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
Abstract
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
Abstract
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
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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