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The Genetic and Epigenetic Basis of Neurodevelopmental Disorders
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The Genetic and Epigenetic Basis of Neurodevelopmental Disorders

A special issue of Genes (ISSN 2073-4425). This special issue belongs to the section "Human Genomics and Genetic Diseases".

Deadline for manuscript submissions: closed (20 December 2024) | Viewed by 6054

Special Issue Editor

Prof. Dr. Zhaolan (Joe) Zhou

E-Mail Website
Guest Editor
Department of Genetics, University of Pennsylvania, Philadelphia, PA, USA
Interests: neuroepigenetics in brain development and disease

Special Issue Information

Dear Colleagues,

Next-generation sequencing technologies have revolutionized gene discovery for a variety of medical conditions, including a group of disorders affecting brain development and function known as neurodevelopmental disorders (NDDs). Despite the common phenotypic heterogeneity present in NDDs, the identification of genetic causes has significantly improved the assessment of recurrent risks and the foreseeing of future medical complications, which has important ramifications for genetic counseling and patient management. Modeling the genetic causes of NDDs in mice and other model organisms has also enhanced the understanding of disease pathophysiology and uncovered new strategies for therapeutic development. To date, hundreds of genes and genomic regions have been implicated in NDDs. Notably, many of these genes are involved in the regulation of DNA methylation, histone modifications, non-coding RNAs, and three-dimensional chromatin organization. The involvement of these fundamental epigenetic processes has not only opened new avenues but also stimulated a community effort to investigate the pathophysiology underlying NDDs through the lens of neuroepigenetics.

In this Special Issue, we solicit original studies and review articles that focus on the genetic and epigenetic basis of NDDs with the aim of better understanding the interplay between genetics, epigenetics, and neurodevelopment. The goal is to reveal new insights into the underlying pathogenic mechanisms and pave the way for potential therapeutic interventions that target and modulate the epigenetic processes to mitigate or reverse clinical symptoms in NDDs.

Prof. Dr. Zhaolan (Joe) Zhou
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Genes is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neurodevelopmental disorders
  • neural development
  • epigenetics
  • DNA methylation
  • histone methylation
  • histone acetylation
  • non-coding RNAs
  • chromatin organization
  • therapeutics

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Published Papers (4 papers)

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Research

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21 pages, 13634 KiB  
Article
Neuronal Network Activation Induced by Forniceal Deep Brain Stimulation in Mice
by Bin Tang, Zhenyu Wu, Qi Wang and Jianrong Tang
Genes 2025, 16(2), 210; https://doi.org/10.3390/genes16020210 - 9 Feb 2025
Viewed by 1417
Abstract
Background: The fimbria-fornix is a nerve fiber bundle that connects various structures of the limbic system in the brain and plays a key role in cognition. It has become a major target of deep brain stimulation (DBS) to treat memory impairment in both [...] Read more.
Background: The fimbria-fornix is a nerve fiber bundle that connects various structures of the limbic system in the brain and plays a key role in cognition. It has become a major target of deep brain stimulation (DBS) to treat memory impairment in both dementia patients and animal models of neurological diseases. Previously, we have reported the beneficial memory effects of chronic forniceal DBS in mouse models of intellectual disability disorders. In Rett syndrome and CDKL5 deficiency disorder models, DBS strengthens hippocampal synaptic plasticity, reduces dentate inhibitory transmission or increases adult hippocampal neurogenesis that aids memory. However, the underlying neuronal circuitry mechanisms remain unknown. This study we explored the neural network circuits involved in forniceal DBS treatment. Methods: We used acute forniceal DBS-induced expression of c-Fos, an activity-dependent neuronal marker, to map the brain structures functionally connected to the fornix. We also evaluated the mouse behavior of locomotion, anxiety, and fear memory after acute forniceal DBS treatment. Results: Acute forniceal DBS induces robust activation of multiple structures in the limbic system. DBS-induced neuronal activation extends beyond hippocampal formation and includes brain structures not directly innervated by the fornix. Conclusions: Acute forniceal DBS activates multiple limbic structures associated with emotion and memory. The neural circuits revealed here help elucidate the neural network effect and pave the way for further research on the mechanism by which forniceal DBS induces benefits on cognitive impairments. Full article
(This article belongs to the Special Issue The Genetic and Epigenetic Basis of Neurodevelopmental Disorders)
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9 pages, 3855 KiB  
Article
16q24.3 Microdeletions Disrupting Upstream Non-Coding Region of ANKRD11 Cause KBG Syndrome
by Aiko Iwata-Otsubo, Alyssa L. Rippert, Jorune Balciuniene, Sarah K. Fiordaliso, Robert Chen, Preetha Markose, Cara M. Skraban, Christopher Gray, Elaine H. Zackai, Holly A Dubbs, Matthew A. Deardorff, Laura K. Conlin and Kosuke Izumi
Genes 2025, 16(2), 136; https://doi.org/10.3390/genes16020136 - 24 Jan 2025
Viewed by 981
Abstract
Background: KBG syndrome is a multisystem developmental disorder characterized by macrodontia of the upper permanent incisors, distinctive facial features, a short stature, developmental delay, variable intellectual disability, and behavioral issues. Heterozygous chromosomal deletion encompassing the partial or entire ANKRD11 gene, as well as [...] Read more.
Background: KBG syndrome is a multisystem developmental disorder characterized by macrodontia of the upper permanent incisors, distinctive facial features, a short stature, developmental delay, variable intellectual disability, and behavioral issues. Heterozygous chromosomal deletion encompassing the partial or entire ANKRD11 gene, as well as the loss of function mutations, result in haploinsufficiency of the gene, leading to KBG syndrome. This indicates that precise levels of ANKRD11 transcripts or protein are essential for human development. Clinical report: Here, we report three individuals who present with clinical features of KBG syndrome. These individuals carry microdeletions encompassing only the non-coding exon 1 of ANKRD11 and its upstream region. Our molecular analysis showed that this deletion leads to reduction in the ANKRD11 transcript and global transcriptome alterations similar to those seen in KBG syndrome patients. Conclusions: We concluded that microdeletions involving non-coding exon 1 of ANKRD11 lead to KBG syndrome. Our study suggests the utility of transcriptome analysis in aiding the interpretation of novel copy number variants in the non-coding genomic region of ANKRD11. Full article
(This article belongs to the Special Issue The Genetic and Epigenetic Basis of Neurodevelopmental Disorders)
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15 pages, 3634 KiB  
Article
Chemogenetic Inhibition of Prefrontal Cortex Ameliorates Autism-Like Social Deficits and Absence-Like Seizures in a Gene-Trap Ash1l Haploinsufficiency Mouse Model
by Kaijie Ma, Kylee McDaniel, Daoqi Zhang, Maria Webb and Luye Qin
Genes 2024, 15(12), 1619; https://doi.org/10.3390/genes15121619 - 18 Dec 2024
Viewed by 899
Abstract
Background: ASH1L (absent, small, or homeotic-like 1), a histone methyltransferase, has been identified as a high-risk gene for autism spectrum disorder (ASD). We previously showed that postnatal Ash1l severe deficiency in the prefrontal cortex (PFC) of male and female mice caused seizures. However, [...] Read more.
Background: ASH1L (absent, small, or homeotic-like 1), a histone methyltransferase, has been identified as a high-risk gene for autism spectrum disorder (ASD). We previously showed that postnatal Ash1l severe deficiency in the prefrontal cortex (PFC) of male and female mice caused seizures. However, the synaptic mechanisms underlying autism-like social deficits and seizures need to be elucidated. Objective: The goal of this study is to characterize the behavioral deficits and reveal the synaptic mechanisms in an Ash1l haploinsufficiency mouse model using a targeted gene-trap knockout (gtKO) strategy. Method: A series of behavioral tests were used to examine behavioral deficits. Electrophysiological and chemogenetic approaches were used to examine and manipulate the excitability of pyramidal neurons in the PFC of Ash1l+/GT mice. Results: Ash1l+/GT mice displayed social deficits, increased self-grooming, and cognitive impairments. Epileptiform discharges were found on electroencephalograms (EEGs) of Ash1l+/GT mice, indicating absence-like seizures. Ash1l haploinsufficiency increased the susceptibility for convulsive seizures when Ash1l+/GT mice were challenged by pentylenetetrazole (PTZ, a competitive GABAA receptor antagonist). Whole-cell patch-clamp recordings showed that Ash1l haploinsufficiency increased the excitability of pyramidal neurons in the PFC by altering intrinsic neuronal properties, enhancing glutamatergic synaptic transmission, and diminishing GABAergic synaptic inhibition. Chemogenetic inhibition of pyramidal neurons in the PFC of Ash1l+/GT mice ameliorated autism-like social deficits and abolished absence-like seizures. Conclusions: We demonstrated that increased neural activity in the PFC contributed to the autism-like social deficits and absence-like seizures in Ash1l+/GT mice, which provides novel insights into the therapeutic strategies for patients with ASH1L-associated ASD and epilepsy. Full article
(This article belongs to the Special Issue The Genetic and Epigenetic Basis of Neurodevelopmental Disorders)
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Review

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25 pages, 779 KiB  
Review
Epigenetic Regulation and Neurodevelopmental Disorders: From MeCP2 to the TCF20/PHF14 Complex
by Gaea Dominguez, Yongji Wu and Jian Zhou
Genes 2024, 15(12), 1653; https://doi.org/10.3390/genes15121653 - 23 Dec 2024
Cited by 1 | Viewed by 1876
Abstract
Background: Neurodevelopmental disorders (NDDs) affect approximately 15% of children and adolescents worldwide. This group of disorders is often polygenic with varying risk factors, with many associated genes converging on shared molecular pathways, including chromatin regulation and transcriptional control. Understanding how NDD-associated chromatin regulators [...] Read more.
Background: Neurodevelopmental disorders (NDDs) affect approximately 15% of children and adolescents worldwide. This group of disorders is often polygenic with varying risk factors, with many associated genes converging on shared molecular pathways, including chromatin regulation and transcriptional control. Understanding how NDD-associated chromatin regulators and protein complexes orchestrate these regulatory pathways is crucial for elucidating NDD pathogenesis and developing targeted therapeutic strategies. Recently, the TCF20/PHF14 chromatin complex was identified in the mammalian brain, expanding the list of chromatin regulatory remodelers implicated in NDDs. This complex—which includes MeCP2, RAI1, TCF20, PHF14, and HMG20A—plays a vital role in epigenetic and transcriptional regulation. Methods: We review and summarize current research and clinical reports pertaining to the different components of the MeCP2-interacting TCF20/PHF14 complex. We examine the NDDs associated with the TCF20/PHF14 complex, explore the molecular and neuronal functions of its components, and discuss emerging therapeutic strategies targeting this complex to mitigate symptoms, with broader applicability to other NDDs. Results: Mutations in the genes encoding the components of the MeCP2-interacting TCF20/PHF14 complex have been linked to various NDDs, underscoring its critical contribution to brain development and NDD pathogenesis. Conclusions: The MeCP2-interacting TCF20/PHF14 complex and its associated NDDs could serve as a model system to provide insight into the interplay between epigenetic regulation and NDD pathogenesis. Full article
(This article belongs to the Special Issue The Genetic and Epigenetic Basis of Neurodevelopmental Disorders)
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