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Molecular Genetics of Autism and Intellectual Disability
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Molecular Genetics of Autism and Intellectual Disability

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (31 July 2022) | Viewed by 29961

Special Issue Editor

Dr. Hyung-Goo Kim

E-Mail Website
Guest Editor
1. Neurological Disorders Research Center, Qatar Biomedical Research Institute, Doha, Qatar
2. Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA
Interests: autism; intellectual disability; human molecular genetics; whole exome sequencing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The recent technological advances in high-throughput whole exome/genome sequencing, single cell sequencing, and array comparative genomic hybridization (CGH) have led to the discovery of novel microdeletion and microduplication syndromes and variants of unknown significance (VUS) in trio and consanguineous family studies.

Furthermore, whole exome sequencing of balanced chromosomal translocations and inversions will identify a large number of novel candidate genes at the breakpoints of carriers affected with these two disorders.

Although more than 654 autosomal dominant genes in intellectual disability or autism have been reported, including 310 candidate genes, the majority of disease genes are still waiting to be discovered.

This Special Issue welcomes insightful reviews and primary research articles that will cover these exciting topics and will provide a valuable update to the current knowledge of the genetic architecture of intellectual disability and autism to unravel the molecular underpinnings of cognitive dysfunction. 

Dr. Hyung Kim
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • autism
  • intellectual disability
  • whole exome sequencing
  • whole genome sequencing
  • microdeletion
  • microduplication
  • balanced translocation
  • balanced inversion
  • variant of unknown significance
  • candidate disease gene

Published Papers (7 papers)

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Editorial

Jump to: Research, Review

4 pages, 192 KiB  
Editorial
Editorial for the IJMS Special Issue on “Molecular Genetics of Autism and Intellectual Disability”
by Hyung-Goo Kim
Int. J. Mol. Sci. 2023, 24(12), 10394; https://doi.org/10.3390/ijms241210394 - 20 Jun 2023
Viewed by 874
Abstract
Autism spectrum disorder (ASD), a neurodevelopmental illness that affects children at an early age with a global prevalence of 1%, is diagnosed based on clinical features such as social impairment, repetitive behaviors, and restricted interests [...] Full article
(This article belongs to the Special Issue Molecular Genetics of Autism and Intellectual Disability)

Research

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14 pages, 1744 KiB  
Article
Characterization of Two Mouse Chd7 Heterozygous Loss-of-Function Models Shows Dysgenesis of the Corpus Callosum and Previously Unreported Features of CHARGE Syndrome
by Stephan C. Collins, Valerie E. Vancollie, Anna Mikhaleva, Christel Wagner, Rebecca Balz, Christopher J. Lelliott and Binnaz Yalcin
Int. J. Mol. Sci. 2022, 23(19), 11509; https://doi.org/10.3390/ijms231911509 - 29 Sep 2022
Cited by 2 | Viewed by 1647
Abstract
CHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 CHD7. Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the Chd7 gene engineered on inbred and outbred [...] Read more.
CHARGE syndrome is a rare congenital disorder frequently caused by mutations in the chromodomain helicase DNA-binding protein-7 CHD7. Here, we developed and systematically characterized two genetic mouse models with identical, heterozygous loss-of-function mutation of the Chd7 gene engineered on inbred and outbred genetic backgrounds. We found that both models showed consistent phenotypes with the core clinical manifestations seen in CHARGE syndrome, but the phenotypes in the inbred Chd7 model were more severe, sometimes having reduced penetrance and included dysgenesis of the corpus callosum, hypoplasia of the hippocampus, abnormal retrosplenial granular cortex, ventriculomegaly, hyperactivity, growth delays, impaired grip strength and repetitive behaviors. Interestingly, we also identified previously unreported features including reduced levels of basal insulin and reduced blood lipids. We suggest that the phenotypic variation reported in individuals diagnosed with CHARGE syndrome is likely due to the genetic background and modifiers. Finally, our study provides a valuable resource, making it possible for mouse biologists interested in Chd7 to make informed choices on which mouse model they should use to study phenotypes of interest and investigate in more depth the underlying cellular and molecular mechanisms. Full article
(This article belongs to the Special Issue Molecular Genetics of Autism and Intellectual Disability)
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11 pages, 1080 KiB  
Article
New Candidates for Autism/Intellectual Disability Identified by Whole-Exome Sequencing
by Lucia Pia Bruno, Gabriella Doddato, Floriana Valentino, Margherita Baldassarri, Rossella Tita, Chiara Fallerini, Mirella Bruttini, Caterina Lo Rizzo, Maria Antonietta Mencarelli, Francesca Mari, Anna Maria Pinto, Francesca Fava, Alessandra Fabbiani, Vittoria Lamacchia, Anna Carrer, Valentina Caputo, Stefania Granata, Elisa Benetti, Kristina Zguro, Simone Furini, Alessandra Renieri and Francesca Arianiadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2021, 22(24), 13439; https://doi.org/10.3390/ijms222413439 - 14 Dec 2021
Cited by 20 | Viewed by 4885
Abstract
Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised [...] Read more.
Intellectual disability (ID) is characterized by impairments in the cognitive processes and in the tasks of daily life. It encompasses a clinically and genetically heterogeneous group of neurodevelopmental disorders often associated with autism spectrum disorder (ASD). Social and communication abilities are strongly compromised in ASD. The prevalence of ID/ASD is 1–3%, and approximately 30% of the patients remain without a molecular diagnosis. Considering the extreme genetic locus heterogeneity, next-generation sequencing approaches have provided powerful tools for candidate gene identification. Molecular diagnosis is crucial to improve outcome, prevent complications, and hopefully start a therapeutic approach. Here, we performed parent–offspring trio whole-exome sequencing (WES) in a cohort of 60 mostly syndromic ID/ASD patients and we detected 8 pathogenic variants in genes already known to be associated with ID/ASD (SYNGAP1, SMAD6, PACS1, SHANK3, KMT2A, KCNQ2, ACTB, and POGZ). We found four de novo disruptive variants of four novel candidate ASD/ID genes: MBP, PCDHA1, PCDH15, PDPR. We additionally selected via bioinformatic tools many variants in unknown genes that alone or in combination can contribute to the phenotype. In conclusion, our data confirm the efficacy of WES in detecting pathogenic variants of known and novel ID/ASD genes. Full article
(This article belongs to the Special Issue Molecular Genetics of Autism and Intellectual Disability)
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20 pages, 4648 KiB  
Article
Alternative Promoter Use Governs the Expression of IgLON Cell Adhesion Molecules in Histogenetic Fields of the Embryonic Mouse Brain
by Toomas Jagomäe, Katyayani Singh, Mari-Anne Philips, Mohan Jayaram, Kadri Seppa, Triin Tekko, Scott F. Gilbert, Eero Vasar and Kersti Lilleväli
Int. J. Mol. Sci. 2021, 22(13), 6955; https://doi.org/10.3390/ijms22136955 - 28 Jun 2021
Cited by 5 | Viewed by 2872
Abstract
The members of the IgLON superfamily of cell adhesion molecules facilitate fundamental cellular communication during brain development, maintain functional brain circuitry, and are associated with several neuropsychiatric disorders such as depression, autism, schizophrenia, and intellectual disabilities. Usage of alternative promoter-specific 1a and 1b [...] Read more.
The members of the IgLON superfamily of cell adhesion molecules facilitate fundamental cellular communication during brain development, maintain functional brain circuitry, and are associated with several neuropsychiatric disorders such as depression, autism, schizophrenia, and intellectual disabilities. Usage of alternative promoter-specific 1a and 1b mRNA isoforms in Lsamp, Opcml, Ntm, and the single promoter of Negr1 in the mouse and human brain has been previously described. To determine the precise spatiotemporal expression dynamics of Lsamp, Opcml, Ntm isoforms, and Negr1, in the developing brain, we generated isoform-specific RNA probes and carried out in situ hybridization in the developing (embryonic, E10.5, E11.5, 13.5, 17; postnatal, P0) and adult mouse brains. We show that promoter-specific expression of IgLONs is established early during pallial development (at E10.5), where it remains throughout its differentiation through adulthood. In the diencephalon, midbrain, and hindbrain, strong expression patterns are initiated a few days later and begin fading after birth, being only faintly expressed during adulthood. Thus, the expression of specific IgLONs in the developing brain may provide the means for regionally specific functionality as well as for specific regional vulnerabilities. The current study will therefore improve the understanding of how IgLON genes are implicated in the development of neuropsychiatric disorders. Full article
(This article belongs to the Special Issue Molecular Genetics of Autism and Intellectual Disability)
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16 pages, 3271 KiB  
Article
Perinatal Exposure to Diesel Exhaust-Origin Secondary Organic Aerosol Induces Autism-Like Behavior in Rats
by Tin-Tin Win-Shwe, Chaw Kyi-Tha-Thu, Yuji Fujitani, Shinji Tsukahara and Seishiro Hirano
Int. J. Mol. Sci. 2021, 22(2), 538; https://doi.org/10.3390/ijms22020538 - 07 Jan 2021
Cited by 9 | Viewed by 2574
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication, poor social interactions, and repetitive behaviors. We aimed to examine autism-like behaviors and related gene expressions in rats exposed to diesel exhaust (DE)-origin secondary organic aerosol (DE-SOA) perinatally. Sprague–Dawley pregnant [...] Read more.
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social communication, poor social interactions, and repetitive behaviors. We aimed to examine autism-like behaviors and related gene expressions in rats exposed to diesel exhaust (DE)-origin secondary organic aerosol (DE-SOA) perinatally. Sprague–Dawley pregnant rats were exposed to clean air (control), DE, and DE-SOA in the exposure chamber from gestational day 14 to postnatal day 21. Behavioral phenotypes of ASD were investigated in 10~13-week-old offspring using a three-chambered social behavior test, social dominance tube test, and marble burying test. Prefrontal cortex was collected to examine molecular analyses including neurological and immunological markers and glutamate concentration, using RT-PCR and ELISA methods. DE-SOA-exposed male and female rats showed poor sociability and social novelty preference, socially dominant behavior, and increased repetitive behavior. Serotonin receptor (5-HT(5B)) and brain-derived neurotrophic factor (BDNF) mRNAs were downregulated whereas interleukin 1 β (IL-β) and heme oxygenase 1 (HO-1) mRNAs were upregulated in the prefrontal cortex of male and female rats exposed to DE-SOA. Glutamate concentration was also increased significantly in DE-SOA-exposed male and female rats. Our results indicate that perinatal exposure to DE-SOA may induce autism-like behavior by modulating molecules such as neurological and immunological markers in rats. Full article
(This article belongs to the Special Issue Molecular Genetics of Autism and Intellectual Disability)
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Review

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40 pages, 3811 KiB  
Review
Autism Spectrum Disorder: Neurodevelopmental Risk Factors, Biological Mechanism, and Precision Therapy
by Ling Wang, Binquan Wang, Chunyan Wu, Jie Wang and Mingkuan Sun
Int. J. Mol. Sci. 2023, 24(3), 1819; https://doi.org/10.3390/ijms24031819 - 17 Jan 2023
Cited by 27 | Viewed by 12805
Abstract
Autism spectrum disorder (ASD) is a heterogeneous, behaviorally defined neurodevelopmental disorder. Over the past two decades, the prevalence of autism spectrum disorders has progressively increased, however, no clear diagnostic markers and specifically targeted medications for autism have emerged. As a result, neurobehavioral abnormalities, [...] Read more.
Autism spectrum disorder (ASD) is a heterogeneous, behaviorally defined neurodevelopmental disorder. Over the past two decades, the prevalence of autism spectrum disorders has progressively increased, however, no clear diagnostic markers and specifically targeted medications for autism have emerged. As a result, neurobehavioral abnormalities, neurobiological alterations in ASD, and the development of novel ASD pharmacological therapy necessitate multidisciplinary collaboration. In this review, we discuss the development of multiple animal models of ASD to contribute to the disease mechanisms of ASD, as well as new studies from multiple disciplines to assess the behavioral pathology of ASD. In addition, we summarize and highlight the mechanistic advances regarding gene transcription, RNA and non-coding RNA translation, abnormal synaptic signaling pathways, epigenetic post-translational modifications, brain-gut axis, immune inflammation and neural loop abnormalities in autism to provide a theoretical basis for the next step of precision therapy. Furthermore, we review existing autism therapy tactics and limits and present challenges and opportunities for translating multidisciplinary knowledge of ASD into clinical practice. Full article
(This article belongs to the Special Issue Molecular Genetics of Autism and Intellectual Disability)
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27 pages, 927 KiB  
Review
Potential of Salivary Biomarkers in Autism Research: A Systematic Review
by Katarína Janšáková, Klaudia Kyselicová, Daniela Ostatníková and Gabriela Repiská
Int. J. Mol. Sci. 2021, 22(19), 10873; https://doi.org/10.3390/ijms221910873 - 08 Oct 2021
Cited by 7 | Viewed by 3238
Abstract
The diagnostic process for autism spectrum disorders (ASD) is based on a behavioral analysis of the suspected individual. Despite intensive research, no specific and valid biomarker has been identified for ASD, but saliva, with its advantages such as non-invasive collection, could serve as [...] Read more.
The diagnostic process for autism spectrum disorders (ASD) is based on a behavioral analysis of the suspected individual. Despite intensive research, no specific and valid biomarker has been identified for ASD, but saliva, with its advantages such as non-invasive collection, could serve as a suitable alternative to other body fluids. As a source of nucleic acid of both human and microbial origin, protein and non-protein molecules, saliva offers a complex view on the current state of the organism. Additionally, the use of salivary markers seems to be less complicated not only for ASD screening but also for revealing the etiopathogenesis of ASD, since enrolling neurotypical counterparts willing to participate in studies may be more feasible. The aim of the presented review is to provide an overview of the current research performed on saliva in relation to ASD, mutual complementing, and discrepancies that result in difficulties applying the observed markers in clinical practice. We emphasize the methodological limitations of saliva collection and processing as well as the lack of information regarding ASD diagnosis, which is critically discussed. Full article
(This article belongs to the Special Issue Molecular Genetics of Autism and Intellectual Disability)
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