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From Genes to Therapy in Autism Spectrum Disorder
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From Genes to Therapy in Autism Spectrum Disorder

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 June 2021) | Viewed by 38214

Special Issue Editors

Prof. Dr. Christine M. Freitag

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Guest Editor
Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe University, 60323 Frankfurt am Main, Germany
Interests: autism spectrum disorder; attention-deficit/hyperactivity disorder; conduct disorder; genetics; neurobiology; intervention
Dr. Jacob A. S. Vorstman

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Guest Editor
Department of Psychiatry, the Hospital for Sick Children, Toronto, ON, Canada
Interests: genetic architecture of neurodevelopmental disorders
Prof. Dr. Antonio Persico

E-Mail Website
Guest Editor
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
Interests: autism; ADHD; intellectual disability; Phelan-McDermid syndrome; child psychiatry; neurogenetics; neurodevelopment; psychopharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with onset in early childhood. While highly heterogeneous, its core manifestations always include persistent difficulties in social interaction and communication, as well as a pattern of restricted interests and/or repetitive behaviors. In addition, psychiatric comorbidity is frequent and genetic risk overlaps with some other mental and neurodevelopmental disorders. This condition in most cases persists over the lifespan, with high social, educational, and health care costs.

Current psychopharmacological treatment can improve many comorbid symptoms, but not core autism symptom domains, which have a dramatic impact on the quality of life of patients and their families. A better understanding of the pathophysiological mechanisms underlying these symptoms is a crucial first step towards the development of such treatments. Over the past decade or so, it has become increasingly clear that ASD is highly heterogeneous, both at the phenotypic level (symptoms, co-morbidity, adaptive behavior, cognition, and trajectory) and at the level of etiology (genotype, environmental factors, neurobiological mechanisms). This heterogeneity poses a formidable challenge to those working to discover pharmacological treatments for the condition.

This challenge is at the heart of this Special Issue. Here, we aim to collect a set of contributions providing state-of-the-art coverage ranging from the theoretical framework linking genetics to human behavior and therapy, to initial practical examples of how genetics can provide valuable insights into the personalized clinical management of individuals with autism. In addition to the role of “autism genes”, special attention will be devoted to function-specific “gene networks”, to what they can tell us about the neurobiological processes underlying ASD, and how this information can in turn generate psychopharmacological predictions, testable using ethical and clinically reliable approaches.

Prof. Christine M. Freitag
Dr. Jacob A. S. Vorstman
Prof. Antonio Persico
Guest Editors

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

  • autism spectrum disorder
  • copy number variation
  • single gene
  • gene network
  • gene ontology
  • mutation
  • neurobiology
  • pharmacologic therapy

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review, Other

8 pages, 230 KiB  
Editorial
From Genes to Therapy in Autism Spectrum Disorder
by Jacob A. S. Vorstman, Christine M. Freitag and Antonio M. Persico
Genes 2022, 13(8), 1377; https://doi.org/10.3390/genes13081377 - 1 Aug 2022
Cited by 3 | Viewed by 2310
Abstract
In recent years, findings from genetic and other biological studies are starting to reveal the role of various molecular mechanisms that contribute to the etiology of ASD [...] Full article
(This article belongs to the Special Issue From Genes to Therapy in Autism Spectrum Disorder)
5 pages, 209 KiB  
Editorial
Developing Gene-Based Personalised Interventions in Autism Spectrum Disorders
by Christine M. Freitag, Antonio M. Persico and Jacob A. S. Vorstman
Genes 2022, 13(6), 1004; https://doi.org/10.3390/genes13061004 - 2 Jun 2022
Cited by 2 | Viewed by 2031
Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder with onset in early childhood [...] Full article
(This article belongs to the Special Issue From Genes to Therapy in Autism Spectrum Disorder)

Research

Jump to: Editorial, Review, Other

13 pages, 1798 KiB  
Article
Actionable Genomics in Clinical Practice: Paradigmatic Case Reports of Clinical and Therapeutic Strategies Based upon Genetic Testing
by Merlin G. Butler, Daniel Moreno-De-Luca and Antonio M. Persico
Genes 2022, 13(2), 323; https://doi.org/10.3390/genes13020323 - 10 Feb 2022
Cited by 9 | Viewed by 3100
Abstract
In clinical settings, the information provided by genetic testing can explain the triggers and processes underlying clinical presentations, such as neurodevelopmental disorders, in up to one third of affected individuals. However, translating this knowledge into better and more personalized clinical management to many [...] Read more.
In clinical settings, the information provided by genetic testing can explain the triggers and processes underlying clinical presentations, such as neurodevelopmental disorders, in up to one third of affected individuals. However, translating this knowledge into better and more personalized clinical management to many appears a distant target. This article presents three paradigmatic cases to exemplify how this translational effort can, at least in some instances, be undertaken today with very positive results: (a) a young girl carrying a chr. 16p11.2 duplication can be screened using targeted exams and undertake therapeutic/preventive interventions related to her genetic diagnosis; (b) a 13-year-old boy with intellectual disability and autism spectrum disorder carries a chr. 11q14.1 deletion, partly spanning the DLG2 gene important for synaptic function, and gained over 20 I.Q. points ostensibly due to carbolithium, prescribed in the absence of affective symptoms, exclusively following the pathophysiology pointed out by the genetic results; (c) a 58-year-old woman carries a COL3A1 gene variant responsible for the vascular form of Ehler–Danlos syndrome with colon rupture. Detection of this variant in six members of her extended family allows for better clinical management of the proband and targeted genetic counselling for family members at risk of this connective tissue disorder. The unprecedented flow of genetic information available today through new technologies, if interpreted in the light of current knowledge in clinical diagnosis and care of those with connective tissue disorders and neurodevelopmental disturbances, in biology and in neuropsychopharmacology, can promote better clinical and pharmacological treatment, disease surveillance, and management provided and incorporated into the clinical setting. Full article
(This article belongs to the Special Issue From Genes to Therapy in Autism Spectrum Disorder)
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18 pages, 2929 KiB  
Article
Longitudinal Changes in Cortical Thickness in Adolescents with Autism Spectrum Disorder and Their Association with Restricted and Repetitive Behaviors
by Valentina Bieneck, Anke Bletsch, Caroline Mann, Tim Schäfer, Hanna Seelemeyer, Njål Herøy, Jennifer Zimmermann, Charlotte Marie Pretzsch, Elke Hattingen and Christine Ecker
Genes 2021, 12(12), 2024; https://doi.org/10.3390/genes12122024 - 20 Dec 2021
Cited by 15 | Viewed by 4303
Abstract
The neuroanatomy of autism spectrum disorder (ASD) shows highly heterogeneous developmental trajectories across individuals. Mapping atypical brain development onto clinical phenotypes, and establishing their molecular underpinnings, is therefore crucial for patient stratification and subtyping. In this longitudinal study we examined intra- and inter-individual [...] Read more.
The neuroanatomy of autism spectrum disorder (ASD) shows highly heterogeneous developmental trajectories across individuals. Mapping atypical brain development onto clinical phenotypes, and establishing their molecular underpinnings, is therefore crucial for patient stratification and subtyping. In this longitudinal study we examined intra- and inter-individual differences in the developmental trajectory of cortical thickness (CT) in childhood and adolescence, and their genomic underpinnings, in 33 individuals with ASD and 37 typically developing controls (aged 11–18 years). Moreover, we aimed to link regional atypical CT development to intra-individual variations in restricted and repetitive behavior (RRB) over a two-year time period. Individuals with ASD showed significantly reduced cortical thinning in several of the brain regions functionally related to wider autism symptoms and traits (e.g., fronto-temporal and cingulate cortices). The spatial patterns of the neuroanatomical differences in CT were enriched for genes known to be associated with ASD at a genetic and transcriptomic level. Further, intra-individual differences in CT correlated with within-subject variability in the severity of RRBs. Our findings represent an important step towards characterizing the neuroanatomical underpinnings of ASD across development based upon measures of CT. Moreover, our findings provide important novel insights into the link between microscopic and macroscopic pathology in ASD, as well as their relationship with different clinical ASD phenotypes. Full article
(This article belongs to the Special Issue From Genes to Therapy in Autism Spectrum Disorder)
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Review

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21 pages, 1011 KiB  
Review
Spatial and Temporal Gene Function Studies in Rodents: Towards Gene-Based Therapies for Autism Spectrum Disorder
by Iris W. Riemersma, Robbert Havekes and Martien J. H. Kas
Genes 2022, 13(1), 28; https://doi.org/10.3390/genes13010028 - 23 Dec 2021
Cited by 6 | Viewed by 4552
Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by differences in social interaction, repetitive behaviors, restricted interests, and sensory differences beginning early in life. Especially sensory symptoms are highly correlated with the severity of other behavioral differences. ASD is [...] Read more.
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that is characterized by differences in social interaction, repetitive behaviors, restricted interests, and sensory differences beginning early in life. Especially sensory symptoms are highly correlated with the severity of other behavioral differences. ASD is a highly heterogeneous condition on multiple levels, including clinical presentation, genetics, and developmental trajectories. Over a thousand genes have been implicated in ASD. This has facilitated the generation of more than two hundred genetic mouse models that are contributing to understanding the biological underpinnings of ASD. Since the first symptoms already arise during early life, it is especially important to identify both spatial and temporal gene functions in relation to the ASD phenotype. To further decompose the heterogeneity, ASD-related genes can be divided into different subgroups based on common functions, such as genes involved in synaptic function. Furthermore, finding common biological processes that are modulated by this subgroup of genes is essential for possible patient stratification and the development of personalized early treatments. Here, we review the current knowledge on behavioral rodent models of synaptic dysfunction by focusing on behavioral phenotypes, spatial and temporal gene function, and molecular targets that could lead to new targeted gene-based therapy. Full article
(This article belongs to the Special Issue From Genes to Therapy in Autism Spectrum Disorder)
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29 pages, 1304 KiB  
Review
Translating the Role of mTOR- and RAS-Associated Signalopathies in Autism Spectrum Disorder: Models, Mechanisms and Treatment
by Verica Vasic, Mattson S. O. Jones, Denise Haslinger, Lisa S. Knaus, Michael J. Schmeisser, Gaia Novarino and Andreas G. Chiocchetti
Genes 2021, 12(11), 1746; https://doi.org/10.3390/genes12111746 - 30 Oct 2021
Cited by 7 | Viewed by 4591
Abstract
Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied [...] Read more.
Mutations affecting mTOR or RAS signaling underlie defined syndromes (the so-called mTORopathies and RASopathies) with high risk for Autism Spectrum Disorder (ASD). These syndromes show a broad variety of somatic phenotypes including cancers, skin abnormalities, heart disease and facial dysmorphisms. Less well studied are the neuropsychiatric symptoms such as ASD. Here, we assess the relevance of these signalopathies in ASD reviewing genetic, human cell model, rodent studies and clinical trials. We conclude that signalopathies have an increased liability for ASD and that, in particular, ASD individuals with dysmorphic features and intellectual disability (ID) have a higher chance for disruptive mutations in RAS- and mTOR-related genes. Studies on rodent and human cell models confirm aberrant neuronal development as the underlying pathology. Human studies further suggest that multiple hits are necessary to induce the respective phenotypes. Recent clinical trials do only report improvements for comorbid conditions such as epilepsy or cancer but not for behavioral aspects. Animal models show that treatment during early development can rescue behavioral phenotypes. Taken together, we suggest investigating the differential roles of mTOR and RAS signaling in both human and rodent models, and to test drug treatment both during and after neuronal development in the available model systems. Full article
(This article belongs to the Special Issue From Genes to Therapy in Autism Spectrum Disorder)
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11 pages, 842 KiB  
Review
Somatic Mosaicism and Autism Spectrum Disorder
by Alissa M. D’Gama
Genes 2021, 12(11), 1699; https://doi.org/10.3390/genes12111699 - 26 Oct 2021
Cited by 12 | Viewed by 3391
Abstract
Autism spectrum disorder (ASD) is a genetically heterogenous neurodevelopmental disorder. In the early years of next-generation sequencing, de novo germline variants were shown to contribute to ASD risk. These germline mutations are present in all of the cells of an affected individual and [...] Read more.
Autism spectrum disorder (ASD) is a genetically heterogenous neurodevelopmental disorder. In the early years of next-generation sequencing, de novo germline variants were shown to contribute to ASD risk. These germline mutations are present in all of the cells of an affected individual and can be detected in any tissue, including clinically accessible DNA sources such as blood or saliva. In recent years, studies have also implicated de novo somatic variants in ASD risk. These somatic mutations arise postzygotically and are present in only a subset of the cells of an affected individual. Depending on the developmental time and progenitor cell in which a somatic mutation occurs, it may be detectable in some tissues and not in others. Somatic mutations detectable at relatively low sequencing coverage in clinically accessible tissues are suggested to contribute to 3–5% of simplex ASD diagnoses, and “brain limited” somatic mutations have been identified in postmortem ASD brain tissue. Somatic mutations likely represent the genetic diagnosis in a proportion of otherwise unexplained individuals with ASD, and brain limited somatic mutations can be used as markers to discover risk genes, cell types, brain regions, and cellular pathways important for ASD pathogenesis and to potentially target for therapeutics. Full article
(This article belongs to the Special Issue From Genes to Therapy in Autism Spectrum Disorder)
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9 pages, 1094 KiB  
Review
Gene Therapies for Monogenic Autism Spectrum Disorders
by Wout Weuring, Jeroen Geerligs and Bobby P. C. Koeleman
Genes 2021, 12(11), 1667; https://doi.org/10.3390/genes12111667 - 22 Oct 2021
Cited by 17 | Viewed by 5918
Abstract
Novel genome editing and transient gene therapies have been developed the past ten years, resulting in the first in-human clinical trials for monogenic disorders. Syndromic autism spectrum disorders can be caused by mutations in a single gene. Given the monogenic aspect and severity [...] Read more.
Novel genome editing and transient gene therapies have been developed the past ten years, resulting in the first in-human clinical trials for monogenic disorders. Syndromic autism spectrum disorders can be caused by mutations in a single gene. Given the monogenic aspect and severity of syndromic ASD, it is an ideal candidate for gene therapies. Here, we selected 11 monogenic ASD syndromes, validated by animal models, and reviewed current gene therapies for each syndrome. Given the wide variety and novelty of some forms of gene therapy, the best possible option must be decided based on the gene and mutation. Full article
(This article belongs to the Special Issue From Genes to Therapy in Autism Spectrum Disorder)
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Graphical abstract

11 pages, 289 KiB  
Review
Genetic Findings as the Potential Basis of Personalized Pharmacotherapy in Phelan-McDermid Syndrome
by Brianna Dyar, Erika Meaddough, Sara M. Sarasua, Curtis Rogers, Katy Phelan and Luigi Boccuto
Genes 2021, 12(8), 1192; https://doi.org/10.3390/genes12081192 - 30 Jul 2021
Cited by 11 | Viewed by 2748
Abstract
Phelan-McDermid syndrome (PMS) is a genetic disorder often characterized by autism or autistic-like behavior. Most cases are associated with haploinsufficiency of the SHANK3 gene resulting from deletion of the gene at 22q13.3 or from a pathogenic variant in the gene. Treatment of PMS [...] Read more.
Phelan-McDermid syndrome (PMS) is a genetic disorder often characterized by autism or autistic-like behavior. Most cases are associated with haploinsufficiency of the SHANK3 gene resulting from deletion of the gene at 22q13.3 or from a pathogenic variant in the gene. Treatment of PMS often targets SHANK3, yet deletion size varies from <50 kb to >9 Mb, potentially encompassing dozens of genes and disrupting regulatory elements altering gene expression, inferring the potential for multiple therapeutic targets. Repurposed drugs have been used in clinical trials investigating therapies for PMS: insulin-like growth factor 1 (IGF-1) for its effect on social and aberrant behaviors, intranasal insulin for improvements in cognitive and social ability, and lithium for reversing regression and stabilizing behavior. The pharmacogenomics of PMS is complicated by the CYP2D6 enzyme which metabolizes antidepressants and antipsychotics often used for treatment. The gene coding for CYP2D6 maps to 22q13.2 and is lost in individuals with deletions larger than 8 Mb. Because PMS has diverse neurological and medical symptoms, many concurrent medications may be prescribed, increasing the risk for adverse drug reactions. At present, there is no single best treatment for PMS. Approaches to therapy are necessarily complex and must target variable behavioral and physical symptoms of PMS. Full article
(This article belongs to the Special Issue From Genes to Therapy in Autism Spectrum Disorder)

Other

10 pages, 1412 KiB  
Concept Paper
Following Excitation/Inhibition Ratio Homeostasis from Synapse to EEG in Monogenetic Neurodevelopmental Disorders
by Lisa Geertjens, Torben W. van Voorst, Arianne Bouman, Maaike A. van Boven, Tjitske Kleefstra, Matthijs Verhage, Klaus Linkenkaer-Hansen, Nael Nadif Kasri, L. Niels Cornelisse and Hilgo Bruining
Genes 2022, 13(2), 390; https://doi.org/10.3390/genes13020390 - 21 Feb 2022
Cited by 4 | Viewed by 3551
Abstract
Pharmacological options for neurodevelopmental disorders are limited to symptom suppressing agents that do not target underlying pathophysiological mechanisms. Studies on specific genetic disorders causing neurodevelopmental disorders have elucidated pathophysiological mechanisms to develop more rational treatments. Here, we present our concerted multi-level strategy ‘BRAINMODEL’, [...] Read more.
Pharmacological options for neurodevelopmental disorders are limited to symptom suppressing agents that do not target underlying pathophysiological mechanisms. Studies on specific genetic disorders causing neurodevelopmental disorders have elucidated pathophysiological mechanisms to develop more rational treatments. Here, we present our concerted multi-level strategy ‘BRAINMODEL’, focusing on excitation/inhibition ratio homeostasis across different levels of neuroscientific interrogation. The aim is to develop personalized treatment strategies by linking iPSC-based models and novel EEG measurements to patient report outcome measures in individual patients. We focus our strategy on chromatin- and SNAREopathies as examples of severe genetic neurodevelopmental disorders with an unmet need for rational interventions. Full article
(This article belongs to the Special Issue From Genes to Therapy in Autism Spectrum Disorder)
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