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 Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.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

DLG4-related synaptopathy: a new rare brain disorder

Giorgio E.;Mandrile G.;
2021-01-01

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 Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants.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. [Figure not available: see fulltext.]
2021
1
12
Rodriguez-Palmero A.; Boerrigter M.M.; Gomez-Andres D.; Aldinger K.A.; Marcos-Alcalde I.; Popp B.; Everman D.B.; Lovgren A.K.; Arpin S.; Bahrambeigi V.; Beunders G.; Bisgaard A.-M.; Bjerregaard V.A.; Bruel A.-L.; Challman T.D.; Cogne B.; Coubes C.; de Man S.A.; Denomme-Pichon A.-S.; Dye T.J.; Elmslie F.; Feuk L.; Garcia-Minaur S.; Gertler T.; Giorgio E.; Gruchy N.; Haack T.B.; Haldeman-Englert C.R.; Haukanes B.I.; Hoyer J.; Hurst A.C.E.; Isidor B.; Soller M.J.; Kushary S.; Kvarnung M.; Landau Y.E.; Leppig K.A.; Lindstrand A.; Kleinendorst L.; MacKenzie A.; Mandrile G.; Mendelsohn B.A.; Moghadasi S.; Morton J.E.; Moutton S.; Muller A.J.; O'Leary M.; Pacio-Miguez M.; Palomares-Bralo M.; Parikh S.; Pfundt R.; Pode-Shakked B.; Rauch A.; Repnikova E.; Revah-Politi A.; Ross M.J.; Ruivenkamp C.A.L.; Sarrazin E.; Savatt J.M.; Schluter A.; Schonewolf-Greulich B.; Shad Z.; Shaw-Smith C.; Shieh J.T.; Shohat M.; Spranger S.; Thiese H.; Mau-Them F.T.; van Bon B.; van de Burgt I.; van de Laar I.M.B.H.; van Drie E.; van Haelst M.M.; van Ravenswaaij-Arts C.M.; Verdura E.; Vitobello A.; Waldmuller S.; Whiting S.; Zweier C.; Prada C.E.; de Vries B.B.A.; Dobyns W.B.; Reiter S.F.; Gomez-Puertas P.; Pujol A.; Tumer Z.
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1788047
Citazioni
  • ???jsp.display-item.citation.pmc??? 4
  • Scopus 18
  • ???jsp.display-item.citation.isi??? 13
social impact