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

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.

Sixty-four probands presenting with at least intellectual disability with marfanoid habitus were analyzed by whole exome sequencing, 33 in a trio and 31 in a solo strategy in order to provide appropriate management, genetic counseling and to study diagnosis yield in this phenotype. After analyzing the data using classical approaches allowing to reach a molecular diagnosis in 53.2% of cases, a bioinformatic filtration procedure was applied on the cohort, consisting of searching 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. This strategy allowed to highlight DLG4 as a novel disease-causing gene responsible for intellectual disability and probably marfanoid features. mRNA studies on the blood of the 3 patients showed decreased gene expression in two patients and aberrant splicing leading to a premature stop codon in one patient confirming the likely pathogenic effect of the variants. DLG4 gene represent a good candidate gene as its PSD-95 protein product is localized at the post-synaptic density, is associated with glutamatergic receptor signaling and participates in dendritogenesis. Several mouse models support the pathogenicity of DLG4 expression deficiency.

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