easily applicable to them., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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24. Rubinstein-Taybi Syndrome: Presentation in the First Month of Life.
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Levetan C, Van Gils J, Saba A, Rodríguez-Fonseca C, Fieggen K, and Tooke L
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- Humans, Infant, Infant, Newborn, Rubinstein-Taybi Syndrome complications, Rubinstein-Taybi Syndrome diagnosis
- Abstract
This web-based survey of 311 respondents from 25 countries provides additional information about the early presentation of Rubinstein-Taybi syndrome. Most (86%) infants present during the neonatal period, with 69% of these within 24 hours of life. Prolonged hospital stay is common (61%)., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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25. De novo coding variants in the AGO1 gene cause a neurodevelopmental disorder with intellectual disability.
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Schalk A, Cousin MA, Dsouza NR, Challman TD, Wain KE, Powis Z, Minks K, Trimouille A, Lasseaux E, Lacombe D, Angelini C, Michaud V, Van-Gils J, Spataro N, Ruiz A, Gabau E, Stolerman E, Washington C, Louie R, Lanpher BC, Kemppainen JL, Innes M, Kooy F, Meuwissen M, Goldenberg A, Lecoquierre F, Vera G, Diderich KEM, Sheidley B, El Achkar CM, Park M, Hamdan FF, Michaud JL, Lewis AJ, Zweier C, Reis A, Wagner M, Weigand H, Journel H, Keren B, Passemard S, Mignot C, van Gassen K, Brilstra EH, Itzikowitz G, O'Heir E, Allen J, Donald KA, Korf BR, Skelton T, Thompson M, Robin NH, Rudy NL, Dobyns WB, Foss K, Zarate YA, Bosanko KA, Alembik Y, Durand B, Tran Mau-Them F, Ranza E, Blanc X, Antonarakis SE, McWalter K, Torti E, Millan F, Dameron A, Tokita M, Zimmermann MT, Klee EW, Piton A, and Gerard B
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- Humans, Amino Acids genetics, Heterozygote, RNA, Messenger, Intellectual Disability genetics, Intellectual Disability pathology, Neurodevelopmental Disorders genetics, Neurodevelopmental Disorders pathology, Argonaute Proteins genetics
- Abstract
Background: High-impact pathogenic variants in more than a thousand genes are involved in Mendelian forms of neurodevelopmental disorders (NDD)., Methods: This study describes the molecular and clinical characterisation of 28 probands with NDD harbouring heterozygous AGO1 coding variants, occurring de novo for all those whose transmission could have been verified (26/28)., Results: A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Recurrently identified variants were present in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del). AGO1 encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linker domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behaviour and additional behavioural manifestations., Conclusion: Our study establishes that de novo coding variants in AGO1 are involved in a novel monogenic form of NDD, highly similar to the recently reported AGO2 -related NDD., Competing Interests: Competing interests: KMW, ET, FM, AD and MJT are employees of GeneDx. ZP and KM are employees of Ambry Genetics., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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26. Hemidystonia with polymicrogyria is part of ATP1A3-related disorders.
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Lacombe D, Van-Gils J, Lebrun M, Trimouille A, Michaud V, Cabet S, Chateil JF, Pedespan JM, Bar C, and Lesca G
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- Humans, Male, Mutation genetics, Phenotype, Sodium-Potassium-Exchanging ATPase genetics, Dystonia, Dystonic Disorders genetics, Polymicrogyria diagnostic imaging, Polymicrogyria genetics
- Abstract
Introduction: Pathogenic variants in ATP1A3 cause various phenotypes of neurological disorders, including alternating hemiplegia of childhood 2, CAPOS syndrome (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss) and rapid-onset dystonia-parkinsonism (RDP). Early developmental and epileptic encephalopathy has also been reported. Polymicrogyria has recently been added to the phenotypic spectrum of ATP1A3-related disorders., Case Report: We report here a male patient with early developmental delay who at 12 months presented dystonia of the right arm which evolved into hemidystonia at the age of 2. A cerebral MRI showed bilateral perisylvian polymicrogyria with intact basal ganglia. Whole-exome and whole-genome sequencing analyses identified a de novo new ATP1A3 missense variant (p.Arg914Lys) predicted pathogenic. Hemidystonia was thought not to be due to polymicrogyria, but rather a consequence of this variant., Conclusion: This case expands the phenotypic spectrum of ATP1A3-related disorders with a new variant associated with hemidystonia and polymicrogyria and thereby, suggests a clinical continuum between the different phenotypes of this condition., Competing Interests: Conflict of interest disclosures The authors declare no competing interests., (Copyright © 2022 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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27. KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism.
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Miceli F, Millevert C, Soldovieri MV, Mosca I, Ambrosino P, Carotenuto L, Schrader D, Lee HK, Riviello J, Hong W, Risen S, Emrick L, Amin H, Ville D, Edery P, de Bellescize J, Michaud V, Van-Gils J, Goizet C, Willemsen MH, Kleefstra T, Møller RS, Bayat A, Devinsky O, Sands T, Korenke GC, Kluger G, Mefford HC, Brilstra E, Lesca G, Milh M, Cooper EC, Taglialatela M, and Weckhuysen S
- Subjects
- Amitriptyline, Gain of Function Mutation, Humans, Infant, Newborn, KCNQ2 Potassium Channel genetics, Seizures, Autistic Disorder, Epilepsy, Infant, Newborn, Diseases, Language Development Disorders
- Abstract
Background: Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline., Methods: Patients were identified using the RIKEE database and through clinical collaborators. Phenotypes were collected by a standardized questionnaire. Functional and pharmacological properties of variant subunits were analyzed by whole-cell patch-clamp recordings., Findings: Detailed clinical information on fifteen patients (14 novel and 1 previously published) was analyzed. All patients had developmental delay with prominent language impairment. R144Q patients were more severely affected than R144W patients. Infantile to childhood onset epilepsy occurred in 40%, while 67% of sleep-EEGs showed sleep-activated epileptiform activity. Ten patients (67%) showed autistic features. Activation gating of homomeric Kv7.2 R144W/Q/G channels was left-shifted, suggesting gain-of-function effects. Amitriptyline blocked channels containing Kv7.2 and Kv7.2 R144Q subunits., Interpretation: Patients carrying KCNQ2 R144 gain-of-function variants have developmental delay with prominent language impairment, autistic features, often accompanied by infantile- to childhood-onset epilepsy and EEG sleep-activated epileptiform activity. The absence of neonatal seizures is a robust and important clinical differentiator between KCNQ2 gain-of-function and loss-of-function variants. The Kv7.2/7.3 channel blocker amitriptyline might represent a targeted treatment., Funding: Supported by FWO, GSKE, KCNQ2-Cure, Jack Pribaz Foundation, European Joint Programme on Rare Disease 2020, the Italian Ministry for University and Research, the Italian Ministry of Health, the European Commission, the University of Antwerp, NINDS, and Chalk Family Foundation., Competing Interests: Declaration of interests SW received consultancy and speaker fees from UCB, Biocodex, Xenon, Zogenix, Lundbeck, Knopp Biosciences, Encoded MT received consultancy fees from Xenon. ECC received consultancy fees from Xenon, Knopp, these activities have been reviewed and approved by Baylor College of Medicine according to its policy on disclosure of outside interests. RSM received consultancy and speaker fees from EISAI and UCB. The remaining authors have no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2022
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28. Accelerated genome sequencing with controlled costs for infants in intensive care units: a feasibility study in a French hospital network.
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Denommé-Pichon AS, Vitobello A, Olaso R, Ziegler A, Jeanne M, Tran Mau-Them F, Couturier V, Racine C, Isidor B, Poë C, Jouan T, Boland A, Fin B, Bacq-Daian D, Besse C, Garde A, Prost A, Garret P, Tisserant É, Delanne J, Nambot S, Juven A, Gorce M, Nizon M, Vincent M, Moutton S, Fradin M, Lavillaureix A, Rollier P, Capri Y, Van-Gils J, Busa T, Sigaudy S, Pasquier L, Barth M, Bruel AL, Flamant C, Prouteau C, Bonneau D, Toutain A, Chantegret C, Callier P, Philippe C, Duffourd Y, Deleuze JF, Sorlin A, Faivre L, and Thauvin-Robinet C
- Subjects
- Child, Feasibility Studies, Humans, Infant, Infant, Newborn, Pilot Projects, Prospective Studies, Hospitals, Intensive Care Units
- Abstract
Obtaining a rapid etiological diagnosis for infants with early-onset rare diseases remains a major challenge. These diseases often have a severe presentation and unknown prognosis, and the genetic causes are very heterogeneous. In a French hospital network, we assessed the feasibility of performing accelerated trio-genome sequencing (GS) with limited additional costs by integrating urgent requests into the routine workflow. In addition to evaluating our capacity for such an approach, this prospective multicentre pilot study was designed to identify pitfalls encountered during its implementation. Over 14 months, we included newborns and infants hospitalized in neonatal or paediatric intensive care units with probable genetic disease and in urgent need for etiological diagnosis to guide medical care. The duration of each step and the pitfalls were recorded. We analysed any deviation from the planned schedule and identified obstacles. Trio-GS was performed for 37 individuals, leading to a molecular diagnosis in 18/37 (49%), and 21/37 (57%) after reanalysis. Corrective measures and protocol adaptations resulted in a median duration of 42 days from blood sampling to report. Accelerated trio-GS is undeniably valuable for individuals in an urgent care context. Such a circuit should coexist with a rapid or ultra-rapid circuit, which, although more expensive, can be used in particularly urgent cases. The drop in GS costs should result in its generalized use for diagnostic purposes and lead to a reduction of the costs of rapid GS., (© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.)
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- 2022
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29. Chromatin Structure and Dynamics: Focus on Neuronal Differentiation and Pathological Implication.
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Nothof SA, Magdinier F, and Van-Gils J
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- Chromatin genetics, DNA Methylation genetics, Protein Processing, Post-Translational genetics, Epigenesis, Genetic, Histones metabolism
- Abstract
Chromatin structure is an essential regulator of gene expression. Its state of compaction contributes to the regulation of genetic programs, in particular during differentiation. Epigenetic processes, which include post-translational modifications of histones, DNA methylation and implication of non-coding RNA, are powerful regulators of gene expression. Neurogenesis and neuronal differentiation are spatio-temporally regulated events that allow the formation of the central nervous system components. Here, we review the chromatin structure and post-translational histone modifications associated with neuronal differentiation. Studying the impact of histone modifications on neuronal differentiation improves our understanding of the pathophysiological mechanisms of chromatinopathies and opens up new therapeutic avenues. In addition, we will discuss techniques for the analysis of histone modifications on a genome-wide scale and the pathologies associated with the dysregulation of the epigenetic machinery.
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- 2022
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30. PURA- Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum.
- Author
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Johannesen KM, Gardella E, Gjerulfsen CE, Bayat A, Rouhl RPW, Reijnders M, Whalen S, Keren B, Buratti J, Courtin T, Wierenga KJ, Isidor B, Piton A, Faivre L, Garde A, Moutton S, Tran-Mau-Them F, Denommé-Pichon AS, Coubes C, Larson A, Esser MJ, Appendino JP, Al-Hertani W, Gamboni B, Mampel A, Mayorga L, Orsini A, Bonuccelli A, Suppiej A, Van-Gils J, Vogt J, Damioli S, Giordano L, Moortgat S, Wirrell E, Hicks S, Kini U, Noble N, Stewart H, Asakar S, Cohen JS, Naidu SR, Collier A, Brilstra EH, Li MH, Brew C, Bigoni S, Ognibene D, Ballardini E, Ruivenkamp C, Faggioli R, Afenjar A, Rodriguez D, Bick D, Segal D, Coman D, Gunning B, Devinsky O, Demmer LA, Grebe T, Pruna D, Cursio I, Greenhalgh L, Graziano C, Singh RR, Cantalupo G, Willems M, Yoganathan S, Góes F, Leventer RJ, Colavito D, Olivotto S, Scelsa B, Andrade AV, Ratke K, Tokarz F, Khan AS, Ormieres C, Benko W, Keough K, Keros S, Hussain S, Franques A, Varsalone F, Grønborg S, Mignot C, Heron D, Nava C, Isapof A, Borlot F, Whitney R, Ronan A, Foulds N, Somorai M, Brandsema J, Helbig KL, Helbig I, Ortiz-González XR, Dubbs H, Vitobello A, Anderson M, Spadafore D, Hunt D, Møller RS, and Rubboli G
- Abstract
Background and Objectives: Purine-rich element-binding protein A ( PURA ) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients., Methods: Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained., Results: A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations., Discussion: The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)
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- 2021
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31. A Microfluidics-Based Screening Tool to Assess the Impact of Blood Plasma Factors on Microvascular Integrity.
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Junaid A, van Duinen V, Stam W, Dólleman S, Yang W, de Rijke Y, Endeman H, van Kooten C, Mashaghi A, de Boer H, van Gils J, Hankemeier T, and van Zonneveld AJ
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- Endothelium, Vascular, Humans, Plasma, SARS-CoV-2, Vascular Endothelial Growth Factor A, COVID-19, Microfluidics
- Abstract
This study provides a method to assess the impact of circulating plasma factors on microvascular integrity by using a recently developed microvessel-on-a-chip platform featuring the human endothelium that is partly surrounded by the extracellular matrix. The system is high-throughput, which allows parallel analysis of organ-level microvessel pathophysiology, including vascular leakage. Ethylenediaminetetraacetic acid plasma samples are mixed with inhibitors for recalcification of the plasma samples to avoid activation of the coagulation- or complement system. Moreover, the assay is validated by spiking vascular endothelial growth factor, histamine, or tumor necrosis factor alpha to recalcified plasma and confirms their modulation of microvessel barrier function at physiologically relevant concentrations. Finally, this study shows that perfusing the microvessels with recalcified plasma samples of coronavirus disease-2019 patients, with a confirmed proinflammatory profile, results in markedly increased leakage of the microvessels. The assay provides opportunities for diagnostic screening of inflammatory or endothelial disrupting plasma factors associated with endothelial dysfunction., (© 2021 The Authors. Advanced Biology published by Wiley-VCH GmbH.)
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- 2021
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32. A comparative study of cognitive and socio-emotional development in children with Rubinstein-Taybi syndrome and children with Autism Spectrum Disorder associated with a severe intellectual disability, and in young typically developing children with matched developmental ages.
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Adrien JL, Taupiac E, Thiébaut E, Paulais MA, Van-Gils J, Kaye K, Blanc R, Gattegno MP, Contejean Y, Michel G, Dean A, Barthélémy C, and Lacombe D
- Subjects
- Child, Child, Preschool, Cognition, Emotions, Humans, Infant, Autism Spectrum Disorder, Intellectual Disability, Rubinstein-Taybi Syndrome
- Abstract
Background: Cognitive and socio-emotional profiles of children with CREBBP-related Rubinstein-Taybi syndrome (RSTS 1), children with Autism Spectrum Disorder (ASD) with severe intellectual disability and developmental ages (DA) under 24 months, and typically developing (TD) children with similar DA were compared., Participants: Thirty-one children with RSTS 1 (mean chronological age, CA = 59,8 months; 33-87) and thirty children with ASD, matched on CA and DA and developmental quotients (DQ), were compared to thirty TD children (CA ranged from 12 to 24 months)., Methods: Cognitive and socio-emotional developmental levels, DA and DQ were assessed with appropriated tests., Results: More socio-emotional developmental similarities were observed between TD and RSTS 1 than between TD and ASD children. Clinical groups displayed similar developmental delays in cognitive (self-image, symbolic play, means-ends, and object permanence) and socio-emotional domains (language and imitation). Children with RSTS 1 exhibited higher developmental levels in behavior regulation, joint attention, affective relations, emotional expression domains, and a lower developmental level in spatial relations domain., Conclusions: Common interventions centered on symbolic play, self-image, language, and imitation for both clinical groups, and differentiated interventions centered on spatial abilities for RSTS 1 children and on social abilities for ASD could be used by caregivers were suggested., (Copyright © 2021 Elsevier Ltd. All rights reserved.)
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- 2021
- Full Text
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