Friday, June 26, 2020

DLG4 neurodevelopmental disorder

Inspired by a colleague's patient

Xi XJ, Tang JH, Zhang BB, et al. Dlg4 and Vamp2 are involved in comorbid epilepsy and attention-deficit hyperactivity disorder: A microarray data study [published online ahead of print, 2020 Jun 21]. Epilepsy Behav. 2020;110:107192. doi:10.1016/j.yebeh.2020.107192

Objective: Children with epilepsy exhibit a significantly higher risk for attention-deficit hyperactivity disorder (ADHD), which is often associated with lower quality of life. In this study, we aimed to identify molecular mechanisms associated with both epilepsy and ADHD.

Materials and methods: Gene expression profiles of GSE12457 and GSE47752 were downloaded from the gene expression omnibus (GEO) database. Differentially expressed genes (DEGs) were separately screened in epilepsy and ADHD samples and compared with controls. Weighted gene coexpression network analysis (WGCNA) was used to identify candidate modules associated with the two disorders. Functional annotation and analysis of hub genes and molecular complex detection (MCODE) was also performed.

Results: Three modules closely related to epilepsy and ADHD were screened using WGCNA; DEGs in this module were involved in the synaptic vesicle cycle, axon and neuron regeneration, and neurotransmission. The Dlg4 and Vamp2 genes were selected as common candidate factors in epilepsy and ADHD pathogenesis.

Conclusion: Dlg4 and Vamp2 could play essential roles in comorbidity between epilepsy and ADHD.

Chevarin M, Duffourd Y, A Barnard R, et al. Excess of de novo variants in genes involved in chromatin remodelling in patients with marfanoid habitus and intellectual disability. J Med Genet. 2020;57(7):466-474. doi:10.1136/jmedgenet-2019-106425

Purpose: Marfanoid habitus (MH) combined with intellectual disability (ID) (MHID) is a clinically and genetically heterogeneous presentation. The combination of array CGH and targeted sequencing of genes responsible for Marfan or Lujan-Fryns syndrome explain no more than 20% of subjects.

Methods: To further decipher the genetic basis of MHID, we performed exome sequencing on a combination of trio-based (33 subjects) or single probands (31 subjects), of which 61 were sporadic.

Results: We identified eight genes with de novo variants (DNVs) in at least two unrelated individuals (ARID1B, ATP1A1, DLG4, EHMT1, NFIX, NSD1, NUP205 and ZEB2). Using simulation models, we showed that five genes (DLG4, NFIX, EHMT1, ZEB2 and ATP1A1) met conservative Bonferroni genomewide significance for an excess of the observed de novo point variants. Overall, at least one pathogenic or likely pathogenic variant was identified in 54.7% of subjects (35/64). These variants fell within 27 genes previously associated with Mendelian disorders, including NSD1 and NFIX, which are known to be mutated in overgrowth syndromes.

Conclusion: We demonstrated that DNVs were enriched in chromatin remodelling (p=2×10-4) and genes regulated by the fragile X mental retardation protein (p=3×10-8), highlighting overlapping genetic mechanisms between MHID and related neurodevelopmental disorders.

Moutton S, Bruel AL, Assoum M, et al. Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features. Clin Genet. 2018;93(6):1172-1178. doi:10.1111/cge.13243

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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