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DLG4-related synaptopathy: a new rare brain disorder

Agustí Rodriguez-Palmero 1, 2, 3 Melissa Maria Boerrigter David Gómez-Andrés 4 Kimberly Aldinger 5 Íñigo Marcos-Alcalde Bernt Popp 6 David Everman Alysia Kern Lovgren Stéphanie Arpin 7 Vahid Bahrambeigi 8 Gea Beunders Anne-Marie Bisgaard V. Bjerregaard Ange-Line Bruel Thomas Challman Benjamin Cogné Christine Coubes Stella de Man Anne-Sophie Denommé-Pichon Thomas Dye Frances Elmslie Lars Feuk Sixto García-Miñaúr Tracy Gertler Elisa Giorgio Nicolas Gruchy 9 Tobias Haack Chad Haldeman-Englert Bjørn Ivar Haukanes Juliane Hoyer Anna Hurst Bertrand Isidor Maria Johansson Soller Sulagna Kushary Malin Kvarnung yuval Landau Kathleen Leppig Anna Lindstrand Lotte Kleinendorst Alex Mackenzie Giorgia Mandrile Bryce Mendelsohn Setareh Moghadasi Jenny Morton Sebastien Moutton Amelie 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 Ross Claudia Ruivenkamp Elisabeth Sarrazin Juliann Savatt Agatha Schlüter Bitten Schönewolf-Greulich Zohra Shad Charles Shaw-Smith Joseph Shieh Motti Shohat Stephanie Spranger Heidi Thiese Frederic Tran Mau-Them Bregje van Bon Ineke van de Burgt Ingrid van de Laar Esmée van Drie Mieke van Haelst Conny van Ravenswaaij-Arts Edgard Verdura Antonio Vitobello Stephan Waldmüller Sharon Whiting Christiane Zweier Carlos Prada Bert de Vries William Dobyns Simone Reiter Paulino Gómez-Puertas Aurora Pujol Zeynep Tümer 
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 Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.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.
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Submitted on : Thursday, April 8, 2021 - 3:48:55 PM
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Agustí Rodriguez-Palmero, Melissa Maria Boerrigter, David Gómez-Andrés, Kimberly Aldinger, Íñigo Marcos-Alcalde, et al.. DLG4-related synaptopathy: a new rare brain disorder. Genetics in Medicine, Nature Publishing Group, 2021, ⟨10.1038/s41436-020-01075-9⟩. ⟨hal-03193180⟩



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