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

Clin Genet. 2018 Feb 20;:

Authors: Sébastien M, Ange-Line B, Mirna A, Martin C, Elisabeth S, Cyril G, Anne-Marie G, Aude C, Perrine C, Delphine H, Anne F, Nada H, Antonio V, Frédéric TM, Christophe P, Yannis D, Christel TR, Laurence F

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 OMIM genes and non-OMIM 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, in order to identity novel MH-ID genes. Only DLG4 gene met these criteria. Data from the literature and various databases also indicated its implication in ID. DLG4 encodes PSD-95, a protein expressed in various tissues including the brain. In neurons, PSD-95 is localized 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 for a consensus splice site variant. Gene expression studies supported their pathogenicity through haploinsufficiency and loss-of-function. Patients showed 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.

PMID: 29460436 [PubMed – as supplied by publisher]

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