6533b862fe1ef96bd12c6204
RESEARCH PRODUCT
DLG4-related synaptopathy: a new rare brain disorder
Edgard VerduraAlex MackenzieRolph PfundtTobias B. HaackAnge Line BruelPaulino Gómez-puertasAnna C.e. HurstBert B.a. De VriesStella A. De ManMaria Johansson SollerBregje W.m. Van BonElisabeth SarrazinAgustí Rodríguez-palmeroStephan WaldmüllerMelanie O’learyAnne-sophie Denommé-pichonBitten Schönewolf-greulichJoseph T. ShiehV. A. BjerregaardVahid BahrambeigiMalin KvarnungAgatha SchlüterAnne Marie BisgaardIngrid M.b.h. Van De LaarElisa GiorgioLars FeukMieke M. Van HaelstThomas D. ChallmanIneke Van De BurgtSulagna KusharySimone F. ReiterDavid B. EvermanZeynep TümerGiorgia MandrileConny M. A. Van Ravenswaaij-artsCharles Shaw-smithJuliane HoyerChad R. Haldeman-englertLotte KleinendorstBryce A. MendelsohnAnna LindstrandChristine CoubesGea BeundersSixto García-miñaurAntonio VitobelloMelissa Maria BoerrigterMelissa Maria BoerrigterAlysia Kern LovgrenAnya Revah-politiAnya Revah-politiCarlos E. PradaCarlos E. PradaBertrand IsidorElena RepnikovaStephanie SprangerEsmée Van DrieFrédéric Tran Mau-themZohra ShadBen Pode-shakkedBen Pode-shakkedAurora PujolChristiane ZweierBjørn Ivar HaukanesDavid Gómez-andrésKathleen A. LeppigMarta Pacio-míguezMotti ShohatYuval LandauBenjamin CognéFrances ElmslieKimberly A. AldingerAnita RauchJuliann M. SavattNicolas GruchySharon WhitingWilliam B. DobynsWilliam B. DobynsThomas J. DyeThomas J. DyeSebastien MouttonHeidi ThieseSetareh MoghadasiIñigo Marcos-alcaldeIñigo Marcos-alcaldeJenny MortonSumit ParikhMaría Palomares-braloStéphanie ArpinTracy S. GertlerMeredith J. RossBernt PoppBernt PoppAmelie J. MüllerClaudia A. L. Ruivenkampsubject
0301 basic medicineAutism Spectrum Disorder[SDV]Life Sciences [q-bio]030105 genetics & heredityBiology03 medical and health sciencesIntellectual DisabilityIntellectual disabilitymedicineMissense mutationHumansGlobal developmental delayExomeGenetics (clinical)GeneticsBrain DiseasesNeurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]Brainmedicine.disease030104 developmental biologyPhenotypeRenal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11]Autism spectrum disorderNeurodevelopmental DisordersSynaptopathyDLG4Postsynaptic densityDisks Large Homolog 4 Proteindescription
Contains fulltext : 245031.pdf (Publisher’s version ) (Closed access) 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-05-01 |