Year: 2021
Type: article
Study design: Observational Study
Abstract: PURPOSE: Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. METHODS: The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. RESULTS: The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. CONCLUSION: The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
Source: Genetics in Medicine
Authors: Agustí Rodríguez-Palmero, Melissa Maria Boerrigter, David Gómez-Andrés, Kimberly A. Aldinger, Íñigo Marcos-Alcalde, Bernt Popp, David B. Everman, Alysia Kern Lovgren, Stephanie Arpin, Vahid Bahrambeigi, Gea Beunders, Anne-Marie Bisgaard, V.A. Bjerregaard, Ange-Line Bruel, Thomas D. Challman, Benjamin Cogné, Christine Coubes, Stella A. de Man, Anne-Sophie Denommé-Pichon, Thomas J. Dye, Frances Elmslie, Lars Feuk, Sixto García-Miñaúr, Tracy Gertler, Elisa Giorgio, Nicolas Gruchy, Tobias B. Haack, Chad R. Haldeman-Englert, Bjørn Ivar Haukanes, Juliane Hoyer, Anna C.E. Hurst, Bertrand Isidor, Maria Johansson Soller, Sulagna Kushary, Malin Kvarnung, Yuval E. Landau, Kathleen A. Leppig, Anna Lindstrand, Lotte Kleinendorst, Alex MacKenzie, Giorgia Mandrile, Bryce A. Mendelsohn, Setareh Moghadasi, Jenny E. Morton, Sebastien Moutton, Amelie J. Müller, Melanie O’Leary, Marta Pacio-Míguez, Maria Palomares-Bralo, Sumit Parikh, Rolph Pfundt, Ben Pode-Shakked, Anita Rauch, Elena Repnikova, Anya Revah-Politi, Meredith J. Ross, Claudia A.L. Ruivenkamp, Elisabeth Sarrazin, Juliann M. Savatt, Agatha Schlüter, Bitten Schönewolf-Greulich, Zohra Shad, Charles Shaw-Smith, Joseph T. Shieh, Motti Shohat, Stephanie Spranger, Heidi Thiese, Frederic Tran Mau-Them, Bregje van Bon, Ineke van de Burgt, Ingrid M.B.H. van de Laar, Esmée van Drie, Mieke M. van Haelst, Conny M. van Ravenswaaij-Arts, Edgard Verdura, Antonio Vitobello, Stephan Waldmüller, Sharon Whiting, Christiane Zweier, Carlos E. Prada, Bert B.A. de Vries, William B. Dobyns, Simone F. Reiter, Paulino Gómez-Puertas, Aurora Pujol, Zeynep Tümer
Institutions: Universitat Autònoma de Barcelona, Institut d'Investigació Biomédica de Bellvitge, Centre for Biomedical Network Research on Rare Diseases, Hospital Universitari Germans Trias i Pujol, Copenhagen University Hospital, Rigshospitalet, Radboud University Medical Center, Kennedy Center, Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Seattle Children's Research Institute, Universidad Francisco de Vitoria, Centro de Biología Molecular Severo Ochoa, Friedrich-Alexander-Universität Erlangen-Nürnberg, University Hospital Leipzig, Leipzig University, Greenwood Genetic Center, Broad Institute, Université de Tours, Inserm, Imaging, Brain, and Neuropsychiatry, Centre Hospitalier Universitaire de Tours, The University of Texas MD Anderson Cancer Center, The University of Texas Health Science Center at Houston, University Medical Center Groningen, Université de Bourgogne, CHU Dijon Bourgogne, Centre de recherche Translationnelle en Médecine moléculaire, Autism & Developmental Medicine Institute, Centre National de la Recherche Scientifique, Centre Hospitalier Universitaire de Nantes, Institut du Thorax, Université de Nantes, Nantes Université, Centre Hospitalier Universitaire de Montpellier, Amphia Ziekenhuis, Cincinnati Children's Hospital Medical Center, University of Cincinnati, University of London, St George's, University of London, Uppsala University, Science for Life Laboratory, Hospital Universitario La Paz, Lurie Children's Hospital, University of Turin, Centre Hospitalier Universitaire de Caen Normandie, Biologie, Génétique et Thérapies ostéoArticulaires et Respiratoires, Université de Caen Normandie, University of Tübingen, Mission Health, Haukeland University Hospital, University of Alabama at Birmingham, Karolinska University Hospital, Karolinska Institutet, Columbia University Irving Medical Center, Tel Aviv University, Schneider Children's Medical Center, Kaiser Permanente, Amsterdam University Medical Centers, University of Amsterdam, University of Ottawa, Children's Hospital of Eastern Ontario, Ospedale San Luigi Gonzaga, University of California, San Francisco, Leiden University Medical Center, Birmingham Women's Hospital, Birmingham Women’s and Children’s NHS Foundation Trust, Maison de Sante Protestante de Bordeaux-Bagatelle, Cleveland Clinic, Sheba Medical Center, Edmond and Lily Safra Children's Hospital, University of Zurich, Children's Mercy Hospital, NewYork–Presbyterian Hospital, Centre Hospitalier Universitaire de Martinique, Cook Children's Medical Center, Royal Devon & Exeter NHS Foundation Trust, Royal Devon University Healthcare NHS Foundation Trust, Praxis für Humangenetik, Klinikum Bremen-Mitte, Erasmus MC, University of Washington, Institució Catalana de Recerca i Estudis Avançats, University of Copenhagen
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,900
Award: G2795716607
OpenAlex ID: W3131452986