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


DOI: 10.1038/s41436-020-01075-9


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 Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.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.]

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Involved external institutions

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

How to cite


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


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

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