Molecular Mechanisms in Neurodevelopmental Disorders

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

Deadline for manuscript submissions: closed (20 February 2023) | Viewed by 9554

Special Issue Editor


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Guest Editor
Biochemistry and Molecular Genetics Department, Hospital Clínic of Barcelona, 08028 Barcelona, Spain
Interests: genetics of rare diseases; next-generation sequencing; cell-free fetal DNA; intellectual disability; neurodevelopmental diseases
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Special Issue Information

Dear Colleagues,

Around 80% of rare diseases have a genetic cause; nevertheless, limitations in diagnostic methods leave more than 30% of cases undiagnosed. Neurodevelopmental disorders (NDDs) are a group of rare diseases that result from abnormal brain development that may give rise to impaired cognition, communication, adaptive behavior, and psychomotor skills. Genetic and epigenetic/environmental factors play a key role in these NDDs, with significant societal impact. Today, multiple studies and research projects are being carried out worldwide on the implications of genetic aspects in the development of neurodevelopmental disorders. Successful implementation of genomic medicine hinges on accurate, evidence-based interpretation of genetic data to ensure both appropriate clinical management and care.

Original research and review papers dealing with all aspects of “Molecular Mechanisms in Neurodevelopmental Disorders” are welcome for inclusion in this Special issue of Genes.

The Special Issue "Molecular Mechanisms in Neurodevelopmental Disorders" welcomes a variety of research papers including new insights into the genetic and/or epigenetic mechanism of neurodevelopmental disorders, reviews of genotype–phenotype correlation, and any other molecular mechanism that can lead to neurodevelopmental disorders.

Dr. Irene Madrigal
Guest Editor

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Keywords

  • neurodevelopmental disorders
  • genetic variants
  • omic technologies

Published Papers (6 papers)

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Editorial

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3 pages, 182 KiB  
Editorial
Editorial for the Molecular Mechanisms in Neurodevelopmental Disorders Special Issue
by Irene Madrigal
Genes 2023, 14(9), 1762; https://doi.org/10.3390/genes14091762 - 04 Sep 2023
Viewed by 533
Abstract
Neurodevelopmental disorders are a group of neurological disorders that may give rise to delayed or impaired cognition, communication, adaptive behavior, and psychomotor skills [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms in Neurodevelopmental Disorders)

Research

Jump to: Editorial

15 pages, 1160 KiB  
Article
Genes Participating in the Ensheathment of Neurons Are Affected by Postnatal Stress and Maternal Immune Activation in the Pituitary Gland
by Samah Alsegehy, Bruce R. Southey, Laurie Rund, Rodney W. Johnson and Sandra L. Rodriguez-Zas
Genes 2023, 14(5), 1007; https://doi.org/10.3390/genes14051007 - 28 Apr 2023
Cited by 3 | Viewed by 1169
Abstract
Immune challenges during gestation are associated with neurodevelopmental disorders and can interact with stress later in life. The pituitary gland participates in endocrine- and immune-related processes that influence development, growth, and reproduction and can modulate physiological and behavioral responses to challenges. The objective [...] Read more.
Immune challenges during gestation are associated with neurodevelopmental disorders and can interact with stress later in life. The pituitary gland participates in endocrine- and immune-related processes that influence development, growth, and reproduction and can modulate physiological and behavioral responses to challenges. The objective of this study was to investigate the effect of stressors at different time points on the molecular mechanisms of the pituitary gland and detect sex differences. RNA sequencing was used to profile the pituitary glands of female and male pigs exposed to weaning stress and virally induced maternal immune activation (MIA), relative to unchallenged groups. Significant effects (FDR-adjusted p-value < 0.05) of MIA and weaning stress were detected in 1829 and 1014 genes, respectively. Of these, 1090 genes presented significant interactions between stressors and sex. The gene ontology biological process of the ensheathment of neurons (GO:0007272), substance abuse, and immuno-related pathways, including the measles disease (ssc05162), encompasses many genes with profiles impacted by MIA and weaning stress. A gene network analysis highlighted the under-expression of myelin protein zero (Mpz) and inhibitors of DNA binding 4 (Id4) among the non-stressed males exposed to MIA, relative to the control and non-MIA males exposed to weaning stress, relative to non-stressed pigs. The detection of changes in the molecular mechanisms of the pituitary gland could advance our understanding of disruptions in the formation of the myelin sheath and the transmission of neuron-to-neuron signals in behavioral disorders associated with maternal immune activation and stress. Full article
(This article belongs to the Special Issue Molecular Mechanisms in Neurodevelopmental Disorders)
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11 pages, 596 KiB  
Article
Implementation of Exome Sequencing in Clinical Practice for Neurological Disorders
by María Isabel Alvarez-Mora, Laia Rodríguez-Revenga, Meritxell Jodar, Miriam Potrony, Aurora Sanchez, Celia Badenas, Josep Oriola, José Luis Villanueva-Cañas, Esteban Muñoz, Francesc Valldeoriola, Ana Cámara, Yaroslau Compta, Mar Carreño, María Jose Martí, Raquel Sánchez-Valle and Irene Madrigal
Genes 2023, 14(4), 813; https://doi.org/10.3390/genes14040813 - 28 Mar 2023
Cited by 2 | Viewed by 1768
Abstract
Neurological disorders (ND) are diseases that affect the brain and the central and autonomic nervous systems, such as neurodevelopmental disorders, cerebellar ataxias, Parkinson’s disease, or epilepsies. Nowadays, recommendations of the American College of Medical Genetics and Genomics strongly recommend applying next generation sequencing [...] Read more.
Neurological disorders (ND) are diseases that affect the brain and the central and autonomic nervous systems, such as neurodevelopmental disorders, cerebellar ataxias, Parkinson’s disease, or epilepsies. Nowadays, recommendations of the American College of Medical Genetics and Genomics strongly recommend applying next generation sequencing (NGS) as a first-line test in patients with these disorders. Whole exome sequencing (WES) is widely regarded as the current technology of choice for diagnosing monogenic ND. The introduction of NGS allows for rapid and inexpensive large-scale genomic analysis and has led to enormous progress in deciphering monogenic forms of various genetic diseases. The simultaneous analysis of several potentially mutated genes improves the diagnostic process, making it faster and more efficient. The main aim of this report is to discuss the impact and advantages of the implementation of WES into the clinical diagnosis and management of ND. Therefore, we have performed a retrospective evaluation of WES application in 209 cases referred to the Department of Biochemistry and Molecular Genetics of the Hospital Clinic of Barcelona for WES sequencing derived from neurologists or clinical geneticists. In addition, we have further discussed some important facts regarding classification criteria for pathogenicity of rare variants, variants of unknown significance, deleterious variants, different clinical phenotypes, or frequency of actionable secondary findings. Different studies have shown that WES implementation establish diagnostic rate around 32% in ND and the continuous molecular diagnosis is essential to solve the remaining cases. Full article
(This article belongs to the Special Issue Molecular Mechanisms in Neurodevelopmental Disorders)
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13 pages, 876 KiB  
Article
High Performance of a Dominant/X-Linked Gene Panel in Patients with Neurodevelopmental Disorders
by Nino Spataro, Juan Pablo Trujillo-Quintero, Carmen Manso, Elisabeth Gabau, Nuria Capdevila, Victor Martinez-Glez, Antoni Berenguer-Llergo, Sara Reyes, Anna Brunet, Neus Baena, Miriam Guitart and Anna Ruiz
Genes 2023, 14(3), 708; https://doi.org/10.3390/genes14030708 - 13 Mar 2023
Cited by 3 | Viewed by 1618
Abstract
Neurodevelopmental disorders (NDDs) affect 2–5% of the population and approximately 50% of cases are due to genetic factors. Since de novo pathogenic variants account for the majority of cases, a gene panel including 460 dominant and X-linked genes was designed and applied to [...] Read more.
Neurodevelopmental disorders (NDDs) affect 2–5% of the population and approximately 50% of cases are due to genetic factors. Since de novo pathogenic variants account for the majority of cases, a gene panel including 460 dominant and X-linked genes was designed and applied to 398 patients affected by intellectual disability (ID)/global developmental delay (GDD) and/or autism (ASD). Pathogenic variants were identified in 83 different genes showing the high genetic heterogeneity of NDDs. A molecular diagnosis was established in 28.6% of patients after high-depth sequencing and stringent variant filtering. Compared to other available gene panel solutions for NDD molecular diagnosis, our panel has a higher diagnostic yield for both ID/GDD and ASD. As reported previously, a significantly higher diagnostic yield was observed: (i) in patients affected by ID/GDD compared to those affected only by ASD, and (ii) in females despite the higher proportion of males among our patients. No differences in diagnostic rates were found between patients affected by different levels of ID severity. Interestingly, patients harboring pathogenic variants presented different phenotypic features, suggesting that deep phenotypic profiling may help in predicting the presence of a pathogenic variant. Despite the high performance of our panel, whole exome-sequencing (WES) approaches may represent a more robust solution. For this reason, we propose the list of genes included in our customized gene panel and the variant filtering procedure presented here as a first-tier approach for the molecular diagnosis of NDDs in WES studies. Full article
(This article belongs to the Special Issue Molecular Mechanisms in Neurodevelopmental Disorders)
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26 pages, 4039 KiB  
Article
Zeb2 DNA-Binding Sites in Neuroprogenitor Cells Reveal Autoregulation and Affirm Neurodevelopmental Defects, Including in Mowat-Wilson Syndrome
by Judith C. Birkhoff, Anne L. Korporaal, Rutger W. W. Brouwer, Karol Nowosad, Claudia Milazzo, Lidia Mouratidou, Mirjam C. G. N. van den Hout, Wilfred F. J. van IJcken, Danny Huylebroeck and Andrea Conidi
Genes 2023, 14(3), 629; https://doi.org/10.3390/genes14030629 - 02 Mar 2023
Cited by 3 | Viewed by 1807
Abstract
Functional perturbation and action mechanism studies have shown that the transcription factor Zeb2 controls cell fate decisions, differentiation, and/or maturation in multiple cell lineages in embryos and after birth. In cultured embryonic stem cells (ESCs), Zeb2’s mRNA/protein upregulation is necessary for the exit [...] Read more.
Functional perturbation and action mechanism studies have shown that the transcription factor Zeb2 controls cell fate decisions, differentiation, and/or maturation in multiple cell lineages in embryos and after birth. In cultured embryonic stem cells (ESCs), Zeb2’s mRNA/protein upregulation is necessary for the exit from primed pluripotency and for entering general and neural differentiation. We edited mouse ESCs to produce Flag-V5 epitope-tagged Zeb2 protein from one endogenous allele. Using chromatin immunoprecipitation coupled with sequencing (ChIP-seq), we mapped 2432 DNA-binding sites for this tagged Zeb2 in ESC-derived neuroprogenitor cells (NPCs). A new, major binding site maps promoter-proximal to Zeb2 itself. The homozygous deletion of this site demonstrates that autoregulation of Zeb2 is necessary to elicit the appropriate Zeb2-dependent effects in ESC-to-NPC differentiation. We have also cross-referenced all the mapped Zeb2 binding sites with previously obtained transcriptome data from Zeb2 perturbations in ESC-derived NPCs, GABAergic interneurons from the ventral forebrain of mouse embryos, and stem/progenitor cells from the post-natal ventricular-subventricular zone (V-SVZ) in mouse forebrain, respectively. Despite the different characteristics of each of these neurogenic systems, we found interesting target gene overlaps. In addition, our study also contributes to explaining developmental disorders, including Mowat-Wilson syndrome caused by ZEB2 deficiency, and also other monogenic syndromes. Full article
(This article belongs to the Special Issue Molecular Mechanisms in Neurodevelopmental Disorders)
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23 pages, 2314 KiB  
Article
Haploinsufficiency as a Foreground Pathomechanism of Poirer-Bienvenu Syndrome and Novel Insights Underlying the Phenotypic Continuum of CSNK2B-Associated Disorders
by Mariateresa Di Stazio, Caterina Zanus, Flavio Faletra, Alessia Pesaresi, Ilaria Ziccardi, Anna Morgan, Giorgia Girotto, Paola Costa, Marco Carrozzi, Adamo P. d’Adamo and Luciana Musante
Genes 2023, 14(2), 250; https://doi.org/10.3390/genes14020250 - 18 Jan 2023
Cited by 2 | Viewed by 1793
Abstract
CSNK2B encodes for the regulatory subunit of the casein kinase II, a serine/threonine kinase that is highly expressed in the brain and implicated in development, neuritogenesis, synaptic transmission and plasticity. De novo variants in this gene have been identified as the cause of [...] Read more.
CSNK2B encodes for the regulatory subunit of the casein kinase II, a serine/threonine kinase that is highly expressed in the brain and implicated in development, neuritogenesis, synaptic transmission and plasticity. De novo variants in this gene have been identified as the cause of the Poirier-Bienvenu Neurodevelopmental Syndrome (POBINDS) characterized by seizures and variably impaired intellectual development. More than sixty mutations have been described so far. However, data clarifying their functional impact and the possible pathomechanism are still scarce. Recently, a subset of CSNK2B missense variants affecting the Asp32 in the KEN box-like domain were proposed as the cause of a new intellectual disability-craniodigital syndrome (IDCS). In this study, we combined predictive functional and structural analysis and in vitro experiments to investigate the effect of two CSNK2B mutations, p.Leu39Arg and p.Met132LeufsTer110, identified by WES in two children with POBINDS. Our data prove that loss of the CK2beta protein, due to the instability of mutant CSNK2B mRNA and protein, resulting in a reduced amount of CK2 complex and affecting its kinase activity, may underlie the POBINDS phenotype. In addition, the deep reverse phenotyping of the patient carrying p.Leu39Arg, with an analysis of the available literature for individuals with either POBINDS or IDCS and a mutation in the KEN box-like motif, might suggest the existence of a continuous spectrum of CSNK2B-associated phenotypes rather than a sharp distinction between them. Full article
(This article belongs to the Special Issue Molecular Mechanisms in Neurodevelopmental Disorders)
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