|Title||DLG4-related synaptopathy: a new rare brain disorder.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Rodríguez-Palmero, A, Boerrigter, MMaria, Gómez-Andrés, D, Aldinger, KA, Marcos-Alcalde, Í, Popp, B, Everman, DB, Lovgren, AKern, Arpin, S, Bahrambeigi, V, Beunders, G, Bisgaard, A-M, Bjerregaard, VA, Bruel, A-L, Challman, TD, Cogné, B, Coubes, C, de Man, SA, Denommé-Pichon, A-S, Dye, TJ, Elmslie, F, Feuk, L, Garcia-Minaur, S, Gertler, T, Giorgio, E, Gruchy, N, Haack, TB, Haldeman-Englert, CR, Haukanes, BIvar, Hoyer, J, Hurst, ACE, Isidor, B, Soller, MJohansson, Kushary, S, Kvarnung, M, Landau, YE, Leppig, KA, Lindstrand, A, Kleinendorst, L, MacKenzie, A, Mandrile, G, Mendelsohn, BA, Moghadasi, S, Morton, JE, Moutton, S, Müller, 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, Schluter, A, Schönewolf-Greulich, B, Shad, Z, Shaw-Smith, C, Shieh, JT, Shohat, M, Spranger, S, Thiese, H, Mau-Them, FTran, 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, Waldmüller, S, Whiting, S, Zweier, C, Prada, CE, de Vries, BBA, Dobyns, WB, Reiter, SF, Gómez-Puertas, P, Pujol, A, Tümer, Z|
|Date Published||2021 05|
|Keywords||Autism Spectrum Disorder, Brain, Brain Diseases, Disks Large Homolog 4 Protein, Humans, Intellectual Disability, Neurodevelopmental Disorders, Phenotype|
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 Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.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.
|Alternate Journal||Genet Med|
|Grant List||UM1 HG008900 / HG / NHGRI NIH HHS / United States|