Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features.
Sebastien MouttonAnge-Line BruelM AssoumM ChevarinE SarrazinC GoizetA-M GuerrotA CharollaisP CharlesD HeronA FaudetN HoucinatA VitobelloF Tran-Mau-ThemC PhilippeY DuffourdC Thauvin-RobinetL FaivrePublished in: Clinical genetics (2018)
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.
Keyphrases
- intellectual disability
- copy number
- end stage renal disease
- genome wide
- gene expression
- newly diagnosed
- ejection fraction
- chronic kidney disease
- autism spectrum disorder
- genome wide identification
- prognostic factors
- peritoneal dialysis
- dna methylation
- multiple sclerosis
- patient reported outcomes
- spinal cord
- escherichia coli
- pseudomonas aeruginosa
- spinal cord injury
- early onset
- functional connectivity
- resting state
- cystic fibrosis
- clinical practice
- transcription factor
- small molecule
- binding protein