DLG4-related synaptopathy: a new rare brain disorder.

TitleDLG4-related synaptopathy: a new rare brain disorder.
Publication TypeJournal Article
Year of Publication2021
AuthorsRodríguez-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
JournalGenet Med
Date Published2021 05
KeywordsAutism 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 Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.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 JournalGenet Med
PubMed ID33597769
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States