DLG4-related synaptopathy: a new rare brain disorder

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. DyeFrances 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

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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 Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.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

Original languageEnglish (US)
Pages (from-to)888-899
Number of pages12
JournalGenetics in Medicine
Issue number5
StatePublished - May 2021
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.


  • Autism Spectrum Disorder/diagnosis
  • Brain
  • Brain Diseases
  • Disks Large Homolog 4 Protein/genetics
  • Humans
  • Intellectual Disability
  • Neurodevelopmental Disorders/diagnosis
  • Phenotype

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't


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