Author: "David Geneviève" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"David Geneviève"' showing total 524 results

Start Over Author "David Geneviève"

524 results on '"David Geneviève"'

1. Biallelic variants in CSMD1 are implicated in a neurodevelopmental disorder with intellectual disability and variable cortical malformations

Author: Elizabeth A. Werren, Emily R. Peirent, Henna Jantti, Alba Guxholli, Kinshuk Raj Srivastava, Naama Orenstein, Vinodh Narayanan, Wojciech Wiszniewski, Mateusz Dawidziuk, Pawel Gawlinski, Muhammad Umair, Amjad Khan, Shahid Niaz Khan, David Geneviève, Daphné Lehalle, K. L. I. van Gassen, Jacques C. Giltay, Renske Oegema, Richard H. van Jaarsveld, Rafiullah Rafiullah, Gudrun A. Rappold, Rachel Rabin, John G. Pappas, Marsha M. Wheeler, Michael J. Bamshad, Yao-Chang Tsan, Matthew B. Johnson, Catherine E. Keegan, Anshika Srivastava, and Stephanie L. Bielas
Subjects: Cytology, QH573-671
Abstract: Abstract CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.
Published: 2024
Full Text: View/download PDF

2. Next generation phenotyping for diagnosis and phenotype–genotype correlations in Kabuki syndrome

Author: Quentin Hennocq, Marjolaine Willems, Jeanne Amiel, Stéphanie Arpin, Tania Attie-Bitach, Thomas Bongibault, Thomas Bouygues, Valérie Cormier-Daire, Pierre Corre, Klaus Dieterich, Maxime Douillet, Jean Feydy, Eva Galliani, Fabienne Giuliano, Stanislas Lyonnet, Arnaud Picard, Thantrira Porntaveetus, Marlène Rio, Flavien Rouxel, Vorasuk Shotelersuk, Annick Toutain, Kevin Yauy, David Geneviève, Roman H. Khonsari, and Nicolas Garcelon
Subjects: Medicine, Science
Abstract: Abstract The field of dysmorphology has been changed by the use Artificial Intelligence (AI) and the development of Next Generation Phenotyping (NGP). The aim of this study was to propose a new NGP model for predicting KS (Kabuki Syndrome) on 2D facial photographs and distinguish KS1 (KS type 1, KMT2D-related) from KS2 (KS type 2, KDM6A-related). We included retrospectively and prospectively, from 1998 to 2023, all frontal and lateral pictures of patients with a molecular confirmation of KS. After automatic preprocessing, we extracted geometric and textural features. After incorporation of age, gender, and ethnicity, we used XGboost (eXtreme Gradient Boosting), a supervised machine learning classifier. The model was tested on an independent validation set. Finally, we compared the performances of our model with DeepGestalt (Face2Gene). The study included 1448 frontal and lateral facial photographs from 6 centers, corresponding to 634 patients (527 controls, 107 KS); 82 (78%) of KS patients had a variation in the KMT2D gene (KS1) and 23 (22%) in the KDM6A gene (KS2). We were able to distinguish KS from controls in the independent validation group with an accuracy of 95.8% (78.9–99.9%, p
Published: 2024
Full Text: View/download PDF

3. Infantile‐onset parkinsonism, dyskinesia, and developmental delay: do not forget polyglutamine defects!

Author: Heidy Baide‐Mairena, Arthur Coget, Nicolas Leboucq, Vincent Procaccio, Maud Blanluet, Pierre Meyer, Marie‐Claire Malinge, Marie‐Céline François‐Heude, Mathis Moreno, David Geneviève, Cecilia Marelli, and Agathe Roubertie
Subjects: Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract We present the phenotype of an infant with the largest ATN1 CAG expansion reported to date (98 repeats). He presented at 4 months with developmental delay, poor eye contact, acquired microcephaly, failure to thrive. He progressively developed dystonia‐parkinsonism with paroxysmal oromandibular and limbs dyskinesia and fatal outcome at 17 months. Cerebral MRI disclosed globus pallidus T2‐WI hyperintensities and brain atrophy. Molecular analysis was performed post‐mortem following the diagnosis of dentatorubral–pallidoluysian atrophy (DRPLA) in his symptomatic father. Polyglutamine expansion defects should be considered when neurodegenerative genetic disease is suspected even in infancy and parkinsonism can be a presentation of infantile‐onset DRPLA.
Published: 2023
Full Text: View/download PDF

4. The impact of lockdown on young people with genetic neurodevelopmental disabilities: a study with the international participatory database GenIDA

Author: Romain Coutelle, Morgane Boedec, Karlijn Vermeulen, Joost Kummeling, David A. Koolen, Tjitske Kleefstra, Camille Fournier, Florent Colin, Axelle Strehle, David Geneviève, Pauline Burger, and Jean-Louis Mandel
Subjects: Intellectual disability, Autism spectrum disorder, Behavioural problems, Genetic disorders, COVID-19, Self-report, Psychiatry, RC435-571
Abstract: Abstract Background Previous publications suggested that lockdown is likely to impact daily living issues of individuals with intellectual disabilities. The authors notably suspected an intensification of behavioural, eating and sleep problems. Methods To test these hypotheses, we conducted an international online survey about the impact of COVID-19-associated first lockdown on people with genetic neurodevelopmental disorders. This survey was carried out using GenIDA, an international participatory database collecting medical information on genetic neurodevelopmental disorders. Patients’ relatives took part in this online survey from 30/04/2020 to 09/06/2020. This survey adapted from GenIDA standard questionnaire requested information on diagnosis, lifestyle and was based on yes/no answers to questions regarding behaviour, diet, and sleep, in the 6-months period before lockdown and during lockdown. We also asked relatives to evaluate the intensity of these problems by severity level. Finally, relatives could freely comment in open fields on the medical and/or quality of life problems they had encountered during lockdown. Results In total 199 participants—144 children and 45 adults—with neurodevelopmental disorders (intellectual disability (79.4%) and/or autism spectrum disorder (21.6%)) of various genetic origins, with near-equal male/female (96/103) contribution and originating mainly from Europe and Northern America, were included. The average lockdown duration at time of the survey was 57 days. We did not find differences in the frequency of behavioural, eating and sleep problems before and during lockdown. Moreover, there was no apparent difference in the intensity of eating and sleep disorders between both periods. However, for persons with behavioural problems at both periods, relatives reported an increase in aggressivity, self-aggressivity, depressiveness, stereotypies, and restricted interests during lockdown, all of which might be interpreted as consequences of a lack of stimulation or a reaction to unexpected changes in daily habits. Conclusions Our results support previous studies that suggest that the negative impact of lockdown does not depend on the intellectual disability per se but on the associated comorbidities such as behavioural disorders. This study addresses the need for prevention of behavioural disturbance in the vulnerable population with genetic neurodevelopmental disabilities.
Published: 2022
Full Text: View/download PDF

5. O46: GenIDA, an international participatory database to better characterize comorbidities of genetic forms of intellectual disability: insights on Koolen-de Vries syndrome

Author: Pauline Burger, Florent Colin, Axelle Strehle, Timothée Mazzucotelli, Nicole Collot, Ariane Bouman, Daphna Landau Prat, David Geneviève, Valentin Ruault, Roseline Caumes, Thomas Smol, Jamal Ghoumid, Joost Kummeling, Charlotte Ockeloen, Tjitske Kleefstra, Pierre Parrend, Amélie Piton, David Koolen, and Jean-Louis Mandel
Subjects: Genetics, QH426-470, Medicine
Published: 2023
Full Text: View/download PDF

6. 10 years of CEMARA database in the AnDDI-Rares network: a unique resource facilitating research and epidemiology in developmental disorders in France

Author: Claude Messiaen, Caroline Racine, Ahlem Khatim, Louis Soussand, Sylvie Odent, Didier Lacombe, Sylvie Manouvrier, Patrick Edery, Sabine Sigaudy, David Geneviève, Christel Thauvin-Robinet, Laurent Pasquier, Florence Petit, Massimiliano Rossi, Marjolaine Willems, Tania Attié-Bitach, Pierre-Henry Roux-Levy, Laurent Demougeot, Lilia Ben Slama, Paul Landais, the AnDDI-Rares network, Anne-Sophie Jannot, Christine Binquet, Arnaud Sandrin, Alain Verloes, and Laurence Faivre
Subjects: Rare disease, Developmental disorders, Data warehouse, Epidemiology, Medicine
Abstract: Abstract Background In France, the Ministry of Health has implemented a comprehensive program for rare diseases (RD) that includes an epidemiological program as well as the establishment of expert centers for the clinical care of patients with RD. Since 2007, most of these centers have entered the data for patients with developmental disorders into the CEMARA population-based registry, a national online data repository for all rare diseases. Through the CEMARA web portal, descriptive demographic data, clinical data, and the chronology of medical follow-up can be obtained for each center. We address the interest and ongoing challenges of this national data collection system 10 years after its implementation. Methods Since 2007, clinicians and researchers have reported the “minimum dataset (MDS)” for each patient presenting to their expert center. We retrospectively analyzed administrative data, demographic data, care organization and diagnoses. Results Over 10 years, 228,243 RD patients (including healthy carriers and family members for whom experts denied any suspicion of RD) have visited an expert center. Among them, 167,361 were patients affected by a RD (median age 11 years, 54% children, 46% adults, with a balanced sex ratio), and 60,882 were unaffected relatives (median age 37 years). The majority of patients (87%) were seen no more than once a year, and 52% of visits were for a diagnostic procedure. Among the 2,869 recorded rare disorders, 1,907 (66.5%) were recorded in less than 10 patients, 802 (28%) in 10 to 100 patients, 149 (5.2%) in 100 to 1,000 patients, and 11 (0.4%) in > 1,000 patients. Overall, 45.6% of individuals had no diagnosis and 6.7% had an uncertain diagnosis. Children were mainly referred by their pediatrician (46%; n = 55,755 among the 121,136 total children referrals) and adults by a medical specialist (34%; n = 14,053 among the 41,564 total adult referrals). Given the geographical coverage of the centers, the median distance from the patient’s home was 25.1 km (IQR = 6.3 km-64.2 km). Conclusions CEMARA provides unprecedented support for epidemiological, clinical and therapeutic studies in the field of RD. Researchers can benefit from the national scope of CEMARA data, but also focus on specific diseases or patient subgroups. While this endeavor has been a major collective effort among French RD experts to gather large-scale data into a single database, it provides tremendous potential to improve patient care.
Published: 2021
Full Text: View/download PDF

7. Disruption of chromatin organisation causes MEF2C gene overexpression in intellectual disability: a case report

Author: Kevin Yauy, Anouck Schneider, Bee Ling Ng, Jean-Baptiste Gaillard, Satish Sati, Christine Coubes, Constance Wells, Magali Tournaire, Thomas Guignard, Pauline Bouret, David Geneviève, Jacques Puechberty, Franck Pellestor, and Vincent Gatinois
Subjects: Intellectual disability (ID), Topologically associated domains (TAD), MEF2C, Internal medicine, RC31-1245, Genetics, QH426-470
Abstract: Abstract Background Balanced structural variants are mostly described in disease with gene disruption or subtle rearrangement at breakpoints. Case presentation Here we report a patient with mild intellectual deficiency who carries a de novo balanced translocation t(3;5). Breakpoints were fully explored by microarray, Array Painting and Sanger sequencing. No gene disruption was found but the chromosome 5 breakpoint was localized 228-kb upstream of the MEF2C gene. The predicted Topologically Associated Domains analysis shows that it contains only the MEF2C gene and a long non-coding RNA LINC01226. RNA studies looking for MEF2C gene expression revealed an overexpression of MEF2C in the lymphoblastoid cell line of the patient. Conclusions Pathogenicity of MEF2C overexpression is still unclear as only four patients with mild intellectual deficiency carrying 5q14.3 microduplications containing MEF2C are described in the literature. The microduplications in these individuals also contain other genes expressed in the brain. The patient presented the same phenotype as 5q14.3 microduplication patients. We report the first case of a balanced translocation leading to an overexpression of MEF2C similar to a functional duplication.
Published: 2019
Full Text: View/download PDF

8. Mosaic complete tetrasomy 21 in a fetus with complete atrioventricular septal defect and minor morphological variations

Author: Vincent Gatinois, Nicole Bigi, Eve Mousty, Jean Chiesa, Yuri Musizzano, Anouck Schneider, Geneviève Lefort, Lucile Pinson, Jean‐Baptiste Gaillard, Clémence Ragon, Marie‐Josée Perez, Magali Tournaire, Patricia Blanchet, Carole Corsini, Emmanuelle Haquet, Patrick Callier, David Geneviève, Franck Pellestor, and Jacques Puechberty
Subjects: atrioventricular septal defect, Down syndrome, Mosaicism, prenatal diagnosis, tetrasomy 21, trisomy 21, Genetics, QH426-470
Abstract: Abstract Background Tetrasomy 21 is a very rare aneuploidy which could clinically resemble a Down syndrome. It was most often described in its partial form than complete. We report the prenatal, pathological and genetic characteristics of a fetus with mosaic complete tetrasomy 21. This is the second well‐documented description of a complete tetrasomy 21 in the literature. Methods Prenatal and fetal pathological examinations, cytogenetic and molecular analyses were performed to characterize fetal features with tetrasomy 21. Results Prenatal ultrasound examination revealed an isolated complete atrioventricular septal defect with normal karyotype on amniotic fluid. After termination of pregnancy, clinical examination of the fetus evoked trisomy 21 or Down syndrome. Chromosomal microarray analysis and FISH on lung tissue showed a mosaicism with four copies of chromosome 21 (tetrasomy 21). Conclusion Our observation and the review of the literature reported the possibility of very weak mosaicism and disease‐causing confined tissue‐specific mosaicism in fetus or alive patients with chromosome 21 aneuploidy, mainly Down syndrome. In case of clinical diagnosis suggestive of Down syndrome, attention must be paid to the risk of false‐negative test due to chromosomal mosaicism (very weak percentage, different tissue distribution). To overcome this risk, it is necessary to privilege the diagnostic techniques without culture step and to increase the number of cells and tissues analyzed, if possible. This study highlights the limits of microarray as the unique diagnostic approach in case of weak mosaic and French cytogenetics guidelines recommend to check anomalies seen in microarray by another technique on the same tissue.
Published: 2019
Full Text: View/download PDF

9. Anatomical and functional abnormalities on MRI in kabuki syndrome

Author: Jennifer Boisgontier, Jean Marc Tacchella, Hervé Lemaître, Natacha Lehman, Ana Saitovitch, Vincent Gatinois, Guilaine Boursier, Elodie Sanchez, Elza Rechtman, Ludovic Fillon, Stanislas Lyonnet, Kim-Hanh Le Quang Sang, Genevieve Baujat, Marlene Rio, Odile Boute, Laurence Faivre, Elise Schaefer, Damien Sanlaville, Monica Zilbovicius, David Grévent, David Geneviève, and Nathalie Boddaert
Subjects: Computer applications to medicine. Medical informatics, R858-859.7, Neurology. Diseases of the nervous system, RC346-429
Abstract: Kabuki syndrome (KS) is a rare congenital disorder (1/32000 births) characterized by distinctive facial features, intellectual disability, short stature, and dermatoglyphic and skeletal abnormalities. In the last decade, mutations in KMT2D and KDM6A were identified as a major cause of kabuki syndrome. Although genetic abnormalities have been highlighted in KS, brain abnormalities have been little explored. Here, we have investigated brain abnormalities in 6 patients with KS (4 males; Mage = 10.96 years, SD = 2.97 years) with KMT2D mutation in comparison with 26 healthy controls (17 males; Mage = 10.31 years, SD = 2.96 years). We have used MRI to explore anatomical and functional brain abnormalities in patients with KS. Anatomical abnormalities in grey matter volume were assessed by cortical and subcortical analyses. Functional abnormalities were assessed by comparing rest cerebral blood flow measured with arterial spin labeling-MRI. When compared to healthy controls, KS patients had anatomical alterations characterized by grey matter decrease localized in the bilateral precentral gyrus and middle frontal gyrus. In addition, KS patients also presented functional alterations characterized by cerebral blood flow decrease in the left precentral gyrus and middle frontal gyrus. Moreover, subcortical analyses revealed significantly decreased grey matter volume in the bilateral hippocampus and dentate gyrus in patients with KS. Our results strongly indicate anatomical and functional brain abnormalities in KS. They suggest a possible neural basis of the cognitive symptoms observed in KS, such as fine motor impairment, and indicate the need to further explore the consequences of such brain abnormalities in this disorder. Finally, our results encourage further imaging-genetics studies investigating the link between genetics, anatomical and functional brain alterations in KS. Keywords: Kabuki syndrome, Congenital disorder, Voxel-based morphometry, Arterial spin labeling, Hippocampus, Brodmann area 6 and 9
Published: 2019
Full Text: View/download PDF

10. How patient-reported outcomes and experience measures (PROMs and PREMs) are implemented in healthcare professional and patient organizations? An environmental scan

Author: Lowry, Véronique, Tremblay-Vaillancourt, Vanessa, Beaupré, Priscilla, Poirier, Marie-Dominique, Perron, Marie-Ève, Bernier, Jessica, Morin, Anaëlle, Cormier, Caroline, Haggerty, Jeannie, Ahmed, Sara, Brodeur, Magaly, David, Geneviève, Lambert, Sylvie, Laberge, Maude, Zidarov, Diana, Visca, Regina, Poder, Thomas G., Zomahoun, Hervé Tchala Vignon, Sasseville, Maxime, and Poitras, Marie-Eve
Published: 2024
Full Text: View/download PDF

11. TMEM187-IRAK1 Polymorphisms Associated with Rheumatoid Arthritis Susceptibility in Tunisian and French Female Populations: Influence of Geographic Origin

Author: Olfa Khalifa, Nathalie Balandraud, Nathalie Lambert, Isabelle Auger, Jean Roudier, Audrey Sénéchal, David Geneviève, Christophe Picard, Gérard Lefranc, Isabelle Touitou, Bakridine M’Madi Mrenda, Cécilia Benedito, Etienne Pardoux, Anne-Laure Gagez, Yves-Marie Pers, Christian Jorgensen, Touhami Mahjoub, and Florence Apparailly
Subjects: Immunologic diseases. Allergy, RC581-607
Abstract: Polymorphisms have been identified in the Xq28 locus as risk loci for rheumatoid arthritis (RA). Here, we investigated the association between three polymorphisms in the Xq28 region containing TMEM187 and IRAK1 (rs13397, rs1059703, and rs1059702) in two unstudied populations: Tunisian and French. The rs13397 G and rs1059703 T major alleles were significantly increased in RA patients (n=408) compared with age-matched controls (n=471) in both Tunisian and French women. These results were confirmed by a meta-analysis replication study including two independent Greek and Korean cohorts. The rs1059702 C major allele was significantly associated with RA, only with French women. In the French population, the GTC haplotype displayed a protective effect against RA, while the ATC, GCC, and GTT haplotypes conferred significant risk for RA. No association for these haplotypes was found in the Tunisian population. Our results replicated for the first time the association of the three Xq28 polymorphisms with RA risk in Tunisian and French populations and suggested that RA susceptibility is associated with TMEM187-IRAK1 polymorphisms in women. Our data further support the involvement of X chromosome in RA susceptibility and evidence ethnicities differences that might be explained by differences in the frequencies of SE HLA-DRB1 alleles between both populations.
Published: 2017
Full Text: View/download PDF

12. Evaluation of a national e-booking system for medical consultation in primary care in a universal health system

Author: Motulsky, Aude, Bosson-Rieutort, Delphine, Usher, Susan, David, Geneviève, Moreault, Marie-Pierre, Gagnon, Marie-Pierre, Schuster, Tibor, and Sicotte, Claude
Published: 2023
Full Text: View/download PDF

13. Artificial Intelligence: Opportunities and Challenges for Public Administration.

Author: David, Geneviève
Subjects: *ARTIFICIAL intelligence, *PUBLIC administration, *RESOURCE management, *PUBLIC interest, *TECHNOLOGY
Abstract: Artificial intelligence (AI) could be at the heart of a fourth revolution by significantly changing professional identity, relationships between individuals and resource management. To help public administration practitioners and researchers cope with changes anticipated by AI, this research note maps existing conceptual approaches on the opportunities and challenges of AI in public administration and proposes a conceptual framework and initiatives that can inform and support effective, public interest‐oriented technology policymaking. This research note outlines a potential research agenda, with multi‐level opportunities and challenges, to accelerate this critical work. [ABSTRACT FROM AUTHOR]
Published: 2024
Full Text: View/download PDF

14. Episignatures in practice: independent evaluation of published episignatures for the molecular diagnostics of ten neurodevelopmental disorders

Author: Thomas Husson, François Lecoquierre, Gaël Nicolas, Anne-Claire Richard, Alexandra Afenjar, Séverine AUDEBERT-BELLANGER, Catherine Badens, Frédéric Bilan, Varoona Bizaoui, Anne Boland, Marie-Noelle Bonnet-Dupeyron, Elise Brischoux-Boucher, Céline Bonnet, Marie Bournez, Odile Boute, Perrine Brunelle, Roseline Caumes, Perrine Charles, Nicolas Chassaing, Nicolas Chatron, Benjamin Cogné, Estelle Colin, Valérie Cormier-Daire, Rodolphe Dard, Benjamin Dauriat, Julian Delanne, Jean-François Deleuze, Florence Demurger, Anne-Sophie Denommé-Pichon, Christel Depienne, Anne Dieux Coeslier, Christèle Dubourg, Patrick Edery, salima EL CHEHADEH, Laurence Faivre, Mélanie FRADIN, Aurore Garde, David Geneviève, Brigitte Gilbert-Dussardier, Cyril Goizet, Alice Goldenberg, Evan Gouy, Anne-Marie Guerrot, Anne Guimier, Ines HARZALLAH, Delphine Héron, Bertrand Isidor, Xavier Le Guillou Horn, Boris Keren, Alma Kuechler, Elodie Lacaze, Alinoë Lavillaureix, Daphné Lehalle, Gaetan Lesca, James Lespinasse, Jonathan Levy, Stanislas Lyonnet, Godelieve Morel, Nolwenn Jean Marçais, Sandrine Marlin, Luisa Marsili, Cyril Mignot, Sophie Nambot, Mathilde Nizon, Robert Olaso, Laurent PASQUIER, Laurine Perrin, Florence Petit, Amélie Piton, Fabienne Prieur, Audrey Putoux, Marc Planes, Sylvie Odent, Chloé Quelin, Sylvia Quemener, Mélanie Rama, Marlène RIO, Massimiliano Rossi, Elise Schaefer, Sophie Rondeau, Pascale SAUGIER-VEBER, Thomas Smol, Sabine Sigaudy, Renaud TOURAINE, Frédéric Tran-Mau-Them, Aurélien Trimouille, Clémence Vanlerberghe, Valérie Vantalon, Gabriella Vera, Marie Vincent, Alban Ziegler, Olivier Guillin, Dominique Campion, and Camille Charbonnier
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 102 carriers of (likely) pathogenic variants in ten different genes, 58 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 less than 40% sensitivity on our dataset. Remaining Cornelia de Lange syndrome, KMT2A, KDM5C and CHD7 signatures reached 70%-100% sensibility 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.
Published: 2023

15. Lessons from two series by physicians and caregivers’ self-reported data, and DNA methylation profile in DDX3X-Related Disorders

Author: David Geneviève, Valentin Ruault, Pauline Burger, Johanna Gradels-Hauguel, Nathalie Ruiz-Pallares, Xtraordinaire Association, Rami Abou Jamra, Alexandra Afenjar, Yves Alembik, Jean-Luc Alessandri, Arpin Stéphanie, Giulia Barcia, Šárka Bendová, Ange-Line Bruel, Perrine Charles, Nicolas Chatron, Maya Chopra, Solène Conrad, Valérie Cormier-Daire, Auriane Cospain, Christine Coubes, Juliette Coursimault, Andrée Delahaye-Duriez, Martine Doco-Fenzy, William Dufour, Benjamin Durand, Camille ENGEL, Laurence Faivre, Fanny Ferroul, Mélanie FRADIN, Hélène Frenkiel, Carlo Fusco, Livia Garavelli, Aurore Garde, Bénédicte Gérard, David Germanaud, Louise Goujon, Aurélie Gouronc, Emmanuelle Ginglinger, Alice Goldenberg, Miroslava Hancarova, Delphine Héron, Bertrand Isidor, Nolwenn Jean Marçais, Boris Keren, Margarete Koch-Hogrebe, Paul Kuentz, Victoria Lamure, Anne-Sophie Lebre, François Lecoquierre, Natacha Lehman, Gaetan Lesca, Stanislas Lyonnet, Delphine Martin, Cyril Mignot, Teresa Neuhann, Gaël Nicolas, Mathilde Nizon, Florence Petit, Christophe Philippe, Amélie Piton, Marzia Pollazzon, Darina Prchalova, Audrey Putoux, Marlène RIO, Sophie Rondeau, Massimiliano Rossi, Quentin Sabbagh, Pascale Saugier-Veber, Ariane Schmetz, Julie Steffann, Christel Thauvin-Robinet, Annick Toutain, Frédéric Tran-Mau-Them, Gabriele Trimarchi, Marie Vincent, Marketa Vlckova, Dagmar Wieczorek, Marjolaine Willems, kevin yauy, Michaela Zelinová, Alban Ziegler, Boris Chaumette, Bekim Sadikovic, and Jean-Louis Mandel
Abstract: We report two series of individuals with DDX3X variations, one (48 individuals) from physicians and one (44 individuals) from caregivers. These two series include several symptoms in common, with fairly similar distribution, which suggests that caregivers’ data are close to physicians’ data. For example, both series identified early childhood symptoms that were not previously described: feeding difficulties, mean walking age and age at first words. Each of the two datasets provide complementary knowledge. We confirmed that symptoms are similar to those in the literature and provide more details on feeding difficulties. Caregivers considered that the symptom attention-deficit/hyperactivity disorder was most worrisome. Both series also reported sleep disturbance. Recently, anxiety has been reported in individuals with DDX3X variants. We strongly suggest that attention-deficit/hyperactivity disorder, anxiety and sleep disorders need to be treated. In addition, we demonstrate preliminary evidence of a mild genome-wide DNA methylation profile in patients carrying mutations in DDX3X.
Published: 2023

16. Toward clinical and molecular dissection of frontonasal dysplasia with facial skin polyps: From Pai syndrome to differential diagnosis through a series of 27 patients

Author: Daphné Lehalle, Ange‐Line Bruel, Antonio Vitobello, Anne‐Sophie Denommé‐Pichon, Yannis Duffourd, Mirna Assoum, Jeanne Amiel, Geneviève Baujat, Bettina Bessieres, Stefania Bigoni, Lydie Burglen, Guillaume Captier, Rodolphe Dard, Patrick Edery, Fernanda Fortunato, David Geneviève, Alice Goldenberg, Laurent Guibaud, Delphine Héron, Muriel Holder‐Espinasse, Damien Lederer, Fermina Lopez Grondona, Sarah Grotto, Sandrine Marlin, Gwenaël Nadeau, Arnaud Picard, Massimiliano Rossi, Joëlle Roume, Damien Sanlaville, Pascale Saugier‐Veber, Stéphane Triau, Maria Irene Valenzuela Palafoll, Clémence Vanlerberghe, Lionel Van Maldergem, Myriam Vezain, Catherine Vincent‐Delorme, Einat Zivi, Julien Thevenon, Pierre Vabres, Christel Thauvin‐Robinet, Patrick Callier, and Laurence Faivre
Subjects: Eye Diseases, Cleft Lip, Neurocutaneous Syndromes, Skin Diseases, Spine, Coloboma, Craniofacial Abnormalities, Diagnosis, Differential, Nasal Polyps, Face, Genetics, Humans, Lipomatosis, Eye Abnormalities, Lipoma, Agenesis of Corpus Callosum, Ear, External, Respiratory System Abnormalities, Genetics (clinical)
Abstract: Unique or multiple congenital facial skin polyps are features of several rare syndromes, from the most well-known Pai syndrome (PS), to the less recognized oculoauriculofrontonasal syndrome (OAFNS), encephalocraniocutaneous lipomatosis (ECCL), or Sakoda complex (SC). We set up a research project aiming to identify the molecular bases of PS. We reviewed 27 individuals presenting with a syndromic frontonasal polyp and initially referred for PS. Based on strict clinical classification criteria, we could confirm only nine (33%) typical and two (7%) atypical PS individuals. The remaining ones were either OAFNS (11/27-41%) or presenting with an overlapping syndrome (5/27-19%). Because of the phenotypic overlap between these entities, OAFNS, ECCL, and SC can be either considered as differential diagnosis of PS or part of the same spectrum. Exome and/or genome sequencing from blood DNA in 12 patients and from affected tissue in one patient failed to identify any replication in candidate genes. Taken together, our data suggest that conventional approaches routinely utilized for the identification of molecular etiologies responsible for Mendelian disorders are inconclusive. Future studies on affected tissues and multiomics studies will thus be required in order to address either the contribution of mosaic or noncoding variation in these diseases.
Published: 2022

17. Extending the prenatal Noonan's phenotype by review of ultrasound and autopsy data

Author: Audrey Lamouroux, Coralie Dauge, Constance Wells, Eve Mousty, Lucile Pinson, Hélène Cavé, Yline Capri, Jean‐Michel Faure, Frédéric Grosjean, Fanny Sauvestre, Tania Attié‐Bitach, Fanny Pelluard, and David Geneviève
Subjects: Phenotype, Pregnancy, Noonan Syndrome, Edema, Humans, Obstetrics and Gynecology, Female, Autopsy, Nuchal Translucency Measurement, Ultrasonography, Prenatal, Genetics (clinical), Retrospective Studies
Abstract: The antenatal phenotypic spectrum of Noonan Syndrome (NS) requires better characterization.This multicenter retrospective observational included 16 fetuses with molecularly confirmed NS admitted for fetopathological examination between 2009 and 2016.Among 12 pathogenic variants (PV) in PTPN11 (80%), 5 (42%) fell between position c.179 and c.182. Ultrasound showed increased nuchal translucency (n = 13/16, 93%), increased nuchal fold after 15 weeks of gestation (n = 12/16, 75%), pleural effusions (n = 11/16, 69%), polyhydramnios (n = 9/16, 56%), hydrops (n = 7/16, 44%), cardiovascular (n = 6/16, 38%) and cerebral (n = 4/16, 25%) anomalies. Fetopathological examination found dysmorphic features in all cases, cardiovascular anomalies (n = 12/15, 80%), pulmonary hypoplasia (n = 10/15, 67%), effusions (n = 7/15, 47%) and neuropathological anomalies (n = 5/15, 33%). Hydrops was significantly (p = 0.02) more frequent in the four fetuses with RIT1, NRAS and RAF1 PV versus the 12 fetuses with PTPN11 PV.Increased nuchal translucency and nuchal fold is common in NS. Noonan Syndrome antenatal phenotype showed high in utero fetal death, hydrops, prenatal pleural effusion and pulmonary hypoplasia, although the inclusion of only deceased fetuses will have selected more severe phenotypes. Non-specific cardiovascular and neurological abnormalities should be added to NS antenatal phenotype. Next generation sequencing will help detect more genotypes, clarifying the prenatal phenotype and identifying genotype-phenotype correlations.
Published: 2022

18. Germline Mosaicism in STAT3: A Pitfall for Genetic Diagnosis, Counseling, and Therapy of Hyper-IgE Syndrome

Author: Quentin Sabbagh, Jean-David Cohen, Jérémie Mortreux, Laure Raymond, Vanna Geromel, Guilaine Boursier, Eric Jeziorski, Vincent Le Moing, Didier Bessis, and David Geneviève
Subjects: Immunology and Allergy, Dermatology
Published: 2023

19. SRSF1 haploinsufficiency is responsible for a syndromic developmental disorder associated with intellectual disability

Author: Elke Bogaert, Aurore Garde, Thierry Gautier, Kathleen Rooney, Yannis Duffourd, Pontus LeBlanc, Emma van Reempts, Frederic Tran Mau-Them, Ingrid M. Wentzensen, Kit Sing Au, Kate Richardson, Hope Northrup, Vincent Gatinois, David Geneviève, Raymond J. Louie, Michael J. Lyons, Lone Walentin Laulund, Charlotte Brasch-Andersen, Trine Maxel Juul, Fatima El It, Nathalie Marle, Patrick Callier, Raissa Relator, Sadegheh Haghshenas, Haley McConkey, Jennifer Kerkhof, Claudia Cesario, Antonio Novelli, Nicola Brunetti-Pierri, Michele Pinelli, Perrine Pennamen, Sophie Naudion, Marine Legendre, Cécile Courdier, Aurelien Trimouille, Martine Doco Fenzy, Lynn Pais, Alison Yeung, Kimberly Nugent, Elizabeth R. Roeder, Tadahiro Mitani, Jennifer E. Posey, Daniel Calame, Hagith Yonath, Jill A. Rosenfeld, Luciana Musante, Flavio Faletra, Francesca Montanari, Giovanna Sartor, Alessandra Vancini, Marco Seri, Claude Besmond, Karine Poirier, Laurence Hubert, Dimitri Hemelsoet, Arnold Munnich, James R. Lupski, Christophe Philippe, Christel Thauvin-Robinet, Laurence Faivre, Bekim Sadikovic, Jérôme Govin, Bart Dermaut, Antonio Vitobello, Bogaert, Elke, Garde, Aurore, Gautier, Thierry, Rooney, Kathleen, Duffourd, Yanni, Leblanc, Pontu, van Reempts, Emma, Tran Mau-Them, Frederic, Wentzensen, Ingrid M, Au, Kit Sing, Richardson, Kate, Northrup, Hope, Gatinois, Vincent, Geneviève, David, Louie, Raymond J, Lyons, Michael J, Laulund, Lone Walentin, Brasch-Andersen, Charlotte, Maxel Juul, Trine, El It, Fatima, Marle, Nathalie, Callier, Patrick, Relator, Raissa, Haghshenas, Sadegheh, Mcconkey, Haley, Kerkhof, Jennifer, Cesario, Claudia, Novelli, Antonio, Brunetti-Pierri, Nicola, Pinelli, Michele, Pennamen, Perrine, Naudion, Sophie, Legendre, Marine, Courdier, Cécile, Trimouille, Aurelien, Fenzy, Martine Doco, Pais, Lynn, Yeung, Alison, Nugent, Kimberly, Roeder, Elizabeth R, Mitani, Tadahiro, Posey, Jennifer E, Calame, Daniel, Yonath, Hagith, Rosenfeld, Jill A, Musante, Luciana, Faletra, Flavio, Montanari, Francesca, Sartor, Giovanna, Vancini, Alessandra, Seri, Marco, Besmond, Claude, Poirier, Karine, Hubert, Laurence, Hemelsoet, Dimitri, Munnich, Arnold, Lupski, James R, Philippe, Christophe, Thauvin-Robinet, Christel, Faivre, Laurence, Sadikovic, Bekim, Govin, Jérôme, Dermaut, Bart, and Vitobello, Antonio
Subjects: SRSF1, splicing, epigenetic signature, Medicine and Health Sciences, Genetics, Drosophila, neurodevelopmental disorder, Genetics (clinical), haploinsufficiency
Abstract: SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity.
Published: 2023

20. Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Author: Marjolaine Willems, Benjamin Durand, Boris Keren, Kristina Pilekær Sørensen, Rosanna Weksberg, Magalie Barth, Christina Fagerberg, Cyril Mignot, Laurence Perrin, Lucas Bronicki, Nathalie Drouot, Imene Boujelbene, Marc Abramowicz, Maria Kibaek, Bertrand Isidor, Thierry Bienvenu, Mathilde Nizon, Perrine Charles, Laurent Pasquier, Yann Herault, Marie Christine Birling, Bruno Delobel, Michel Guipponi, Lydie Burglen, Mélanie Fradin, Anne Sophie Denommé, Florence Demurger, Benjamin Cogné, Sébastien Moutton, Allan Bayat, Frederic Tran Mau Them, Christèle Dubourg, Alice Goldenberg, Christine Francannet, Jean-Louis Mandel, Laurence Faivre, Jérémie Courraud, Anne Marie Guerrot, Julia Metreau, Loréline Genschik, Bénédicte Demeer, Marie Vincent, Mathilde Renaud, Julien Thevenon, Sandrine Passemard, Christine Coubes, Amélie Piton, David Geneviève, Maria del Mar Muniz Moreno, Bénédicte Gérard, Estelle Colin, Valérie Layet, Michèle Mathieu-Dramard, Salima El Chehadeh, Katrine M Johannesen, Julie D. Thompson, Cathrine Elisabeth Tronhjem, Pascale Saugier, Elise Schaefer, Eric Chater-Diehl, Séverine Drunat, Rikke S. Møller, Paul Kuentz, Claire Feger, Albert David, Antonio Vitobello, Marlène Rio, Khaoula Khachnaoui, Joane Svane, Stéphane Auvin, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The Hospital for sick children [Toronto] (SickKids), Centre hospitalier universitaire de Nantes (CHU Nantes), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Les Hôpitaux Universitaires de Strasbourg (HUS), Hôpital Universitaire de Genève, Children's hospital of Eastern Ontario Research Institute [Ottawa, canada] (CHEO), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Hôpital Saint Vincent de Paul de Lille, Groupe Hospitalier de l'Institut Catholique de Lille (GHICL), Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Hôpital Robert Debré, CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Hôpital Sud [CHU Rennes], CHU Pontchaillou [Rennes], CHU Clermont-Ferrand, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark], University of Southern Denmark (SDU), Odense University Hospital (OUH), CHU Amiens-Picardie, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Odense University Hospital [Odense, Denmark], Centre Hospitalier Universitaire [Grenoble] (CHU), Groupe Hospitalier du Havre, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Institut Clinique de la Souris, Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de psychiatrie et neurosciences de Paris (IPNP - U1266 Inserm), Hôpital Cochin [AP-HP], Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), University of Toronto, Institut Universitaire de France (IUF), Ministère de l'Education nationale, de l’Enseignement supérieur et de la Recherche (M.E.N.E.S.R.), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Sorbonne Université, Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015 - 2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Centre for Integrative Biology - CBI (Inserm U964 - CNRS UMR7104 - IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), 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 ), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Agence de Biomédecine, Fondation APLM, Fondation Maladies Rares and Fondation Jérome Lejeune, univOAK, Archive ouverte, Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Matériaux et nanosciences d'Alsace (FMNGE), and Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], DYRK1A, [SDV]Life Sciences [q-bio], [SDV.GEN] Life Sciences [q-bio]/Genetics, Protein Serine-Threonine Kinases, Biology, [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Mice, 03 medical and health sciences, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual Disability, medicine, Animals, Humans, Missense mutation, Kinase activity, Gene, Genetics (clinical), Cellular localization, 030304 developmental biology, Genetics, [SDV.GEN]Life Sciences [q-bio]/Genetics, 0303 health sciences, Protein-Tyrosine Kinases, medicine.disease, Phenotype, Human genetics, 3. Good health, 030220 oncology & carcinogenesis, Microcephaly
Abstract: Purpose: DYRK1A syndrome is among the most frequent monogenic forms of intellectual disability (ID). We refined the molecular and clinical description of this disorder and developed tools to improve interpretation of missense variants, which remains a major challenge in human genetics. Methods: We reported clinical and molecular data for 50 individuals with ID harboring DYRK1A variants and developed (1) a specific DYRK1A clinical score; (2) amino acid conservation data generated from 100 DYRK1A sequences across different taxa; (3) in vitro overexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins; and (4) a specific blood DNA methylation signature. Results: This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, still reported as likely pathogenic, and showed it does not cause an obvious phenotype in mice. Conclusion: Our study demonstrated the need for caution when interpreting variants in DYRK1A, even those occurring de novo. The tools developed will be useful to interpret accurately the variants identified in the future in this gene. Graphic abstract: [Figure not available: see fulltext.]
Published: 2021

21. Learning phenotypic patterns in genetic diseases by symptom interaction modeling

Author: Julien Thevenon, Kevin Yauy, Nicolas Duforet-Frebourg, Quentin Testard, Sacha Beaumeunier, Jerome Audoux, Benoit Simard, DImitri Larue, Michael Blum, VIrginie Bernard, David Geneviève, Denis Bertrand, and Nicolas Philippe
Abstract: Observing phenotyping practices from an international cohort of 1,686 cases revealed heterogeneity of phenotype reporting among clinicians. Heterogeneity limited their exploitation for diagnosis as only 43% of symptom-gene associations in the cohort were available in public databases. We developed a symptom interaction model that summarized 16,600 terms into 390 groups of interacting symptoms and detected 3,222,053 novel symptom-gene associations. By learning phenotypic patterns in genetic diseases, symptom interaction modeling handled heterogeneity in phenotyping, to the extent of covering 99.8% of our cohort’s symptom-gene associations. Using these symptom interactions improved the diagnostic performance in gene prioritization by 42% (median rank 80 to 41) compared to the best algorithms. Symptom interaction modeling will provide new discoveries in precision medicine by standardizing clinical descriptions.
Published: 2022

22. CDK13-related disorder: a deep characterization of speech and language abilities and addition of 33 novel cases

Author: Angela Morgan, Lottie Morison, Olivia van Reyk, Elana Forbes, Flavien Rouxel, Laurence Faivre, Fiona Bruinsma, Marie Vincent, Marie-Line Jacquemont, Natalie Dykzeul, David Geneviève, and David Amor
Subjects: Genetics, Genetics (clinical)
Abstract: Speech and language impairments are central features of CDK13-related disorder. While pathogenic CDK13 variants have been associated with childhood apraxia of speech (CAS), a systematic characterisation of communication has not been conducted. Here we examined speech, language, non-verbal communication skills, social behaviour and health and development in 41 individuals with CDK-13 related disorder (male = 22, median-age 7 years 1 month, range 1–25 years; 33 novel). Most participants used augmentative and alternative communication (AAC) in early childhood (24/41). CAS was common (14/22). Performance varied widely across intellectual ability, social behaviour and expressive language skills, with participants ranging from within average through to the severely impaired range. Receptive language was significantly stronger than expressive language ability. Social motivation was a relative strength. In terms of broader phenotype, a quarter had one or more of: renal, urogenital, musculoskeletal and cardiac malformations, vision impairment, ear infections and/or sleep disturbance. All had gross and fine motor impairments (41/41). Other conditions included mild-moderate intellectual disability (16/22) and autism (7/41). No genotype-phenotype correlations were found. Recognition of CAS, a rare speech disorder, is required to ensure appropriately targeted therapy. The high prevalence of speech and language impairment underscores the importance of tailored speech therapy, particularly early access to AAC supports.
Published: 2022

23. Knowledge exchange sessions on primary health care research findings in public libraries: A qualitative study with citizens in Quebec.

Author: Laberge, Maude, Brundisini, Francesca Katherine, Zomahoun, Hervé Tchala Vignon, Sawadogo, Jasmine, Massougbodji, José, Gogovor, Amédé, David, Geneviève, and Légaré, France
Subjects: PUBLIC spaces, PRIMARY health care, INFORMATION sharing, PUBLIC libraries, SCIENTIFIC knowledge, INAPPROPRIATE prescribing (Medicine)
Abstract: Little is known about knowledge transfer with the public. We explored how citizens, physicians, and communication specialists understand knowledge transfer in public spaces such as libraries. The initial study aimed at evaluating the scaling up of a program on disseminating research findings on potentially inappropriate medication. Twenty-two citizen workshops were offered by 16 physicians and facilitated by 6 communication specialists to 322 citizens in libraries during spring 2019. We did secondary analysis using the recorded workshop discussions to explore the type of knowledge participants used. Participants described four kinds of knowledge: biomedical, sociocultural beliefs, value-based reasoning, and institutional knowledge. Biomedical knowledge included scientific evidence, research methods, clinical guidelines, and access to research outcomes. Participants discussed beliefs in scientific progress, innovative clinical practices, and doctors' behaviours. Participants discussed values related to reliability, transparency, respect for patient autonomy and participation in decision-making. All categories of participants used these four kinds of knowledge. However, their descriptions varied particularly for biomedical knowledge which was described by physician-speakers and communication specialists-facilitators as scientific evidence, epidemiological and clinical practice guidelines, and pathophysiological theories. Communication specialists-facilitators also described scientific journalistic sources and scientific journalistic reports as proxies of scientific evidence. Citizens described biomedical knowledge in terms of knowledge to make informed decisions. These findings offer insights for future scientific knowledge exchange interventions with the public. [ABSTRACT FROM AUTHOR]
Published: 2023
Full Text: View/download PDF

24. Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement

Author: Christy W. LaFlamme, Cassandra Rastin, Soham Sengupta, Helen E. Pennington, Sophie J. Russ-Hall, Amy L. Schneider, Emily S. Bonkowski, Edith P. Almanza Fuerte, Talia J. Allan, Miranda Perez-Galey Zalusky, Joy Goffena, Sophia B. Gibson, Denis M. Nyaga, Nico Lieffering, Malavika Hebbar, Emily V. Walker, Daniel Darnell, Scott R. Olsen, Pandurang Kolekar, Mohamed Nadhir Djekidel, Wojciech Rosikiewicz, Haley McConkey, Jennifer Kerkhof, Michael A. Levy, Raissa Relator, Dorit Lev, Tally Lerman-Sagie, Kristen L. Park, Marielle Alders, Gerarda Cappuccio, Nicolas Chatron, Leigh Demain, David Genevieve, Gaetan Lesca, Tony Roscioli, Damien Sanlaville, Matthew L. Tedder, Sachin Gupta, Elizabeth A. Jones, Monika Weisz-Hubshman, Shamika Ketkar, Hongzheng Dai, Kim C. Worley, Jill A. Rosenfeld, Hsiao-Tuan Chao, Undiagnosed Diseases Network, Geoffrey Neale, Gemma L. Carvill, University of Washington Center for Rare Disease Research, Zhaoming Wang, Samuel F. Berkovic, Lynette G. Sadleir, Danny E. Miller, Ingrid E. Scheffer, Bekim Sadikovic, and Heather C. Mefford
Subjects: Science
Abstract: Abstract Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.
Published: 2024
Full Text: View/download PDF

25. Clinical and functional heterogeneity associated with the disruption of Retinoic Acid Receptor beta

Author: Véronique Caron, Nicolas Chassaing, Nicola Ragge, Felix Boschann, Angelina My-Hoa Ngu, Elisabeth Meloche, Sarah Chorfi, Saquib A. Lakhani, Weizhen Ji, Laurie Steiner, Julien Marcadier, Philip R. Jansen, Laura A. van de Pol, Johanna M. van Hagen, Alvaro Serrano Russi, Gwenaël Le Guyader, Magnus Nordenskjöld, Ann Nordgren, Britt-Marie Anderlid, Julie Plaisancié, Corinna Stoltenburg, Denise Horn, Anne Drenckhahn, Fadi F. Hamdan, Mathilde Lefebvre, Tania Attie-Bitach, Peggy Forey, Vasily Smirnov, Françoise Ernould, Marie-Line Jacquemont, Sarah Grotto, Alberto Alcantud, Alicia Coret, Rosario Ferrer-Avargues, Siddharth Srivastava, Catherine Vincent-Delorme, Shelby Romoser, Nicole Safina, Dimah Saade, James R. Lupski, Daniel G. Calame, David Geneviève, Nicolas Chatron, Caroline Schluth-Bolard, Kenneth A. Myers, William B. Dobyns, Patrick Calvas, Caroline Salmon, Richard Holt, Frances Elmslie, Marc Allaire, Daniil M. Prigozhin, André Tremblay, Jacques L. Michaud, Pediatrics, Human genetics, and Amsterdam Reproduction & Development (AR&D)
Subjects: Genetics (clinical)
Abstract: Purpose: Dominant variants in the retinoic acid receptor beta (RARB) gene underlie a syndromic form of microphthalmia, known as MCOPS12, which is associated with other birth anomalies and global developmental delay with spasticity and/or dystonia. Here, we report 25 affected individuals with 17 novel pathogenic or likely pathogenic variants in RARB. This study aims to characterize the functional impact of these variants and describe the clinical spectrum of MCOPS12. Methods: We used in vitro transcriptional assays and in silico structural analysis to assess the functional relevance of RARB variants in affecting the normal response to retinoids. Results: We found that all RARB variants tested in our assays exhibited either a gain-of-function or a loss-of-function activity. Loss-of-function variants disrupted RARB function through a dominant-negative effect, possibly by disrupting ligand binding and/or coactivators’ recruitment. By reviewing clinical data from 52 affected individuals, we found that disruption of RARB is associated with a more variable phenotype than initially suspected, with the absence in some individuals of cardinal features of MCOPS12, such as developmental eye anomaly or motor impairment. Conclusion: Our study indicates that pathogenic variants in RARB are functionally heterogeneous and associated with extensive clinical heterogeneity.
Published: 2023

26. Predominance of

Author: Pascal, Pujol, Kevin, Yauy, Amandine, Coffy, Nicolas, Duforet-Frebourg, Sana, Gabteni, Jean-Pierre, Daurès, Frédérique, Penault Llorca, Frédéric, Thomas, Kevin, Hughes, Clare, Turnbull, Virginie, Galibert, Chloé, Rideau, Carole, Corsini, Laetitia, Collet, Benoit, You, David, Geneviève, and Nicolas, Philippe
Abstract: Poly(ADP-ribose) polymerase 1 inhibitor (PARPi) agents can improve progression-free survival of patients with breast cancer who carry a germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant (gBRCA) in both the metastatic and adjuvant setting. Therefore, we need to reassess the frequency of gBRCA1 and gBRCA2 in order to redefine the criteria for women and tumor phenotype that should be tested.We studied the relative distribution of gBRCA1 and gBRCA2 in unselected populations of women with breast cancer and in unaffected individuals. We also analyzed the proportion of estrogen receptor (ER)-positive (ER+) tumors in unselected breast cancer patients with gBRCA.We performed a meta-analysis of studies of unselected breast cancer that analyzed the relative contribution of gBRCA1 versus gBRCA2 among unselected breast cancer cases in gBRCA carriers. We then performed a meta-analysis of gBRCA carriage in unaffected individuals from genome-wide population studies, the gnomAD databank, and case-control studies.TheThis meta-analysis showed that gBRCA2 carriage is predominant in unselected breast cancer patients and unaffected individuals. ER+ tumors among women with gBRCA-related breast cancer are predominant and have been underestimated. Because PARPi agents improve progression-free survival with ER+ gBRCA breast cancer in most clinical trials, breast cancer should be considered, regardless of ER status, for
Published: 2022

27. The Globally search for a Regular Expression and Print matching lines (GREP) strategy: an innovative reanalysis strategy combining bibliographic monitoring with fast GREP directly applied to a massive genomic database to rapidly improve diagnosis

Author: Frédéric Tran Mau Them, Alexis Overs, ange-line bruel, Romain Duquet, Mylene Thareau, Anne-Sophie Denommé-Pichon, Antonio Vitobello, Arthur Sorlin, Hana Safraou, Sophie Nambot, Julian Delanne, Sebastien Moutton, Caroline RACINE, Camille Engel, Melchior D’agay, Daphné Lehalle, Alice Goldenberg, Marjolaine Willems, christine Coubes, David Geneviève, Alain Verloes, Yline CAPRI, Laurence Perrin, Marie-Line Jacquemont, Laetitia Lambert, Elodie Lacaze, Julien Thevenon, Nadine Hanna, Van-Gils Julien, Charlotte Dubucs, Varoona Bizaoui, Marion Gerard, James Lespinasse, Sandra Mercier, Anne-Marie Guerrot, Isabelle Maystadt, Emilie Tisserant, Laurence Faivre, Christophe Philippe, Yannis Duffourd, and Christel Thauvin-Robinet
Subjects: genetic structures
Abstract: Purpose: Exome sequencing has a diagnostic yield ranging from 25% to 70% in rare diseases and regularly implicates genes in novel disorders. Prospective data reanalysis has demonstrated strong efficacy in improving diagnosis, but poses organizational difficulties for clinical laboratories. We applied a reanalysis strategy based on intensive prospective bibliographic monitoring, and directly applied the Globally search for a Regular Expression and Print matching lines (GREP) command-line to a massive ES database. Methods: For 18 months, we submitted daily the same 5 keywords of interest (( intellectual disability, ( neuro)developmental delay, (neuro)developmental disorder)) to PubMed, to identify recently published, novel disease-gene associations, or new phenotypes in genes already implicated in human pathology. We used the Linux GREP command-line and an in-house script, to collect all variants in these genes from our 5459 exome database. Results: We grepped 128 genes and collected 56 candidate variants in 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, we confirmed pathogenicity in 21/2875 undiagnosed affected probands (0.7%). Conclusion: The GREP command-line is efficient, and less tedious than complete periodical reanalysis. It is an interesting reanalysis strategy to improve diagnosis.
Published: 2022

28. L'expérience citoyenne dans la participation à la gouvernance municipale : un cadre favorable à une communication stratégique basée sur l'émergence d'une relation empathique et durable

Author: David, Geneviève, Baillargeon, Dany, David, Geneviève, and Baillargeon, Dany
Abstract: La communication stratégique dans les organisations municipales joue un rôle important dans la planification d'une expérience de participation citoyenne. Ce mémoire s'intéresse aux composantes de la construction d’une relation empathique basée sur l’acquisition de compétences citoyennes, sur l’accumulation d’expériences positives de participation, sur la confiance entre les parties prenantes et les organisations, tout en réitérant les postulats d’un positionnement professionnel et social de la spécialiste ou du spécialiste en communication en quête de reconnaissance. L'analyse réflexive de ce travail mène à la proposition d'un outil de sensibilisation intitulé « La communication comme levier d’une participation publique durable : Un guide de sensibilisation pour les communicatrices et les communicateurs en milieu municipal pour une mise en valeur de leur rôle stratégique et de leur impact social ».
Published: 2022

29. Second-tier trio exome sequencing after negative solo clinical exome sequencing: an efficient strategy to increase diagnostic yield and decipher molecular bases in undiagnosed developmental disorders

Author: Sebastien Moutton, Martin Chevarin, Nada Houcinat, Sophie Nambot, Yannis Duffourd, Laurence Faivre, Anne-Laure Mosca-Boidron, François Lecoquierre, Christel Thauvin-Robinet, Julian Delanne, Alice Masurel-Paulet, Arthur Sorlin, Charlotte Poe, Caroline Racine, Marjolaine Willems, Julien Thevenon, Steven A. Kushner, David Geneviève, Ange-Line Bruel, Patrick Callier, Frédéric Tran Mau-Them, Christophe Philippe, Emilie Tisserant, Thibaut Jouan, Christine Coubes, Antonio Vitobello, Nolwenn Jean-Marçais, Daphné Lehalle, Femke M.S. de Vrij, and Psychiatry
Subjects: Male, Candidate gene, Developmental Disabilities, Population, Biology, Compound heterozygosity, 03 medical and health sciences, Intellectual Disability, Genotype, Exome Sequencing, Genetics, Humans, Exome, Genetic Predisposition to Disease, education, Gene, Genetics (clinical), Exome sequencing, 030304 developmental biology, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Genomics, Phenotype, Human genetics, Female
Abstract: Developmental disorders (DD), characterized by malformations/dysmorphism and/or intellectual disability, affecting around 3% of worldwide population, are mostly linked to genetic anomalies. Despite clinical exome sequencing (cES) centered on genes involved in human genetic disorders, the majority of patients affected by DD remain undiagnosed after solo-cES. Trio-based strategy is expected to facilitate variant selection thanks to rapid parental segregation. We performed a second step trio-ES (not only focusing on genes involved in human disorders) analysis in 70 patients with negative results after solo-cES. All candidate variants were shared with a MatchMaking exchange system to identify additional patients carrying variants in the same genes and with similar phenotype. In 18/70 patients (26%), we confirmed causal implication of nine OMIM-morbid genes and identified nine new strong candidate genes (eight de novo and one compound heterozygous variants). These nine new candidate genes were validated through the identification of patients with similar phenotype and genotype thanks to data sharing. Moreover, 11 genes harbored variants of unknown significance in 10/70 patients (14%). In DD, a second step trio-based ES analysis appears an efficient strategy in diagnostic and translational research to identify highly candidate genes and improve diagnostic yield.
Published: 2020

30. A second individual with rhizomelic spondyloepimetaphyseal dysplasia and homozygous variant in GNPNAT1

Author: Quentin Sabbagh, Fanny Alkar, Karine Patte, Olivier Prodhomme, Caroline Janel, Renaud Touraine, Claire Jeandel, and David Geneviève
Subjects: Rare Diseases, Homozygote, Genetics, Glucosamine 6-Phosphate N-Acetyltransferase, Mutation, Missense, Humans, Dwarfism, Female, General Medicine, Child, Osteochondrodysplasias, Genetics (clinical), Bone and Bones
Abstract: Spondyloepimetaphyseal dysplasias (SEMDs) belong to a clinically and genetically heterogeneous group of inherited skeletal disorders defined by a defect in the growth and shape of vertebrae, epiphyses and metaphyses. Rhizomelic SEMD is characterized by a disproportionate small stature caused by severe shortening and deformation of the limbs' proximal bones, with the cranio-facial sphere unaffected. We report a second individual, an 8-year-old girl, with autosomal recessive rhizomelic SEMD associated with a homozygous exonic missense variant, c.226G A p.(Glu76Lys), in GNPNAT1 identified by trio genome sequencing. Our data corroborate the recent findings of Ain et al. and further delineate the clinical and radiographic features of this form of SEMD associated with rhizomelic dysplasia while outlining a potential hotspot in this newly described genetic disorder.
Published: 2022

31. A recessive form of craniodiaphyseal dysplasia caused by a homozygous missense variant in SP7/Osterix

Author: Gretl Hendrickx, Eveline Boudin, Ellen Steenackers, Corinne Collet, Geert R. Mortier, David Geneviève, and Wim Van Hul
Subjects: Histology, Physiology, Endocrinology, Diabetes and Metabolism, Human medicine
Abstract: Craniodiaphyseal dysplasia (CDD) is an ultra-rare and severe sclerosing bone dysplasia, usually presenting in early childhood with progressive sclerosis of the cranial and facial bones. Heterozygous variants in the SOST gene have been reported in two unrelated CDD patients. We now report on two subjects from a large consanguineous family with mild phenotypic features of CDD. Physical examination revealed facial dysmorphism, short stature and a lean body habitus. Radiographs showed severe hyperostosis of the calvarium, skull base and mandibula, broadened claviculae and ribs, scoliosis, and diaphyseal expansion of the long bones. One of the two subjects had a history of recurrent fractures. Serum analysis in the proband revealed very high levels of bone formation (P1NP, osteocalcin) and resorption markers (CTX-1, TRAcP 5b), suggesting a high bone turnover. Exome sequencing led to the identification of a homozygous missense variant (c.913T>C, p.(Tyr305His)) in SP7, encoding the Osterix transcription factor. The variant is located in the first zinc-finger domain, a highly conserved region responsible for DNA-binding. Luciferase reporter assays were performed to investigate the DNA-binding capacity of mutant Osterix to AT-rich sequences, as these motifs mediate the transcription of genes in osteoblasts. This analysis showed a 90 % loss in binding capacity of mutant Osterix. Based on our data, we hypothesize that our variant may have neomorphic effects resulting in the SP7-related autosomal recessive CDD phenotype. Further studies are required to dissect the precise mechanisms on how bi-allelic variants in SP7 can cause a sclerosing bone dysplasia.
Published: 2023

32. The impact of lockdown on young people with genetic neurodevelopmental disabilities: a study with the international participatory database GenIDA

Author: Romain Coutelle, Morgane Boedec, Karlijn Vermeulen, Joost Kummeling, David A. Koolen, Tjitske Kleefstra, Camille Fournier, Florent Colin, Axelle Strehle, David Geneviève, Pauline Burger, and Jean-Louis Mandel
Subjects: Adult, Male, Sleep Wake Disorders, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Adolescent, Autism Spectrum Disorder, COVID-19, Psychiatry and Mental health, All institutes and research themes of the Radboud University Medical Center, Intellectual Disability, Communicable Disease Control, Quality of Life, Humans, Female, Child
Abstract: Background Previous publications suggested that lockdown is likely to impact daily living issues of individuals with intellectual disabilities. The authors notably suspected an intensification of behavioural, eating and sleep problems. Methods To test these hypotheses, we conducted an international online survey about the impact of COVID-19-associated first lockdown on people with genetic neurodevelopmental disorders. This survey was carried out using GenIDA, an international participatory database collecting medical information on genetic neurodevelopmental disorders. Patients’ relatives took part in this online survey from 30/04/2020 to 09/06/2020. This survey adapted from GenIDA standard questionnaire requested information on diagnosis, lifestyle and was based on yes/no answers to questions regarding behaviour, diet, and sleep, in the 6-months period before lockdown and during lockdown. We also asked relatives to evaluate the intensity of these problems by severity level. Finally, relatives could freely comment in open fields on the medical and/or quality of life problems they had encountered during lockdown. Results In total 199 participants—144 children and 45 adults—with neurodevelopmental disorders (intellectual disability (79.4%) and/or autism spectrum disorder (21.6%)) of various genetic origins, with near-equal male/female (96/103) contribution and originating mainly from Europe and Northern America, were included. The average lockdown duration at time of the survey was 57 days. We did not find differences in the frequency of behavioural, eating and sleep problems before and during lockdown. Moreover, there was no apparent difference in the intensity of eating and sleep disorders between both periods. However, for persons with behavioural problems at both periods, relatives reported an increase in aggressivity, self-aggressivity, depressiveness, stereotypies, and restricted interests during lockdown, all of which might be interpreted as consequences of a lack of stimulation or a reaction to unexpected changes in daily habits. Conclusions Our results support previous studies that suggest that the negative impact of lockdown does not depend on the intellectual disability per se but on the associated comorbidities such as behavioural disorders. This study addresses the need for prevention of behavioural disturbance in the vulnerable population with genetic neurodevelopmental disabilities.
Published: 2021

33. Reconstruction 3D du fœtus humain entre 7 et 14 semaines d’aménorrhée dans le cadre du projet FETTAL : optimisation du contraste en micro-TDM

Author: A. Lamouroux, Guillaume Captier, Célia Bottero, David Geneviève, Christophe Goze-Bac, Maida Cardoso, Laboratoire Charles Coulomb (L2C), and Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, 03 medical and health sciences, 030219 obstetrics & reproductive medicine, 0302 clinical medicine, [SDV]Life Sciences [q-bio], Anatomy, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: Introduction Les coupes histologiques sont la technique de reference pour visualiser un fœtus en coupe. Cependant, elles sont destructrices et presentent des inconvenients pour la reconstruction 3D. Les techniques de micro-imagerie, comme le micro-TDM, sont adaptees a la taille des echantillons, sont non destructrices et permettent la reconstruction 3D. L’objectif de ce travail etait d’optimiser le contraste des images obtenues par micro-TDM afin de realiser des reconstructions 3D du fœtus humain pour realiser des fœtopsies virtuelles. Materiels et methodes Les echantillons sont inclus apres consentement entre 7 et 14 SA et sont issus d’interruptions volontaires de grossesse (projet FETTAL, autorisation ABM). Les acquisitions en micro-TDM sont realisees sur le microtomographe RX Skyscan 1276. Differents bains de contrastes utilisant du Lugol, de l’ethanol et de l’acide phosphotungstique (EPTA) ont ete testes afin d’augmenter le contraste des tissus mous pour optimiser la visualisation des structures anatomiques. Plusieurs bains ont ete testes sur un meme echantillon grâce a l’utilisation de bain thiosulfate de sodium dilue, pour comparer la qualite des images par deux experts. Resultats Huit echantillons entre 7 et 12 SA ont pu etre testes. Les bains et protocoles decrits par Lombardi et al. [1] , Metscher et al. [2] (iodine et EPTA), Vymazalova et al. [3] et Hutchinson et al. [4] (formol et lugol) ont ete testes. Certains bains induisaient un retrecissement tissulaire et un moindre contraste. Apres comparaison par les experts, des images obtenues, le meilleur compromis entre contraste des tissus et retrecissement tissulaire semble etre le protocole decrit par Hutchinson et al. Discussion Le protocole de Hutchinson et al. permet d’avoir le meilleur contraste pour la visualisation 3D des structures anatomiques avec le plus faible retrecissement, quel que soit le stade fœtal. Des problematiques concernant l’impact des bains sur des prelevements histologiques a visee diagnostique futurs restent cependant a prendre en compte.
Published: 2021

34. Clinical spectrum of MTOR-related hypomelanosis of Ito with neurodevelopmental abnormalities

Author: Yannis Duffourd, Catherine Sarret, B. Catteau, Rachel G. Knox, Chloé Quélin, Cyril Mignot, Martin Chevarin, P. Callier, Diana Rodriguez, Alexis Arzimanoglou, Robert Olaso, David Geneviève, Arthur Sorlin, Sylvie Odent, Christel Thauvin, Victoria E. R. Parker, Pierre Vabres, Louise Goujon, Malika Keddar, Melissa Riachi, Sylvie Fraitag, Laurence Faivre, Emmanuelle Blanchard, Satyamaanasa Polubothu, Marie-Line Jacquemont, Jean-Baptiste Rivière, Anne Boland, Jean-François Deleuze, Paul Rollier, Véronique Darmency, Marie-Hélène Aubriot-Lorton, Yline Capri, V. Carmignac, Daniel Amram, Catherine Vincent-Delorme, Paul Kuentz, Marc Delepine, Didier Bessis, Robert K. Semple, Sarah Grotto, Veronica A. Kinsler, Laurent Guibaud, Christophe Philippe, Jean-Benoît Courcet, Apollo - University of Cambridge Repository, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), University of Cambridge [UK] (CAM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Great Ormond Street Hospital for Children [London] (GOSH), University College of London [London] (UCL), Institut de Génomique d'Evry (IG), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU Pontchaillou [Rennes], AP-HP Hôpital universitaire Robert-Debré [Paris], Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), CHI Créteil, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hospices Civils de Lyon (HCL), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Pascal (IP), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne (UCA)-Institut national polytechnique Clermont Auvergne (INP Clermont Auvergne), Université Clermont Auvergne (UCA)-Université Clermont Auvergne (UCA), CHU Clermont-Ferrand, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), University of Edinburgh, and BOHAUD, FRANCOISE
Subjects: 0301 basic medicine, Pathology, medicine.medical_specialty, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Melanocyte, Mechanistic Target of Rapamycin Complex 1, Article, 03 medical and health sciences, Tuberous sclerosis, Epilepsy, 0302 clinical medicine, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Megalencephaly, Genetics (clinical), PI3K/AKT/mTOR pathway, Hypopigmentation, business.industry, Mosaicism, TOR Serine-Threonine Kinases, Macrocephaly, Correction, medicine.disease, 030104 developmental biology, medicine.anatomical_structure, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, business, 030217 neurology & neurosurgery, Immunostaining
Abstract: Hypomelanosis of Ito (HI) is a skin marker of somatic mosaicism. Mosaic MTOR pathogenic variants have been reported in HI with brain overgrowth. We sought to delineate further the pigmentary skin phenotype and clinical spectrum of neurodevelopmental manifestations of MTOR-related HI. From two cohorts totaling 71 patients with pigmentary mosaicism, we identified 14 patients with Blaschko-linear and one with flag-like pigmentation abnormalities, psychomotor impairment or seizures, and a postzygotic MTOR variant in skin. Patient records, including brain magnetic resonance image (MRI) were reviewed. Immunostaining (n = 3) for melanocyte markers and ultrastructural studies (n = 2) were performed on skin biopsies. MTOR variants were present in skin, but absent from blood in half of cases. In a patient (p.[Glu2419Lys] variant), phosphorylation of p70S6K was constitutively increased. In hypopigmented skin of two patients, we found a decrease in stage 4 melanosomes in melanocytes and keratinocytes. Most patients (80%) had macrocephaly or (hemi)megalencephaly on MRI. MTOR-related HI is a recognizable neurocutaneous phenotype of patterned dyspigmentation, epilepsy, intellectual deficiency, and brain overgrowth, and a distinct subtype of hypomelanosis related to somatic mosaicism. Hypopigmentation may be due to a defect in melanogenesis, through mTORC1 activation, similar to hypochromic patches in tuberous sclerosis complex.
Published: 2021

35. Genome Alert!: a standardized procedure for genomic variant reinterpretation and automated genotype-phenotype reassessment in clinical routine

Author: Sophie Coutant, Armelle Luscan, Quentin Fort, Nicolas Soirat, Abdoulaye Hama Diallo, Mélanie Broutin, Julien Thevenon, Nicolas Philippe, Stéphanie Baert-Desurmont, David Geneviève, Raphaël Lanos, Sacha Beaumeunier, Laurent Mesnard, Jean-Marc Costa, Jérôme Audoux, Kevin Yauy, Laure Raymond, Vanna Geromel, Denis Bertrand, Jean-Marc Holder, Stenzel Cackowski, Aïcha Boughalem, Detlef Trost, Anne-Laure Bougé, Gaël Nicolas, Pascale Richard, Nicolas Duforet-Frebourg, François Lecoquierre, and Quentin Testard
Subjects: Population genomics, Reinterpretation, business.industry, Medicine, Clinical significance, Computational biology, Clinical routine, business, Genome, New diagnosis, Exome sequencing, Genotype phenotype
Abstract: Numerous countries have set up population genomics plans, allowing an unprecedented growth in the ability of interpreting variants in human diseases. Retrospective interpretation of sequenced data in the light of the current literature is a major concern of the field. Moreover, such reinterpretation is manual and both the human resources and the variable operating procedures are main bottlenecks.This work describes the Genome Alert! standardized procedure. This open-source method automatically reports changes with potential clinical significance in variant classification between releases of the ClinVar database. Using ClinVar submissions across time, this method assigns gene-disease associations validity category. Genome Alert! was assessed on a retrospective 29 months multicentric series of 5,959 consecutive individuals screened by targeted or exome sequencing.Between July 2017 and December 2019, the retrospective analysis of ClinVar submissions revealed a monthly median of 1,247 changes in variant classification with potential clinical significance and 23 new gene-disease associations. Reexamination of 4,929 targeted sequencing files highlighted 45 changes, which 89% classifications were expert validated, leading to four additional diagnoses. Genome Alert! gene-disease association catalog provided 75 high-confidence associations not available in the OMIM morbid list, where 20% became OMIM morbid 8 months later. Over 356 negative exome sequencing data that were reannotated for variants in these 75 genes, this elective approach led to a new diagnosis.Genome Alert! (https://genomealert.univ-grenoble-alpes.fr/) enables the systematic and reproducible reinterpretation of acquired sequencing data in a clinical routine with a limited human resource impact.Graphical abstract
Published: 2021

36. Severe phenotype in patients with large deletions of NF1

Author: Laurence, Pacot, Dominique, Vidaud, Audrey, Sabbagh, Ingrid, Laurendeau, Audrey, Briand-Suleau, Audrey, Coustier, Théodora, Maillard, Cécile, Barbance, Fanny, Morice-Picard, Sabine, Sigaudy, Olga O, Glazunova, Lena, Damaj, Valérie, Layet, Chloé, Quelin, Brigitte, Gilbert-Dussardier, Frédérique, Audic, Hélène, Dollfus, Anne-Marie, Guerrot, James, Lespinasse, Sophie, Julia, Marie-Christine, Vantyghem, Magali, Drouard, Marilyn, Lackmy, Bruno, Leheup, Yves, Alembik, Alexia, Lemaire, Patrick, Nitschké, Florence, Petit, Anne, Dieux Coeslier, Eugénie, Mutez, Alain, Taieb, Mélanie, Fradin, Yline, Capri, Hala, Nasser, Lyse, Ruaud, Benjamin, Dauriat, Sylvie, Bourthoumieu, David, Geneviève, Séverine, Audebert-Bellanger, Mathilde, Nizon, Radka, Stoeva, Geoffroy, Hickman, Gaël, Nicolas, Juliette, Mazereeuw-Hautier, Arnaud, Jannic, Salah, Ferkal, Béatrice, Parfait, Michel, Vidaud, Members Of The Nf France Network, Pierre, Wolkenstein, Eric, Pasmant, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Cancer Research and Personalized Medicine - CARPEM [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-CHU Necker - Enfants Malades [AP-HP], GHU AP-HP Centre Université de Paris, Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 216), Institut de Recherche pour le Développement (IRD)-Université de Paris (UP), Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pontchaillou [Rennes], Groupe Hospitalier du Havre, Centre de référence Maladies Rares CLAD-Ouest [Rennes], Hôpital Sud [CHU Rennes], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Laboratoire de Génétique Médicale (LGM), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Centre Hospitalier Métropole Savoie [Chambéry], CHU Toulouse [Toulouse], Hôpital Purpan [Toulouse], Recherche translationnelle sur le diabète - U 1190 (RTD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, CHU Pointe-à-Pitre/Abymes [Guadeloupe], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Hôpital de Hautepierre [Strasbourg], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CHU Lille, Lille Neurosciences & Cognition - U 1172 (LilNCog (ex-JPARC)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Bordeaux [Bordeaux], Hôpital Robert Debré, Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), CHU Limoges, Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Morvan - CHRU de Brest (CHU - BREST ), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Le Mans (CH Le Mans), Hopital Saint-Louis [AP-HP] (AP-HP), Université de Rouen Normandie (UNIROUEN), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hôpital Henri Mondor, Centre d'Investigation Clinique Henri Mondor (CIC Henri Mondor), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by grants by Association Neurofibromatoses et Recklinghausen Fondation CAP NF, Ligue Française Contre les Neurofibromatoses, INSERM (Nf1GeneModif project), and Ministère de l’Enseignement Supérieur et de la Recherche., Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Mère et enfant en milieu tropical : pathogènes, système de santé et transition épidémiologique (MERIT - UMR_D 261), Institut de Recherche pour le Développement (IRD)-Université Paris Cité (UPCité), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lille Neurosciences & Cognition - U 1172 (LilNCog), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Admin, Oskar
Subjects: Genotype-phenotype correlation, congenital, hereditary, and neonatal diseases and abnormalities, cardiovascular abnormalities, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, dysmorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, skeletal abnormalities, neurofibromatosis type 1, Article, [SDV.CAN] Life Sciences [q-bio]/Cancer, MPNSTs, learning disabilities, Neurofi-bromas, neoplasms, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, NF1 deletion, genotype–phenotype correlation, eye diseases, nervous system diseases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, NF1, neurofibromas, NFs, malignant peripheral nerve sheath tumors, tumor predisposition
Abstract: Simple Summary Neurofibromatosis type 1 (NF1) is a genetic disorder caused by pathogenic variants in the NF1 tumor suppressor gene. In 5–10% of NF1 patients, a large heterozygous deletion of the whole NF1 gene is identified, leading to the commonly called “NF1 microdeletion syndrome”. NF1-deleted patients were previously reported to develop a particularly severe form of the disease with frequent cognitive impairment and an increased risk of benign and malignant tumors. Here, we performed a comprehensive clinical assessment of the largest NF1-deleted cohort to date, including 126 NF1 patients with a deletion of the NF1 gene. This work provides new insights into the specific phenotype associated with NF1 deletions and may contribute to improve the follow-up care of NF1 patients. Abstract Complete deletion of the NF1 gene is identified in 5–10% of patients with neurofibromatosis type 1 (NF1). Several studies have previously described particularly severe forms of the disease in NF1 patients with deletion of the NF1 locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. NF1-deleted patients were enrolled and phenotypically characterized with a standardized questionnaire between 2005 and 2020 from a large French NF1 cohort. Statistical analyses for main NF1-associated symptoms were performed versus an NF1 reference population. A deletion of the NF1 gene was detected in 4% (139/3479) of molecularly confirmed NF1 index cases. The median age of the group at clinical investigations was 21 years old. A comprehensive clinical assessment showed that 93% (116/126) of NF1-deleted patients fulfilled the NIH criteria for NF1. More than half had café-au-lait spots, skinfold freckling, Lisch nodules, neurofibromas, neurological abnormalities, and cognitive impairment or learning disabilities. Comparison with previously described “classic” NF1 cohorts showed a significantly higher proportion of symptomatic spinal neurofibromas, dysmorphism, learning disabilities, malignancies, and skeletal and cardiovascular abnormalities in the NF1-deleted group. We described the largest NF1-deleted cohort to date and clarified the more severe phenotype observed in these patients.
Published: 2021

37. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

Author: Jonathan A. Bernstein, Leah J. Rowe, Kimberly Foss, Samin A. Sajan, Kun Xia, Juliane Hoyer, Anita E. Beck, Shayna Svihovec, Vincent Gatinois, Lance H. Rodan, Roksana Sasanfar, Christiane Zweier, Alban Ziegler, Sonal Mahida, Kristin G. Monaghan, Charlotte W. Ockeloen, André Reis, Milen Velinov, Janson White, Evan E. Eichler, Nasim Vasli, Jennifer Friedman, Constance Smith-Hicks, Gilles Morin, Rachel Westman, Sandra Yang, Joshua Scheck, Christian Thiel, John B. Vincent, Deborah A. Nickerson, Michelle E. Ernst, Jacqueline Harris, Natasha Zeid, Bernt Popp, Francesca Mattioli, Zehra Agha, Ellen van Binsbergen, Julian A. Martinez-Agosto, Karen W. Gripp, Gwenaël Le Guyader, Catherine Vincent-Delorme, Lori-Anne Schillaci, Jennefer N. Kohler, Kimberly A. Aldinger, Laurence J. Walsh, Jessica X. Chong, David Geneviève, Rami Abou Jamra, Amy Yang, Cigdem I. Akman, Sha Tang, Ricardo Harripaul, Rick Person, Marleen Simon, Hui Guo, Muhammad Ayub, Laura S. Farach, Patricia Blanchet, Austin Larson, Marie Vincent, Luis Rohena, Michael J. Bamshad, Raheel Qamar, Gregory M. Enns, Joshua Rotenberg, Katelyn Payne, William J. Sunderland, Anne C.-H. Tsai, Annika M. Dries, Michèle Mathieu-Dramard, Dominique Bonneau, Ghayda M. Mirzaa, Bénédicte Gérard, Elise Schaefer, Amélie Piton, Patricia G Wheeler, Division of Medical Genetics [Seattle], University of Washington [Seattle], Détoxication et réparation tissulaire, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Central South University [Changsha], Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Center for Integrative Brain Research, Ambry Genetics [Aliso Viejo, CA, USA], China Agricultural University (CAU), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Kennedy Krieger Institute [Baltimore], Institute of Human Genetics [Erlangen, Allemagne], Universität Leipzig, Yale University [New Haven], Oregon Health and Science University [Portland] (OHSU), McGovern Medical School [Houston, Texas], Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Indiana University [South Bend], The University of Texas at San Antonio (UTSA), New York State Psychiatric Institute, Columbia University [New York], Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Strasbourg, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Medical Center [Utrecht], Stanford University School of Medicine [CA, USA], Memorial Hermann Heart and Vascular Institute [Houston, TX, USA], University of Central Florida [Orlando] (UCF), Department of Pediatrics [Univ California San Diego] (UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), University of Colorado Anschutz [Aurora], Department of Chemistry and Biochemistry [Bern], University of Bern, Columbia University Irving Medical Center (CUIMC), Signal Processing Lab [Boise - Idaho], Boise State University, University Hospitals Case Medical Center (CLEVELAND - UHCMC), University Hospitals Case Medical Center, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Psychology [University North Carolina Wilmington], University of North Carolina [Wilmington] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Queen's University [Kingston, Canada], Department of Molecular Genetics [Toronto], University of Toronto, GeneDx [Gaithersburg, MD, USA], Department of Genome Sciences [Seattle] (GS), Department of Pediatrics [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford School of Medicine [Stanford], Stanford University, University of California (UC), COMSATS Institute of Information Technology [Islamabad] (CIIT), Boston Children's Hospital, University of California [Los Angeles] (UCLA), Radboud University Medical Center [Nijmegen], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Psychiatry, Seattle University [Seattle], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig [Leipzig], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Pediatrics [san Diego], UC San Diego School of Medicine, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and University of California
Subjects: 0301 basic medicine, Proband, Male, Adolescent, Autism Spectrum Disorder, autism spectrum disorders, Nerve Tissue Proteins, Neuroimaging, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Neurodevelopmental disorder, ZNF292, Intellectual disability, mental disorders, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), Exome sequencing, Genetics, Zinc finger, next generation sequencing, Genetic heterogeneity, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, intellectual disability, Neurodevelopmental Disorders, Child, Preschool, next-generation sequencing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Carrier Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Contains fulltext : 218267.pdf (Publisher’s version ) (Closed access) PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.
Published: 2019

38. Pycnodysostosis: Natural history and management guidelines from 27 French cases and a literature review

Author: Martine Cohen-Solal, Caroline Michot, Massimiliano Rossi, Sabine Baron, Elise Schaefer, Anne Dieux, Varoona Bizaoui, Yline Capri, Corinne Collet, Sophie Monnot, Geneviève Baujat, Anya Rothenbuhler, Bertrand Isidor, Cyril Amouroux, Valérie Cormier-Daire, David Geneviève, Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre hospitalier universitaire de Nantes (CHU Nantes), AP-HP Hôpital universitaire Robert-Debré [Paris], Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Os et articulations, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Service de génétique médicale - Unité de génétique clinique [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), and CHU Strasbourg
Subjects: Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Genotype, Pycnodysostosis, 030105 genetics & heredity, Short stature, 03 medical and health sciences, Bone fragility, Genetics, medicine, Humans, Genetic Predisposition to Disease, Alleles, Genetic Association Studies, Genetics (clinical), Chiari malformation, Psychomotor learning, CTSK, business.industry, Disease Management, Sleep apnea, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Psychological evaluation, Radiography, Natural history, Phenotype, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, Dysplasia, Mutation, Practice Guidelines as Topic, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, business, Osteosclerosis
Abstract: International audience; Pycnodysostosis is a lysosomal autosomal recessive skeletal dysplasia characterized by osteosclerosis, short stature, acro-osteolysis, facial features and an increased risk of fractures. The clinical heterogeneity of the disease and its rarity make it difficult to provide patients an accurate prognosis, as well as appropriate care and follow-up. French physicians from the OSCAR network have been asked to fill out questionnaires collecting molecular and clinical data for 27 patients issued from 17 unrelated families. All patients showed short stature (mean = -3.5 SD) which was more severe in females (P = .006). The mean fracture rate was moderate (0.21 per year), with four fractures in total average. About 75% underwent at least one surgery, with an average number of 2.1 interventions per patient. About 50% required non-invasive assisted ventilation due to sleep apnea (67%). About 29% showed psychomotor difficulties and 33% needed a school assistant or adapted schooling. No patient had any psychological evaluation or follow-up. Molecular data were available for 14 families. Growth hormone administration was efficient on linear growth in 40% of cases. We propose several axis of management, such as systematic cerebral MRI for Chiari malformation screening at diagnosis and regular psychological follow-up.
Published: 2019

39. Predominance of BRCA2 mutation and estrogen receptor-positive breast cancer among BRCA1/2 mutation carriers

Author: Pascal Pujol, Kévin Yauy, Amandine Coffy, Nicolas Duforet-Frebourg, Sana Gabteni, Jean-Pierre Daurès, Frédérique Penault-Llorca, Frédéric Thomas, Kevin Hughes, Clare Turnbull, Virginie Galibert, Chloé Rideau, Laetitia Collet, Benoit You, David Geneviève, and Nicolas Philippe
Subjects: Cancer Research, Oncology
Abstract: Background: PARP inhibitor (PARPi) agents can improve progression-free survival of patients with breast cancer (BC) who carry a germline BRCA1 or BRCA2 pathogenic or likely pathogenic variant (gBRCA1/2) in both the metastatic and adjuvant setting. Therefore, we need to redefine the criteria of women and tumor phenotype that should be tested for gBRCA1/2. Objective: We studied the relative distribution of gBRCA1 and gBRCA2 in unselected populations of women with BC and in unaffected individuals. We also analyzed the proportion of estrogen receptor (ER)-positive (ER+) tumors in unselected BC patients with gBRCA1/2.Design: We performed a meta-analysis of studies of unselected BC that analyzed the relative contribution of gBRCA1 versus gBRCA2 and ER+ tumors among gBRCA1/2 carriers. We then performed a meta-analysis of gBRCA1/2 carriage in unaffected individuals, from genome-wide population studies, the gnomAD databank, and case–control studies. Results: The BRCA2 gene was involved in 54% of BC in unselected patients with gBRCA1/2 (n=108,699) and 59% of unaffected individuals (n=238,973) as compared with 38% of gBRCA1/2 family cohorts (n=29,700). The meta-analysis showed that 1.66% (95% CI 1.08-2.54) and 1.71% (95% CI 1.33-2.2) of unselected BC patients carried a gBRCA1 and gBRCA2, respectively. In unaffected individuals, the frequency of heterozygosity for gBRCA1 and gBRCA2 was estimated at 1/434 and 1/288, respectively. Nearly 0.5% of unaffected individuals in the studied populations carried a gBRCA1/2. Overall, 58% of breast tumors occurring in women carrying a gBRCA1/2 were ER+ (n=86,870).Conclusion: This meta-analysis showed that gBRCA2 carriage is predominant in unselected BC and in unaffected individuals. ER+ tumors among women with gBRCA1/2-related BC is predominant and has been underestimated. Because PARPi agents improve progression-free survival with ER+ gBRCA1/2 BC in both the adjuvant and metastatic setting, BC should be considered regardless of ER status for BRCA1/2 screening for therapeutic purposes.
Published: 2022

40. No Association of Early-Onset Breast or Ovarian Cancer with Early-Onset Cancer in Relatives in

Author: Marion, Imbert-Bouteille, Carole, Corsini, Marie-Christine, Picot, Lucas, Mizrahy, Sandrine, Akouete, Helena, Huguet, Frédéric, Thomas, David, Geneviève, Patrice, Taourel, Marc, Ychou, Virginie, Galibert, Chloé, Rideau, Karen, Baudry, Tatiana, Kogut Kubiak, Isabelle, Coupier, Rémy, Hobeika, Yvette, Macary, Alain, Toledano, Jérôme, Solassol, Antoine, Maalouf, Jean-Pierre, Daures, and Pascal, Pujol
Subjects: Adult, BRCA2 Protein, Ovarian Neoplasms, BRCA1 Protein, Breast Neoplasms, Middle Aged, BRCA1, BRCA2, Article, Young Adult, breast cancer, ovarian cancer, Risk Factors, Mutation, Humans, Family, Female, Genetic Predisposition to Disease, early-onset, France, Age of Onset, Retrospective Studies
Abstract: According to clinical guidelines, the occurrence of very early-onset breast cancer (VEO-BC) (diagnosed ≤ age 30 years) or VEO ovarian cancer (VEO-OC) (diagnosed ≤ age 40 years) in families with BRCA1 or BRCA2 mutation (BRCAm) prompts advancing the age of risk-reducing strategies in relatives. This study aimed to assess the relation between the occurrence of VEO-BC or VEO-OC in families with BRCAm and age at BC or OC diagnosis in relatives. We conducted a retrospective multicenter study of 448 consecutive families with BRCAm from 2003 to 2018. Mean age and 5-year–span distribution of age at BC or OC in relatives were compared in families with or without VEO-BC or VEO-OC. Conditional probability calculation and Cochran–Mantel–Haenszel chi-square tests were used to investigate early-onset cancer occurrence in relatives of VEO-BC and VEO-OC cases. Overall, 15% (19/245) of families with BRCA1m and 9% (19/203) with BRCA2m featured at least one case of VEO-BC; 8% (37/245) and 2% (2/203) featured at least one case of VEO-OC, respectively. The cumulative prevalence of VEO-BC was 5.1% (95% CI 3.6–6.6) and 2.5% (95% CI 1.4–3.6) for families with BRCA1m and BRCA2m, respectively. The distribution of age and mean age at BC diagnosis in relatives did not differ by occurrence of VEO-BC for families with BRCA1m or BRCA2m. Conditional probability calculations did not show an increase of early-onset BC in VEO-BC families with BRCA1m or BRCA2m. Conversely, the probability of VEO-BC was not increased in families with early-onset BC. VEO-BC or VEO-OC occurrence may not be related to young age at BC or OC onset in relatives in families with BRCAm. This finding—together with a relatively high VEO-BC risk for women with BRCAm—advocates for MRI breast screening from age 25 regardless of family history.
Published: 2021

41. Integrative approach to interpret DYRK1A variants, leading to a frequent neurodevelopmental disorder

Author: Anne-Sophie Denommé, Christine Francannet, Loréline Genschik, Claire Feger, Maria Kibaek, Imene Boujelbene, Paul Kuentz, Michel Guipponi, Marie-Christine Birling, Sébastien Moutton, Allan Bayat, Frederic Tran Mau Them, Mathilde Renaud, Joane Svane, Yann Herault, Sandrine Passemard, Christèle Dubourg, Mélanie Fradin, Marjolaine Willems, Julien Thevenon, Rosanna Weksberg, Bertrand Isidor, David Geneviève, Benjamin Cogné, Magalie Barth, Laurence Faivre, Jérémie Courraud, Boris Keren, Albert David, Laurence Perrin, Anne-Marie Guerrot, Christine Coubes, Thierry Bienvenu, Alice Goldenberg, Bénédicte Gérard, Amélie Piton, Lucas Bronicki, Julia Metreau, Mathilde Nizon, Elise Schaefer, Eric Chater-Diehl, Maria del Mar Muniz Moreno, Bruno Delobel, Katrine M Johannesen, Florence Demurger, Nathalie Drouot, Marie Vincent, Antonio Vitobello, Kristina Pilekær Sørensen, Christina Fagerberg, Cyril Mignot, Estelle Colin, Valérie Layet, Michèle Mathieu-Dramard, Jean-Louis Mandel, Cathrine Elisabeth Tronhjem, Benjamin Durand, Pascale Saugier, Séverine Drunat, Rikke S. Møller, Perrine Charles, Lydie Burglen, Bénédicte Demeer, Salima El Chehadeh, Marc Abramowicz, Laurent Pasquier, and Julie D. Thompson
Subjects: Genetics, Neurodevelopmental disorder, DYRK1A, Intellectual disability, medicine, Missense mutation, Kinase activity, Biology, medicine.disease, Phenotype, Human genetics, Cellular localization
Abstract: ABBSTRACTDYRK1A-related intellectual disability (ID) is among the most frequent monogenic form of ID. We refined the description of this disorder by reporting clinical and molecular data of forty individuals with ID harboringDYRK1Avariants. We developed a combination of tools to interpret missense variants, which remains a major challenge in human genetics: i) a specificDYRK1Aclinical score, ii) amino acid conservation data generated from one hundred of DYRK1A sequences across different taxa, iii)in vitrooverexpression assays to study level, cellular localization, and kinase activity of DYRK1A mutant proteins, and iv) a specific blood DNA methylation signature. This integrative approach was successful to reclassify several variants as pathogenic. However, we questioned the involvement of some others, such as p.Thr588Asn, yet reported as pathogenic, and showed it does not cause obvious phenotype in mice, emphasizing the need to take care when interpreting variants, even those occurringde novo.
Published: 2021

42. High rate of hypomorphic variants as the cause of inherited ataxia and related diseases: study of a cohort of 366 families

Author: Sylvain Vergnet, Jean Phillipe Azulay, Isabelle Meunier, Audrey Riquet, Olivier Patat, Anna Castrioto, Laurent Pasquier, Cyril Charlin, Lena Damaj, Cécile Acquaviva, Nicolas Lebouc, Bérénice Doray, Cecilia Marelli, Morgane Pointaux, Pierre Meyer, Perrine Charles, Danielle Cuntz-Shadfar, Caroline Tillikete, Frederic Villega, Cathy Lieutard-Haag, Michel Koenig, François Rivier, Idriss Bousquet, Ganaëlle Remerand, Ulrike Walther-Louvier, Clarisse Carra-Dalliere, Victoria Gonzales, Alexandre Eusebio, Brigitte Chabrol, Emilie Carme, Pierre Labauge, Adrian Degardin, Elise Brischoux-Boucher, Brice Laurens, Laurent Kremer, Giovanni Castelnovo, Mélanie Fradin, Mehdi Benkirane, Karine Nguyen, Jean-Marie Ravel, Vincent Laugel, Emilien Bernard, Claire Guissart, Cyril Goizet, Samira Sissaoui, Agathe Roubertie, Christine Francannet, Sylvie Odent, Yosra Halleb, Xavier Ayrignac, Shahram Attarian, Fabienne Ory Magne, David Geneviève, Joel Victor Fluss, Alain Verloes, Anne Rolland, Martial Mallaret, Lydia Abou Haidar, Nadia Bahi-Buisson, David Baux, Catherine Sarret, Nicolas Carrière, Christine Coubes, Mathilde Renaud, Claire Ewenczyk, Patrick Calvas, Solène Frismand, Leila Lazaro, Bertrand Isidor, Annabelle Chaussenot, Sophie Julia, Valerie Fraix, Elsa Kaphan, Tatiana Witjas, Frédérique Fluchère, Mathieu Anheim, Christine Tranchant, William Camu, Eric Thouvenot, Lise Larrieu, Eric Bieth, Ariane Choumert, Raoul Morales, Marinha Costa Moreira, Elizabeth Ollagnon, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Hospices Civils de Lyon (HCL), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Toulouse [Toulouse], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Clermont-Ferrand, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Bordeaux [Bordeaux], Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Strasbourg, CHU Pontchaillou [Rennes], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Centre Hospitalier Universitaire de Nice (CHU Nice), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Institut de Génomique Fonctionnelle (IGF), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Necker - Enfants Malades [AP-HP], Interdisciplinary Institute for Neuroscience [Bordeaux] (IINS), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Geneva University Hospitals and Geneva University, Hôpital Robert Debré, and Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)
Subjects: medicine.medical_specialty, Ataxia, Cerebellar Ataxia, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Receptors, Cytoplasmic and Nuclear, Genomics, Biology, PEX10, Cohort Studies, Peroxins, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, medicine, Humans, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, Translation reinitiation, 0303 health sciences, Molecular pathology, 030305 genetics & heredity, Phenotype, Human genetics, United States, 3. Good health, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Medical genetics, medicine.symptom, 030217 neurology & neurosurgery
Abstract: International audience; Purpose: Diagnosis of inherited ataxia and related diseases represents a real challenge given the tremendous heterogeneity and clinical overlap of the various causes. We evaluated the efficacy of molecular diagnosis of these diseases by sequencing a large cohort of undiagnosed families.Methods: We analyzed 366 unrelated consecutive patients with undiagnosed ataxia or related disorders by clinical exome-capture sequencing. In silico analysis was performed with an in-house pipeline that combines variant ranking and copy-number variant (CNV) searches. Variants were interpreted according to American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines.Results: We established the molecular diagnosis in 46% of the cases. We identified 35 mildly affected patients with causative variants in genes that are classically associated with severe presentations. These cases were explained by the occurrence of hypomorphic variants, but also rarely suspected mechanisms such as C-terminal truncations and translation reinitiation.Conclusion: A significant fraction of the clinical heterogeneity and phenotypic overlap is explained by hypomorphic variants that are difficult to identify and not readily predicted. The hypomorphic C-terminal truncation and translation reinitiation mechanisms that we identified may only apply to few genes, as it relies on specific domain organization and alterations. We identified PEX10 and FASTKD2 as candidates for translation reinitiation accounting for mild disease presentation.
Published: 2021

43. Using deep-neural-network-driven facial recognition to identify distinct Kabuki syndrome 1 and 2 gestalt

Author: Didier Lacombe, Claire Duflos, David Geneviève, Jeanne Amiel, Elodie Sanchez, Yline Capri, Damien Sanlaville, Marlène Rio, Alexandra Afenjar, Fabienne Giuliano, Elise Brischoux-Boucher, Mathilde Nizon, Stanislas Lyonnet, Sébastien Moutton, Vincent Gatinois, Stéphanie Arpin, Annick Toutain, Mouna Barat-Houari, Guilaine Boursier, Flavien Rouxel, Sophie Julia, Klaus Dieterich, Aurélia Jacquette, Boris Keren, Kevin Yauy, Patricia Blanchet, Marie-Line Jacquemont, Damien Haye, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de génétique médicale, Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) (U1211 INSERM/MRGM), Université de Bordeaux (UB)-Groupe hospitalier Pellegrin-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Imagerie et cerveau (iBrain - Inserm U1253 - UNIV Tours ), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Université de Lausanne (UNIL), AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pitié-Salpêtrière [AP-HP], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC), CHU Necker - Enfants Malades [AP-HP], [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), CHU Grenoble, Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), CHU Toulouse [Toulouse], Centre hospitalier universitaire de Nantes (CHU Nantes), GRC ConCer-LD, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maison de Santé Protestante Bagatelle, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), and Hospices Civils de Lyon (HCL)
Subjects: Image Series, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, Biology, [INFO.INFO-NE]Computer Science [cs]/Neural and Evolutionary Computing [cs.NE], Facial recognition system, Article, Genetics, medicine, Humans, Abnormalities, Multiple, Genetics (clinical), [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, Artificial neural network, Receiver operating characteristic, business.industry, Significant difference, Genetic disorder, [INFO.INFO-CV]Computer Science [cs]/Computer Vision and Pattern Recognition [cs.CV], Pattern recognition, medicine.disease, Hematologic Diseases, Vestibular Diseases, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Face, Mutation, Gestalt psychology, Artificial intelligence, business, Kabuki syndrome, Facial Recognition
Abstract: International audience; Kabuki syndrome (KS) is a rare genetic disorder caused by mutations in two major genes, KMT2D and KDM6A, that are responsible for Kabuki syndrome 1 (KS1, OMIM147920) and Kabuki syndrome 2 (KS2, OMIM300867), respectively. We lack a description of clinical signs to distinguish KS1 and KS2. We used facial morphology analysis to detect any facial morphological differences between the two KS types. We used a facial-recognition algorithm to explore any facial morphologic differences between the two types of KS. We compared several image series of KS1 and KS2 individuals, then compared images of those of Caucasian origin only (12 individuals for each gene) because this was the main ethnicity in this series. We also collected 32 images from the literature to amass a large series. We externally validated results obtained by the algorithm with evaluations by trained clinical geneticists using the same set of pictures. Use of the algorithm revealed a statistically significant difference between each group for our series of images, demonstrating a different facial morphotype between KS1 and KS2 individuals (mean area under the receiver operating characteristic curve = 0.85 [p = 0.027] between KS1 and KS2). The algorithm was better at discriminating between the two types of KS with images from our series than those from the literature (p = 0.0007). Clinical geneticists trained to distinguished KS1 and KS2 significantly recognised a unique facial morphotype, which validated algorithm findings (p = 1.6e-11). Our deep-neural-network-driven facial-recognition algorithm can reveal specific composite gestalt images for KS1 and KS2 individuals.
Published: 2021

44. Public awareness of organic agriculture: creation of the 1st MOOC on organic farming in Europe

Author: Marliac, Gaëlle, Bellon, Stéphane, Nesme, Thomas, Peigne, Josephine, David, Geneviève, Deguine, Jean-Philippe, Sautereau, Natacha, and Balard, Eve
Abstract: Given the many sources of information available on organic agriculture (OA), it is difficult for the public to build an opinion. The first, francophone MOOC on organic farming and food (MOOC BIO) was built to provide updated information on the development status and challenges of OA and to allow as many people as possible to build an objective and informed opinion on OA. For 8 weeks, a broad range of themes (regulation, stakeholders, history, production techniques, marketing systems and territorial development) were addressed. Almost 20,000 students have participated to the MOOC, with large international coverage, illustrating the great interest paid to OA. In addition, the organization of events around the MOOC has broadened the target audience. Through a partnership with OA stakeholders in Senegal we even reached an international dimension. For wider dissemination, translation into others languages is a perspective. Background: The development and media coverage of organic farming has resulted in the wide dissemination of information on organic farming and food. Anyone can learn about organic farming by browsing the wide internet. However, the diversity in nature and quality related to this information and also controversies between researchers (See for instance the debate after the publication In Nature Searchinger et al., 2018) may lead to some confusion and misinformation for the general public. Organic farming stakeholders, citizens and consumers need to form a critical opinion on some of the issues raised by the OA: what is the right price for organic products? Are organic products better for human and environmental health? In the digital age, the MOOC BIO (Massive Open Online Course on OA) aims to support this public in building informed opinion on organic agriculture. To our knowledge, this is the first MOOC dedicated to organic agriculture, started in 2018. Core messages and conclusions: The main messages are: - Two MOOC sessions have already unfolded in 2018 and 2019, and attracted almost 20,000 participants coming from more than 100 countries. This underlines the interest that OA represents for learners, citizens, consumers and organic farming actors. - The MOOC addresses seven dimensions of organic agriculture, namely: regulation, stakeholders, history, production techniques, marketing systems linked to consumption and territorial development. The deepening of controversial cross-cutting issues (OA and biodiversity; OA and prices; OA and human health; OA and water), based on selected resources and promoting exchanges between registered participants (thanks to forums and collective synthesis work) enriched the participants' positioning. The learners were also led to develop a reflexive approach on the evolution of their representations of OA, between the beginning and the end of the MOOC training. - The cross-disciplinary of this MOOC was made possible thanks to the diversity of the authors' fields of expertise (Figure1). It has led to the creation of a network around organic farming in higher education in France - The construction of an informed opinion on learners' organic farming was built thanks to the original structure of the MOOC: a more transmitted part (although punctuated by varied activities) and another part where knowledge is co-constructed by the participants (Figure 2). - This online training also includes meetings in France (between MOOC participants and organic farming actors) via surveys that participants carried out or via events organized by MOOC authors. - The dissemination of the knowledge developed in the MOOC has also reached a wider audience through events organised by the MOOC's designers: Interventions with high school students (“Fête de la science” event), the resources produced have also been used in face-to-face training for future agricultural engineers in France. - International collaborations (with actors of agroecology in Senegal and with the CIRAD) enable us to propose resources outside the European context. 111 -A further perspective is to translate this MOOC into several languages (English and Spanish) for the next sessions in order to increase its international visibility.
Published: 2021

45. Neuropsychological study in 19 French patients with White‐Sutton syndrome and POGZ mutations

Author: Anne Miret, Lola Lemasson, Benjamin Cogné, Laurence Perrin, Frédéric Tran Mau-Them, Rémi Mathevet, Marion Boucon, Elise Schaefer, Christel Thauvin-Robinet, Christine Juif, Juliette Piard, Solène Bourgouin, Jenny Cornaton, Bertrand Isidor, Catherine Sarret, Fabienne Prieur, Coralie Gonin-Olympiade, Alexandra Afenjar, Christine Coubes, Boris Keren, Bénédicte Gérard, Catherine Vincent-Delorme, Kim Giraudat, Laurence Faivre, Amélie Piton, Antonio Vitobello, Thomas Smol, Annick Toutain, Arthur Sorlin, Sylvie Odent, Yann Trousselet, Fanny Tessier, Martin Chevarin, David Geneviève, Sébastien Moutton, Anne-Claire Gelineau, Ange-Line Bruel, Claire Nicolas, Aurore Garde, Philippe Khau-Van-Kien, Christophe Philippe, Solveig Heide, Hôpital d'Enfants [CHU Dijon], Hôpital du Bocage, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Nîmes (CHU Nîmes), Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Service de génétique [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Hôpital Bretonneau, Les Hôpitaux Universitaires de Strasbourg (HUS), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Institut Pascal (IP), SIGMA Clermont (SIGMA Clermont)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), CHU Clermont-Ferrand, Centre de génétique humaine [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Saint-Etienne, Hôpital Bretonneau-Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, and SIGMA Clermont (SIGMA Clermont)-Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])
Subjects: Adult, Male, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Adolescent, Autism Spectrum Disorder, Developmental Disabilities, [SDV]Life Sciences [q-bio], Neurocognitive Disorders, Transposases, Neuropsychological Tests, 030105 genetics & heredity, Cohort Studies, Young Adult, 03 medical and health sciences, [SCCO]Cognitive science, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Genetic Predisposition to Disease, Global developmental delay, Child, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Dysexecutive syndrome, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Neuropsychology, Genetic Variation, medicine.disease, 3. Good health, Developmental disorder, Phenotype, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, Mutation, Autism, Female, France, business, Neurocognitive
Abstract: White-Sutton syndrome is a rare developmental disorder characterized by global developmental delay, intellectual disabilities (ID), and neurobehavioral abnormalities secondary to pathogenic pogo transposable element-derived protein with zinc finger domain (POGZ) variants. The purpose of our study was to describe the neurocognitive phenotype of an unbiased national cohort of patients with identified POGZ pathogenic variants. This study is based on a French collaboration through the AnDDI-Rares network, and includes 19 patients from 18 families with POGZ pathogenic variants. All clinical data and neuropsychological tests were collected from medical files. Among the 19 patients, 14 patients exhibited ID (six mild, five moderate and three severe). The five remaining patients had learning disabilities and shared a similar neurocognitive profile, including language difficulties, dysexecutive syndrome, attention disorders, slowness, and social difficulties. One patient evaluated for autism was found to have moderate autism spectrum disorder. This study reveals that the cognitive phenotype of patients with POGZ pathogenic variants can range from learning disabilities to severe ID. It highlights that pathogenic variations in the same genes can be reported in a large spectrum of neurocognitive profiles, and that children with learning disabilities could benefit from next generation sequencing techniques.
Published: 2020

46. 9 - Stratégie de recherche axée sur le patient

Author: David, Geneviève, Baron, Marie, and LeBlanc, Annie
Published: 2020
Full Text: View/download PDF

47. Scaling Up Citizen Workshops in Public Libraries to Disseminate and Discuss Primary Care Research Results: Quasi-Experimental Study.

Author: Massougbodji, José, Zomahoun, Hervé Tchala Vignon, Adisso, Evehouenou Lionel, Sawadogo, Jasmine, Borde, Valérie, Cameron, Cynthia, Moisan, Hélène, Paquette, Jean-Sébastien, Akbaraly, Zamzam, Châteauneuf, Lëa-Kim, David, Geneviève, and Légaré, France
Subjects: CITIZENS, PUBLIC libraries, PRIMARY care, OLDER people, DRUGS
Abstract: Background: Little is known about engaging patients and stakeholders in the process of scaling up effective knowledge translation interventions targeting the public. Objective: Using an integrated knowledge translation approach, we aimed to scale up and evaluate an effective pilot program to disseminate research results in public libraries. Methods: We conducted a scaling-up study targeting the public. On the basis of our successful pilot project, we codeveloped and implemented a large-scale program of free citizen workshops in public libraries, in a close research partnership with stakeholders and patient representatives. Citizen workshops, each facilitated by 1 participating physician and 1 science communicator, consisted of a 45-minute computer-assisted presentation and a 45-minute open exchange. The intervention outcome was knowledge gained. The scale-up outcomes were satisfaction, appropriateness, coverage, and costs. An evaluation questionnaire was used to collect data of interest. Both quantitative and qualitative analyses were performed. Results: The workshop theme chosen by the patient and stakeholder representatives was the high prevalence of medication overuse among people aged =65 years. From April to May 2019, 26 workshops were conducted in 25 public libraries reaching 362 people. The mean age of participants was 64.8 (SD 12.5) years. In total, 18 participating physicians and 6 science communicators facilitated the workshops. Participants reported significant knowledge gain (mean difference 2.1, 95% CI 2.0-2.2; P<.001). The median score for overall public satisfaction was 9 out of 10 (IQR 8-10). The public participants globally rated the workshops as having a high level of appropriateness. Coverage was 92% (25/27) of the total number of public libraries targeted. Costs were CAD $6051.84 (US $4519.69) for workshop design and CAD $22,935.41 (US $17,128.85) for scaling them up. Conclusions: This project successfully established a large-scale and successful implementation science or knowledge translation bridge among researchers, clinicians, and citizens via public libraries. This study provides a model for a dissemination practice that benefits the public by both engaging them in the dissemination process and targeting them directly. [ABSTRACT FROM AUTHOR]
Published: 2022
Full Text: View/download PDF

48. Author response for '<scp>Smith‐Magenis</scp> syndrome ( <scp>SMS</scp> ): clinical and behavioral characteristics in a large retrospective cohort'

Author: David Geneviève, Jamal Ghoumid, Myriam Mikaty, Hélène Deleersnyder, Nicole Philip, Delphine Héron, Laurence Perrin, Lyse Ruaud, Faustine Ageorge, Adeline Jacquinet, Laurence Faivre, Sophie Chancenotte, Jennifer Gallard, Didier Lacombe, Nicolas Rive Le Gouard, Natacha Lehman, Patrick Edery, Christel Thauvin-Robinet, Sylvie Manouvrier-Hanu, Coralie Rastel, Sylvie Odent, and Alain Verloes
Subjects: Pediatrics, medicine.medical_specialty, business.industry, medicine, Retrospective cohort study, Smith–Magenis syndrome, medicine.disease, business
Published: 2020

49. Developmental and epilepsy spectrum of KCNB1 encephalopathy with long‐term outcome

Author: Rima Nabbout, Patrick Berquin, Sylvie Odent, Mathieu Kuchenbuch, Gwenaël Le Guyader, Marieke F. van Dooren, Jamel Chelly, Edor Kabashi, Melanie Jennesson, Giulia Barcia, Cyril Mignot, Tayeb Sekhara, Alexandra Afenjar, Marlène Rio, Anne Rolland, Claude Besmond, Andrés Rodríguez-Sacristán Cascajo, Gaetano Terrone, Isabelle Marey, Boris Keren, Alice Goldenberg, A.S. Lebre, Heather C Mefford, Gaetan Lesca, Anne de Saint Martin, Susanna Negrin, Nathalie Dorison, Hélène Maurey, Agnès Guët, David Geneviève, Marie Claire Y. de Wit, Jeremy L. Freeman, Pierre Meyer, Thierry Billette de Villemeur, Ingrid E. Scheffer, Katherine B. Howell, Anca Nica, Raphael Levy, Martino Montomoli, Renzo Guerrini, Elena Parrini, Candace T. Myers, Bertrand Isidor, Alice Poisson, Marion Gérard, Salima El Chehadeh, Lynette G. Sadleir, Julien Durigneux, Pascal Vrielynck, Amy L Schneider, Emmanuel Scalais, Laurence Hubert, Sophie Dupont, Vesna Brankovic, Damien Lederer, Hervé Isnard, Delphine Breuillard, Claire Bar, Alberto Danieli, Diane Doummar, Arnold Munnich, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Unité neurovasculaire et troubles cognitifs (Neuvacod), Université de Poitiers, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Strasbourg, Centre for the Diagnosis and management of genetic psychiatric disorders [Bron] (GénoPsy), Centre Hospitalier le Vinatier [Bron], Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique [Rennes] (CIC), Université de Rennes (UR)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pontchaillou [Rennes], 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 Rouen, Normandie Université (NU), CHU Amiens-Picardie, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), CHU Pitié-Salpêtrière [AP-HP], FP7 Ideas: European Research Council, National Health and Medical Research Council, Health Research Council of New Zealand, ANR‐10-IAHU‐01, Agence Nationale de la Recherche, Fondation Bettencourt Schueller, 602531, Seventh Framework Programme, ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), ANR‐10IAHU‐01, Agence Nationale de la Recherche, Clinical Genetics, Neurology, and 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)
Subjects: 0301 basic medicine, Adult, Male, Pediatrics, medicine.medical_specialty, Time Factors, Adolescent, autism spectrum disorders, [SDV]Life Sciences [q-bio], Encephalopathy, Severe epilepsy, Imaging data, Cohort Studies, 03 medical and health sciences, Epilepsy, Young Adult, 0302 clinical medicine, Shab Potassium Channels, drug-resistant epilepsy, Intellectual disability, medicine, Missense mutation, Humans, In patient, developmental and epileptic encephalopathy, Child, ComputingMilieux_MISCELLANEOUS, Retrospective Studies, Brain Diseases, sudden unexpected death in epilepsy, developmental encephalopathy, business.industry, Genetic Variation, Infant, Cognition, Electroencephalography, medicine.disease, potassium channels, 3. Good health, 030104 developmental biology, Treatment Outcome, Neurology, Child, Preschool, Female, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: Objective: We aimed to delineate the phenotypic spectrum and long-term outcome of individuals with KCNB1 encephalopathy. Methods: We collected genetic, clinical, electroencephalographic, and imaging data of individuals with KCNB1 pathogenic variants recruited through an international collaboration, with the support of the family association “KCNB1 France.” Patients were classified as having developmental and epileptic encephalopathy (DEE) or developmental encephalopathy (DE). In addition, we reviewed published cases and provided the longterm outcome in patients older than 12 years from our series and from literature. Results: Our series included 36 patients (21 males, median age = 10 years, range = 1.6 months-34 years). Twenty patients (56%) had DEE with infantile onset seizures (seizure onset = 10 months, range = 10 days-3.5 years), whereas 16 (33%) had DE with late onset epilepsy in 10 (seizure onset = 5 years, range = 18 months-25 years) and without epilepsy in six. Cognitive impairment was more severe in individuals with DEE compared to those with DE. Analysis of 73 individuals with KCNB1 pathogenic variants (36 from our series and 37 published individuals in nine reports) showed developmental delay in all with severe to profound intellectual disability in 67% (n = 41/61) and autistic features in 56% (n = 32/57). Long-term outcome in 22 individuals older than 12 years (14 in our series and eight published individuals) showed poor cognitive, psychiatric, and behavioral outcome. Epilepsy course was variable. Missense variants were associated with more frequent and more severe epilepsy compared to truncating variants. Significance: Our study describes the phenotypic spectrum of KCNB1 encephalopathy, which varies from severe DEE to DE with or without epilepsy. Although cognitive impairment is worse in patients with DEE, long-term outcome is poor for most and missense variants are associated with more severe epilepsy outcome. Further understanding of disease mechanisms should facilitate the development of targeted therapies, much needed to improve the neurodevelopmental prognosis.
Published: 2020

50. Smith-Magenis syndrome: Clinical and behavioral characteristics in a large retrospective cohort

Author: Jamal Ghoumid, Patrick Edery, Christel Thauvin-Robinet, Sophie Chancenotte, Nicole Philip, Alain Verloes, Myriam Mikaty, Didier Lacombe, Coralie Rastel, Lyse Ruaud, David Geneviève, Natacha Lehman, Laurence Faivre, Laurence Perrin, Nicolas Rive Le Gouard, Hélène Deleersnyder, Adeline Jacquinet, Faustine Ageorges, Delphine Héron, Jennifer Gallard, Sylvie Odent, Sylvie Manouvrier-Hanu, Département de génétique [Robert Debré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Maladies neurodéveloppementales et neurovasculaires (NeuroDiderot (UMR_S_1141 / U1141)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Centre Hospitalier Universitaire de Liège (CHU-Liège), Hôpital Pellegrin, CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de génétique médicale [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Arnaud de Villeneuve, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), 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), Hôpital Femme Mère Enfant [CHU - HCL] (HFME), Hospices Civils de Lyon (HCL), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Parents, Pediatrics, Developmental Disabilities, Smith-Magenis, 030105 genetics & heredity, Overweight, Epilepsy, Neurodevelopmental disorder, Prenatal Diagnosis, Child, clinical characteristics, Genetics (clinical), Growth Disorders, Tetralogy of Fallot, Sleep disorder, Smith–Magenis syndrome, 3. Good health, Phenotype, Child, Preschool, Education, Special, Family Relations, medicine.symptom, Chromosome Deletion, Sleep Wake Disorders, medicine.medical_specialty, Adolescent, Scoliosis, Child Behavior Disorders, obstipation, 03 medical and health sciences, Young Adult, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Retrospective Studies, business.industry, Retrospective cohort study, Patient Acceptance of Health Care, medicine.disease, neurodevelopmental disorder, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, social impact, 17p11.2, Smith-Magenis Syndrome, business, Chromosomes, Human, Pair 17
Abstract: International audience; Smith-Magenis syndrome (SMS), characterized by dysmorphic features, neurodevelopmental disorder, and sleep disturbance, is due to an interstitial deletion of chromosome 17p11.2 (90%) or to point mutations in the RAI1 gene. In this retrospective cohort, we studied the clinical, cognitive, and behavioral profile of 47 European patients with SMS caused by a 17p11.2 deletion. We update the clinical and neurobehavioral profile of SMS. Intrauterine growth was normal in most patients. Prenatal anomalies were reported in 15%. 60% of our patients older than 10 years were overweight. Prevalence of heart defects (6.5% tetralogy of Fallot, 6.5% pulmonary stenosis), ophthalmological problems (89%), scoliosis (43%), or deafness (32%) were consistent with previous reports. Epilepsy was uncommon (2%). We identified a high prevalence of obstipation (45%). All patients had learning difficulties and developmental delay, but ID range was wide and 10% of patients had IQ in the normal range. Behavioral problems included temper tantrums and other difficult behaviors (84%) and night-time awakenings (86%). Optimal care of SMS children is multidisciplinary and requires important parental involvement. In our series, half of patients were able to follow adapted schooling, but 70% of parents had to adapt their working time, illustrating the medical, social, educative, and familial impact of having a child with SMS.
Published: 2020

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Publication Type

Journal

Region

Database

Publisher

524 results on '"David Geneviève"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources