DLG4-related synaptopathy: a new rare brain disorder

Rodriguez-Palmero A, Boerrigter MM, Gomez-Andres D, Aldinger KA, Marcos-Alcalde I, Popp B, Everman DB, Lovgren AK, Arpin S, Bahrambeigi V, Beunders G, Bisgaard AM, Bjerregaard VA, Bruel AL, Challman TD, Cogne B, Coubes C, De Man SA, Denomme-Pichon AS, Dye TJ, Elmslie F, Feuk L, Garcia-Minaur S, Gertler T, Giorgio E, Gruchy N, Haack TB, Haldeman-Englert CR, Haukanes BI, Hoyer J, Hurst ACE, Isidor B, Soller MJ, Kushary S, Kvarnung M, Landau YE, Leppig KA, Lindstrand A, Kleinendorst L, Mackenzie A, Mandrile G, Mendelsohn BA, Moghadasi S, Morton JE, Moutton S, Mueller AJ, O'Leary M, Pacio-Miguez M, Palomares-Bralo M, Parikh S, Pfundt R, Pode-Shakked B, Rauch A, Repnikova E, Revah-Politi A, Ross MJ, Ruivenkamp CAL, Sarrazin E, Savatt JM, Schlueter A, Schoenewolf-Greulich B, Shad Z, Shaw-Smith C, Shieh JT, Shohat M, Spranger S, Thiese H, Mau-Them FT, Van Bon B, Van De Burgt I, Van De Laar IMBH, Van Drie E, Van Haelst MM, Van Ravenswaaij-Arts CM, Verdura E, Vitobello A, Waldmueller S, Whiting S, Zweier C, Prada CE, De Vries BBA, Dobyns WB, Reiter SF, Gomez-Puertas P, Pujol A, Tumer Z (2021)

Publication Type: Journal article

Publication year: 2021

Journal

DOI: 10.1038/s41436-020-01075-9

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 Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.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. [Figure not available: see fulltext.]

Authors with CRIS profile

Involved external institutions

Université Bourgogne Franche-Comté France (FR) Nantes University Hospital / Centre hospitalier universitaire de Nantes (CHU) France (FR) Geisinger Medical Center United States (USA) (US) Spanish National Research Council / Consejo Superior de Investigaciones Científicas (CSIC) Spain (ES) Chaim Sheba Medical Center at Tel HaShomer / המרכז הרפואי עש חיים שיבא – תל השומר‎‎ Israel (IL) Eli and Edythe L. Broad Institute of MIT and Harvard United States (USA) (US) Karolinska Institute Sweden (SE) Greenwood Genetic Center United States (USA) (US) Columbia University United States (USA) (US) Copenhagen University Hospital Denmark (DK) University of Amsterdam Netherlands (NL) Tel Aviv University Israel (IL) Leiden University Netherlands (NL) Erasmus University Medical Center (MC) Netherlands (NL) Klinikverbund Bremen (Gesundheit Nord) Germany (DE) Royal Devon & Exeter NHS Foundation Trust United Kingdom (GB) Cincinnati Children's Hospital Medical Center United States (USA) (US) Eberhard Karls Universität Tübingen Germany (DE) Ann & Robert H. Lurie Children's Hospital of Chicago United States (USA) (US) Hospital Universitario La Paz Spain (ES) University of Turin / Università degli Studi di Torino (UNITO) Italy (IT) Uppsala University Sweden (SE) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Bellvitge Biomedical Research Institute (IDIBELL) Spain (ES) Amphia Ziekenhuis Netherlands (NL) University of Ottawa Canada (CA) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) Kaiser Permanente United States (USA) (US) Centre Hospitalier Universitaire de Montpellier (CHU/CHRU MTP) France (FR) University of Cincinnati United States (USA) (US) Radboud University Nijmegen Netherlands (NL) CHU Martinique Martinique (MQ) UNICAEN Université de Caen Normandie France (FR) Birmingham Women's and Children's NHS Foundation Trust United Kingdom (GB) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) Ospedale San Luigi Gonzaga Italy (IT) Children's Mercy Hospital United States (USA) (US) University College London (UCL) United Kingdom (GB) Cleveland Clinic United States (USA) (US) University of California San Francisco (UCSF) United States (USA) (US) Leumit Health Care Services Israel (IL) University of Alabama at Birmingham (UAB) United States (USA) (US) Seattle Children's Hospital United States (USA) (US) Cook Children's Health Care System United States (USA) (US) University of Zurich / Universität Zürich (UZH) Switzerland (CH)

How to cite

APA:

Rodriguez-Palmero, A., Boerrigter, M.M., Gomez-Andres, D., Aldinger, K.A., Marcos-Alcalde, I., Popp, B.,... Tumer, Z. (2021). DLG4-related synaptopathy: a new rare brain disorder. Genetics in Medicine. https://doi.org/10.1038/s41436-020-01075-9

MLA:

Rodriguez-Palmero, Agusti, et al. "DLG4-related synaptopathy: a new rare brain disorder." Genetics in Medicine (2021).

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