Special Issue "Genetic and Phenotypic Subtypes of 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: 20 February 2022.

Special Issue Editor

Dr. M. E. Suzanne Lewis
E-Mail Website
Guest Editor
The Department of Medical Genetics and Genomics, University of British Columbia and BC Children’s Hospital Research Institute, Vancouver, BC V6H 3N1, Canada
Interests: autism genomics; deep pPhenotypes; autism subtypes; whole exome/genome sequencing; clinical genetics

Special Issue Information

Dear Colleagues,

Autism Spectrum Disorder (ASD) is a heterogeneous spectrum, both clinically and etiologically, making it a prime candidate for ‘precision medicine’ based on understanding of cause, rather than behaviours alone. The diagnosis of ASD does not imply etiology, but rather a complex constellation of behavioural and developmental symptoms of a group of conditions comprising discrete genetic, metabolic, congenital, and environmental causes.  For complex genetic disorders, such as ASDs, it is important to identify biological markers that distinguish subtypes. For some disorders, this could be a phenotypic trait that is specific to one subgroup of individuals with the condition; for others, it could be a genomic, biochemical or chromosomal difference.  With current genomics technologies, it is possible to capture a molecular profile of individuals with ASD through their DNA, gut and organ microbes, metabolomic by-products, and the physical and developmental outcomes caused by the interaction of these factors with the environment.

In this special issue we welcome contributions that integrate standardized metrics for subgrouping the ASD phenome (the sum of all phenotypic traits) with its genomic underpinnings. It is the aim of this issue to provide a deeper understanding of genetic and phenotypic subtypes of ASD that can serve as etiologically valid biomarkers for incisive molecular analyses of genes, and gene pathways, which underlie susceptibility to autism and its pathogenesis, that may ultimately enable early diagnosis and more precise, effective treatments.

Dr. M. E. Suzanne Lewis
Guest Editor

Manuscript Submission Information

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Keywords

  • Autism 
  • Genomics 
  • Next Generation Sequencing 
  • Deep Phenotypes 
  • Clusters/Subtypes 
  • Precision Medicine 
  • Gene Pathways 
  • Pathogenesis 
  • Neurodevelopment

Published Papers (5 papers)

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Research

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Article
Autism Spectrum Disorders: Analysis of Mobile Elements at 7q11.23 Williams–Beuren Region by Comparative Genomics
Genes 2021, 12(10), 1605; https://doi.org/10.3390/genes12101605 - 12 Oct 2021
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Abstract
Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders, characterized by a deficit in social interaction and communication. Many genetic variants are associated with ASD, including duplication of 7q11.23 encompassing 26–28 genes. Symmetrically, the hemizygous deletion of 7q11.23 causes Williams–Beuren syndrome [...] Read more.
Autism spectrum disorders (ASD) are a group of complex neurodevelopmental disorders, characterized by a deficit in social interaction and communication. Many genetic variants are associated with ASD, including duplication of 7q11.23 encompassing 26–28 genes. Symmetrically, the hemizygous deletion of 7q11.23 causes Williams–Beuren syndrome (WBS), a multisystem disorder characterized by “hyper-sociability” and communication skills. Interestingly, deletion of four non-exonic mobile elements (MEs) in the “canine WBS locus” were associated with the behavioral divergence between the wolf and the dog and dog sociability and domestication. We hypothesized that indel of these MEs could be involved in ASD, associated with its different phenotypes and useful as biomarkers for patient stratification and therapeutic design. Since these MEs are non-exonic they have never been discovered before. We searched the corresponding MEs and loci in humans by comparative genomics. Interestingly, they mapped on different but ASD related genes. The loci in individuals with phenotypically different autism and neurotypical controls were amplified by PCR. A sub-set of each amplicon was sequenced by Sanger. No variant resulted associated with ASD and neither specific phenotypes were found but novel small-scale insertions and SNPs were discovered. Since MEs are hyper-methylated and epigenetically modulate gene expression, further investigation in ASD is necessary. Full article
(This article belongs to the Special Issue Genetic and Phenotypic Subtypes of Autism Spectrum Disorder)
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Article
Environmental Influences Measured by Epigenetic Clock and Vulnerability Components at Birth Impact Clinical ASD Heterogeneity
Genes 2021, 12(9), 1433; https://doi.org/10.3390/genes12091433 - 17 Sep 2021
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Abstract
Although Autism Spectrum Disorders (ASD) is recognized as being heavily influenced by genetic factors, the role of epigenetic and environmental factors is still being established. This study aimed to identify ASD vulnerability components based on familial history and intrauterine environmental stress exposure, explore [...] Read more.
Although Autism Spectrum Disorders (ASD) is recognized as being heavily influenced by genetic factors, the role of epigenetic and environmental factors is still being established. This study aimed to identify ASD vulnerability components based on familial history and intrauterine environmental stress exposure, explore possible vulnerability subgroups, access DNA methylation age acceleration (AA) as a proxy of stress exposure during life, and evaluate the association of ASD vulnerability components and AA to phenotypic severity measures. Principal Component Analysis (PCA) was used to search the vulnerability components from 67 mothers of autistic children. We found that PC1 had a higher correlation with psychosocial stress (maternal stress, maternal education, and social class), and PC2 had a higher correlation with biological factors (psychiatric family history and gestational complications). Comparing the methylome between above and below PC1 average subgroups we found 11,879 statistically significant differentially methylated probes (DMPs, p < 0.05). DMPs CpG sites were enriched in variably methylated regions (VMRs), most showing environmental and genetic influences. Hypermethylated probes presented higher rates in different regulatory regions associated with functional SNPs, indicating that the subgroups may have different affected regulatory regions and their liability to disease explained by common variations. Vulnerability components score moderated by epigenetic clock AA was associated with Vineland Total score (p = 0.0036, adjR2 = 0.31), suggesting risk factors with stress burden can influence ASD phenotype. Full article
(This article belongs to the Special Issue Genetic and Phenotypic Subtypes of Autism Spectrum Disorder)
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Article
Environmental Enrichment Rescues Social Behavioral Deficits and Synaptic Abnormalities in Pten Haploinsufficient Mice
Genes 2021, 12(9), 1366; https://doi.org/10.3390/genes12091366 - 30 Aug 2021
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Abstract
Pten germline haploinsufficient (Pten+/−) mice, which model macrocephaly/autism syndrome, show social and repetitive behavior deficits, early brain overgrowth, and cortical–subcortical hyperconnectivity. Previous work indicated that altered neuronal connectivity may be a substrate for behavioral deficits. We hypothesized that exposing Pten [...] Read more.
Pten germline haploinsufficient (Pten+/−) mice, which model macrocephaly/autism syndrome, show social and repetitive behavior deficits, early brain overgrowth, and cortical–subcortical hyperconnectivity. Previous work indicated that altered neuronal connectivity may be a substrate for behavioral deficits. We hypothesized that exposing Pten+/− mice to environmental enrichment after brain overgrowth has occurred may facilitate adaptation to abnormal “hard-wired” connectivity through enhancing synaptic plasticity. Thus, we reared Pten+/− mice and their wild-type littermates from weaning under either standard (4–5 mice per standard-sized cage, containing only bedding and nestlet) or enriched (9–10 mice per large-sized cage, containing objects for exploration and a running wheel, plus bedding and nestlet) conditions. Adult mice were tested on social and non-social assays in which Pten+/− mice display deficits. Environmental enrichment rescued sex-specific deficits in social behavior in Pten+/− mice and partially rescued increased repetitive behavior in Pten+/− males. We found that Pten+/− mice show increased excitatory and decreased inhibitory pre-synaptic proteins; this phenotype was also rescued by environmental enrichment. Together, our results indicate that environmental enrichment can rescue social behavioral deficits in Pten+/− mice, possibly through normalizing the excitatory synaptic protein abundance. Full article
(This article belongs to the Special Issue Genetic and Phenotypic Subtypes of Autism Spectrum Disorder)
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Article
Contribution of Multiple Inherited Variants to Autism Spectrum Disorder (ASD) in a Family with 3 Affected Siblings
Genes 2021, 12(7), 1053; https://doi.org/10.3390/genes12071053 - 08 Jul 2021
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Abstract
Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited [...] Read more.
Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder in children and shows high heritability. However, how inherited variants contribute to ASD in multiplex families remains unclear. Using whole-genome sequencing (WGS) in a family with three affected children, we identified multiple inherited DNA variants in ASD-associated genes and pathways (RELN, SHANK2, DLG1, SCN10A, KMT2C and ASH1L). All are shared among the three children, except ASH1L, which is only present in the most severely affected child. The compound heterozygous variants in RELN, and the maternally inherited variant in SHANK2, are considered to be major risk factors for ASD in this family. Both genes are involved in neuron activities, including synaptic functions and the GABAergic neurotransmission system, which are highly associated with ASD pathogenesis. DLG1 is also involved in synapse functions, and KMT2C and ASH1L are involved in chromatin organization. Our data suggest that multiple inherited rare variants, each with a subthreshold and/or variable effect, may converge to certain pathways and contribute quantitatively and additively, or alternatively act via a 2nd-hit or multiple-hits to render pathogenicity of ASD in this family. Additionally, this multiple-hits model further supports the quantitative trait hypothesis of a complex genetic, multifactorial etiology for the development of ASDs. Full article
(This article belongs to the Special Issue Genetic and Phenotypic Subtypes of Autism Spectrum Disorder)
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Review

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Review
In Prototypical Autism, the Genetic Ability to Learn Language Is Triggered by Structured Information, Not Only by Exposure to Oral Language
Genes 2021, 12(8), 1112; https://doi.org/10.3390/genes12081112 - 22 Jul 2021
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Abstract
What does the way that autistic individuals bypass, learn, and eventually master language tell us about humans’ genetically encoded linguistic ability? In this theoretical review, we argue that autistic non-social acquisition of language and autistic savant abilities provide a strong argument for an [...] Read more.
What does the way that autistic individuals bypass, learn, and eventually master language tell us about humans’ genetically encoded linguistic ability? In this theoretical review, we argue that autistic non-social acquisition of language and autistic savant abilities provide a strong argument for an innate, human-specific orientation towards (and mastery of) complex embedded structures. Autistic non-social language learning may represent a widening of the material processed during development beyond oral language. The structure detection and manipulation and generative production of non-linguistic embedded and chained material (savant abilities in calendar calculation, musical composition, musical interpretation, and three-dimensional drawing) may thus represent an application of such innate mechanisms to non-standard materials. Typical language learning through exposure to the child’s mother tongue may represent but one of many possible achievements of the same capacity. The deviation from typical language development in autism may ultimately allow access to oral language, sometimes in its most elaborate forms, and also explain the possibility of the absence of its development when applied exclusively to non-linguistic structured material. Such an extension of human capacities beyond or in parallel to their usual limits call into question what we consider to be specific or expected in humans and therefore does not necessarily represent a genetic “error”. Regardless of the adaptive success or failure of non-social language learning, it is the duty of science and ethical principles to strive to maintain autism as a human potentiality to further foster our vision of a plural society. Full article
(This article belongs to the Special Issue Genetic and Phenotypic Subtypes of Autism Spectrum Disorder)
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