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Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features

Abstract : Marfanoid habitus (MH) combined with intellectual disability (ID) is a genetically and clinically heterogeneous group of overlapping disorders. We performed exome sequencing in 33 trios and 31 single probands to identify novel genes specific to MH-ID. After the search for variants in known disease-causing genes and non-disease-causing genes with classical approaches, we searched for variants in non-disease-causing genes whose pLI was above 0.9 (ExAC Consortium data), in which truncating variants were found in at least 3 unrelated patients. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes post-synaptic density protein 95 (PSD-95), a protein expressed in various tissues, including the brain. In neurons, PSD-95 is located at the post-synaptic density, and is associated with glutamatergic receptor signaling (NMDA and AMPA). PSD-95 probably participates in dendritogenesis. Two patients were heterozygous for de novo frameshift variants and one patient carried a a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients exhibited mild-to-moderate ID, similar marfanoid features, including a long face, high-arched palate, long and thin fingers, pectus excavatum, scoliosis and ophthalmological manifestations (nystagmus or strabismus). Our study emphasizes the role of DLG4 as a novel post-synaptic-associated gene involved in syndromic ID associated with MH.
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Contributeur : LNC - université de Bourgogne Connectez-vous pour contacter le contributeur
Soumis le : jeudi 27 septembre 2018 - 10:47:01
Dernière modification le : jeudi 4 août 2022 - 17:21:00



S. Moutton, A.-L. Bruel, M. Assoum, E. Sarrazin, M. Chevarin, et al.. Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features. Clinical Genetics, Wiley, 2018, 93 (6), pp.1172 - 1178. ⟨10.1111/cge.13243⟩. ⟨hal-01882559⟩



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