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Special Issue "The Identification of the Genetic Components of Autism Spectrum Disorders"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 January 2015).

Special Issue Editor

Prof. Dr. Merlin G. Butler
E-Mail Website
Guest Editor
Departments of Psychiatry & Behavioral Sciences and Pediatrics, University of Kansas Medical Center, Kansas City, KS 66160, USA
Interests: Prader-Willi syndrome; fragile X syndrome; microdeletion syndromes; autism spectrum disorders; genetics of autism; obesity and intellectual disability; chromosomal microarray analysis; next generation sequencing; delineation of rare genetic disorders; genotype-phenotype relationships
Special Issues and Collections in MDPI journals

Special Issue Information

Dear Colleagues,

This journal issue is dedicated to the study of the genetics of autism and a collection of original research or review articles and studies related to this topic. Highlights in the field of autism research and identification and characterization of genetic components will be addressed.

Autism spectrum disorders (ASD) are neurobehavioral disorders characterized by three behavioral domains and currently affect about 1% of children, however, this is on the rise. Significant genetic contributions and mechanisms underlie the causation of ASD. About 50% of individuals are diagnosed with chromosomal abnormalities, submicroscopic deletions or duplications, single gene disorders or metabolic disturbances. The advancement of genetic technology with high resolution structural and microarrays and bioinformatics has led to the discovery of well over 600 genes contributing to ASD. Further, next generation (exome) sequencing for ASD leading to potential pharmaceutical intervention/treatment may vary from patient to patient depending on the specific genomic finding and associated characteristics for autism. New discoveries and continued identification of candidate genes will be addressed and genotype-phenotype correlations. Genetic evaluations requiring the use of advanced genetic testing options will be discussed along with psychiatric/behavioral co-morbidities seen in ASD and approaches to treatment.

Prof. Dr. Merlin G. Butler
Guest Editor

Manuscript Submission Information

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Keywords

  • microarray
  • next generation (exome) sequencing
  • copy number variants (CNVs) candidate genes
  • autism and autism spectrum disorders (ASD)
  • gene polymorphisms
  • genetic causation
  • gene expression
  • non-coding RNAs
  • biomarkers
  • treatment

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Published Papers (10 papers)

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Research

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Article
Novel Systems Modeling Methodology in Comparative Microbial Metabolomics: Identifying Key Enzymes and Metabolites Implicated in Autism Spectrum Disorders
Int. J. Mol. Sci. 2015, 16(4), 8949-8967; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms16048949 - 22 Apr 2015
Cited by 6 | Viewed by 3718
Abstract
Autism spectrum disorders are a group of mental illnesses highly correlated with gastrointestinal dysfunction. Recent studies have shown that there may be one or more microbial “fingerprints” in terms of the composition characterizing individuals with autism, which could be used for diagnostic purposes. [...] Read more.
Autism spectrum disorders are a group of mental illnesses highly correlated with gastrointestinal dysfunction. Recent studies have shown that there may be one or more microbial “fingerprints” in terms of the composition characterizing individuals with autism, which could be used for diagnostic purposes. This paper proposes a computational approach whereby metagenomes characteristic of “healthy” and autistic individuals are artificially constructed via genomic information, analyzed for the enzymes coded within, and then these enzymes are compared in detail. This is a text mining application. A custom-designed online application was built and used for the comparative metabolomics study and made publically available. Several of the enzyme-catalyzing reactions involved with the amino acid glutamate were curiously missing from the “autism” microbiome and were coded within almost every organism included in the “control” microbiome. Interestingly, there exists a leading hypothesis regarding autism and glutamate involving a neurological excitation/inhibition imbalance; but the association with this study is unclear. The results included data on the transsulfuration and transmethylation pathways, involved with oxidative stress, also of importance to autism. The results from this study are in alignment with leading hypotheses in the field, which is impressive, considering the purely in silico nature of this study. The present study provides new insight into the complex metabolic interactions underlying autism, and this novel methodology has potential to be useful for developing new hypotheses. However, limitations include sparse genome data availability and conflicting literature experimental data. We believe our software tool and methodology has potential for having great utility as data become more available, comprehensive and reliable. Full article
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Article
Phenotypic and Molecular Convergence of 2q23.1 Deletion Syndrome with Other Neurodevelopmental Syndromes Associated with Autism Spectrum Disorder
Int. J. Mol. Sci. 2015, 16(4), 7627-7643; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms16047627 - 07 Apr 2015
Cited by 25 | Viewed by 4488
Abstract
Roughly 20% of autism spectrum disorders (ASD) are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5) is a recently identified genetic neurodevelopmental disorder [...] Read more.
Roughly 20% of autism spectrum disorders (ASD) are syndromic with a well-established genetic cause. Studying the genes involved can provide insight into the molecular and cellular mechanisms of ASD. 2q23.1 deletion syndrome (causative gene, MBD5) is a recently identified genetic neurodevelopmental disorder associated with ASD. Mutations in MBD5 have been found in ASD cohorts. In this study, we provide a phenotypic update on the prevalent features of 2q23.1 deletion syndrome, which include severe intellectual disability, seizures, significant speech impairment, sleep disturbance, and autistic-like behavioral problems. Next, we examined the phenotypic, molecular, and network/pathway relationships between nine neurodevelopmental disorders associated with ASD: 2q23.1 deletion Rett, Angelman, Pitt-Hopkins, 2q23.1 duplication, 5q14.3 deletion, Kleefstra, Kabuki make-up, and Smith-Magenis syndromes. We show phenotypic overlaps consisting of intellectual disability, speech delay, seizures, sleep disturbance, hypotonia, and autistic-like behaviors. Molecularly, MBD5 possibly regulates the expression of UBE3A, TCF4, MEF2C, EHMT1 and RAI1. Network analysis reveals that there could be indirect protein interactions, further implicating function for these genes in common pathways. Further, we show that when MBD5 and RAI1 are haploinsufficient, they perturb several common pathways that are linked to neuronal and behavioral development. These findings support further investigations into the molecular and pathway relationships among genes linked to neurodevelopmental disorders and ASD, which will hopefully lead to common points of regulation that may be targeted toward therapeutic intervention. Full article
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Article
High-Resolution Chromosome Ideogram Representation of Currently Recognized Genes for Autism Spectrum Disorders
Int. J. Mol. Sci. 2015, 16(3), 6464-6495; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms16036464 - 20 Mar 2015
Cited by 30 | Viewed by 5691
Abstract
Recently, autism-related research has focused on the identification of various genes and disturbed pathways causing the genetically heterogeneous group of autism spectrum disorders (ASD). The list of autism-related genes has significantly increased due to better awareness with advances in genetic technology and expanding [...] Read more.
Recently, autism-related research has focused on the identification of various genes and disturbed pathways causing the genetically heterogeneous group of autism spectrum disorders (ASD). The list of autism-related genes has significantly increased due to better awareness with advances in genetic technology and expanding searchable genomic databases. We compiled a master list of known and clinically relevant autism spectrum disorder genes identified with supporting evidence from peer-reviewed medical literature sources by searching key words related to autism and genetics and from authoritative autism-related public access websites, such as the Simons Foundation Autism Research Institute autism genomic database dedicated to gene discovery and characterization. Our list consists of 792 genes arranged in alphabetical order in tabular form with gene symbols placed on high-resolution human chromosome ideograms, thereby enabling clinical and laboratory geneticists and genetic counsellors to access convenient visual images of the location and distribution of ASD genes. Meaningful correlations of the observed phenotype in patients with suspected/confirmed ASD gene(s) at the chromosome region or breakpoint band site can be made to inform diagnosis and gene-based personalized care and provide genetic counselling for families. Full article
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Article
Whole Exome Sequencing for a Patient with Rubinstein-Taybi Syndrome Reveals de Novo Variants besides an Overt CREBBP Mutation
Int. J. Mol. Sci. 2015, 16(3), 5697-5713; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms16035697 - 11 Mar 2015
Cited by 5 | Viewed by 5291
Abstract
Rubinstein-Taybi syndrome (RSTS) is a rare condition with a prevalence of 1 in 125,000–720,000 births and characterized by clinical features that include facial, dental, and limb dysmorphology and growth retardation. Most cases of RSTS occur sporadically and are caused by de novo mutations. [...] Read more.
Rubinstein-Taybi syndrome (RSTS) is a rare condition with a prevalence of 1 in 125,000–720,000 births and characterized by clinical features that include facial, dental, and limb dysmorphology and growth retardation. Most cases of RSTS occur sporadically and are caused by de novo mutations. Cytogenetic or molecular abnormalities are detected in only 55% of RSTS cases. Previous genetic studies have yielded inconsistent results due to the variety of methods used for genetic analysis. The purpose of this study was to use whole exome sequencing (WES) to evaluate the genetic causes of RSTS in a young girl presenting with an Autism phenotype. We used the Autism diagnostic observation schedule (ADOS) and Autism diagnostic interview revised (ADI-R) to confirm her diagnosis of Autism. In addition, various questionnaires were used to evaluate other psychiatric features. We used WES to analyze the DNA sequences of the patient and her parents and to search for de novo variants. The patient showed all the typical features of Autism, WES revealed a de novo frameshift mutation in CREBBP and de novo sequence variants in TNC and IGFALS genes. Mutations in the CREBBP gene have been extensively reported in RSTS patients, while potential missense mutations in TNC and IGFALS genes have not previously been associated with RSTS. The TNC and IGFALS genes are involved in central nervous system development and growth. It is possible for patients with RSTS to have additional de novo variants that could account for previously unexplained phenotypes. Full article
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Article
Pharmacogenetics Informed Decision Making in Adolescent Psychiatric Treatment: A Clinical Case Report
Int. J. Mol. Sci. 2015, 16(3), 4416-4428; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms16034416 - 20 Feb 2015
Cited by 11 | Viewed by 4935
Abstract
Advances made in genetic testing and tools applied to pharmacogenetics are increasingly being used to inform clinicians in fields such as oncology, hematology, diabetes (endocrinology), cardiology and expanding into psychiatry by examining the influences of genetics on drug efficacy and metabolism. We present [...] Read more.
Advances made in genetic testing and tools applied to pharmacogenetics are increasingly being used to inform clinicians in fields such as oncology, hematology, diabetes (endocrinology), cardiology and expanding into psychiatry by examining the influences of genetics on drug efficacy and metabolism. We present a clinical case example of an adolescent male with anxiety, attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder who did not tolerate numerous medications and dosages over several years in attempts to manage his symptoms. Pharmacogenetics testing was performed and DNA results on this individual elucidated the potential pitfalls in medication use because of specific pharmacodynamic and pharmacokinetic differences specifically involving polymorphisms of genes in the cytochrome p450 enzyme system. Future studies and reports are needed to further illustrate and determine the type of individualized medicine approach required to treat individuals based on their specific gene patterns. Growing evidence supports this biological approach for standard of care in psychiatry. Full article
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Article
Autism and Intellectual Disability Associated with Mitochondrial Disease and Hyperlactacidemia
Int. J. Mol. Sci. 2015, 16(2), 3870-3884; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms16023870 - 11 Feb 2015
Cited by 14 | Viewed by 4409
Abstract
Autism spectrum disorder (ASD) with intellectual disability (ID) is a life-long debilitating condition, which is characterized by cognitive function impairment and other neurological signs. Children with ASD-ID typically attain motor skills with a significant delay. A sub-group of ASD-IDs has been linked to [...] Read more.
Autism spectrum disorder (ASD) with intellectual disability (ID) is a life-long debilitating condition, which is characterized by cognitive function impairment and other neurological signs. Children with ASD-ID typically attain motor skills with a significant delay. A sub-group of ASD-IDs has been linked to hyperlactacidemia and alterations in mitochondrial respiratory chain activity. The objective of this report is to describe the clinical features of patients with these comorbidities in order to shed light on difficult diagnostic and therapeutic approaches in such patients. We reported the different clinical features of children with ID associated with hyperlactacidemia and deficiencies in mitochondrial respiratory chain complex II–IV activity whose clinical presentations are commonly associated with the classic spectrum of mitochondrial diseases. We concluded that patients with ASD and ID presenting with persistent hyperlactacidemia should be evaluated for mitochondrial disorders. Administration of carnitine, coenzyme Q10, and folic acid is partially beneficial, although more studies are needed to assess the efficacy of this vitamin/cofactor treatment combination. Full article
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Article
Whole Exome Sequencing in Females with Autism Implicates Novel and Candidate Genes
Int. J. Mol. Sci. 2015, 16(1), 1312-1335; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms16011312 - 07 Jan 2015
Cited by 49 | Viewed by 6279
Abstract
Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions known as Autism Spectrum Disorders (ASD). Heritability is estimated as high as 90% for ASD with a recently reported compilation of 629 clinically relevant candidate and known genes. We chose [...] Read more.
Classical autism or autistic disorder belongs to a group of genetically heterogeneous conditions known as Autism Spectrum Disorders (ASD). Heritability is estimated as high as 90% for ASD with a recently reported compilation of 629 clinically relevant candidate and known genes. We chose to undertake a descriptive next generation whole exome sequencing case study of 30 well-characterized Caucasian females with autism (average age, 7.7 ± 2.6 years; age range, 5 to 16 years) from multiplex families. Genomic DNA was used for whole exome sequencing via paired-end next generation sequencing approach and X chromosome inactivation status. The list of putative disease causing genes was developed from primary selection criteria using machine learning-derived classification score and other predictive parameters (GERP2, PolyPhen2, and SIFT). We narrowed the variant list to 10 to 20 genes and screened for biological significance including neural development, function and known neurological disorders. Seventy-eight genes identified met selection criteria ranging from 1 to 9 filtered variants per female. Five females presented with functional variants of X-linked genes (IL1RAPL1, PIR, GABRQ, GPRASP2, SYTL4) with cadherin, protocadherin and ankyrin repeat gene families most commonly altered (e.g., CDH6, FAT2, PCDH8, CTNNA3, ANKRD11). Other genes related to neurogenesis and neuronal migration (e.g., SEMA3F, MIDN), were also identified. Full article
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Review

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Review
Broader Autism Phenotype in Siblings of Children with ASD—A Review
Int. J. Mol. Sci. 2015, 16(6), 13217-13258; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms160613217 - 10 Jun 2015
Cited by 39 | Viewed by 4532
Abstract
Although less pronounced, social, cognitive, and personality characteristics associated with autism spectrum disorders (ASD) may be present in people who do not meet ASD diagnostic criteria, especially in first-degree relatives of individuals with ASD. Research on these characteristics, referred to as broader autism [...] Read more.
Although less pronounced, social, cognitive, and personality characteristics associated with autism spectrum disorders (ASD) may be present in people who do not meet ASD diagnostic criteria, especially in first-degree relatives of individuals with ASD. Research on these characteristics, referred to as broader autism phenotype (BAP), provides valuable data on potential expressions of autism-specific deficits in the context of family relations. This paper offers a review of research on BAP in siblings of individuals with ASD, focusing on reports regarding social, communication, and cognitive deficits, published from 1993 to 2014. The studies are divided into two groups based on participants’ age: papers on preschool and older siblings of individuals with ASD; and publications on infants at risk for ASD. On the basis of this review, suggestions are offered for further research and its significance for our understanding of the genetic determinants of autism. Full article
Review
Modulation of the Genome and Epigenome of Individuals Susceptible to Autism by Environmental Risk Factors
Int. J. Mol. Sci. 2015, 16(4), 8699-8718; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms16048699 - 20 Apr 2015
Cited by 14 | Viewed by 3695
Abstract
Diverse environmental factors have been implicated with the development of autism spectrum disorders (ASD). Genetic factors also underlie the differential vulnerability to environmental risk factors of susceptible individuals. Currently the way in which environmental risk factors interact with genetic factors to increase the [...] Read more.
Diverse environmental factors have been implicated with the development of autism spectrum disorders (ASD). Genetic factors also underlie the differential vulnerability to environmental risk factors of susceptible individuals. Currently the way in which environmental risk factors interact with genetic factors to increase the incidence of ASD is not well understood. A greater understanding of the metabolic, cellular, and biochemical events involved in gene x environment interactions in ASD would have important implications for the prevention and possible treatment of the disorder. In this review we discuss various established and more alternative processes through which environmental factors implicated in ASD can modulate the genome and epigenome of genetically-susceptible individuals. Full article
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Review
The 15q11.2 BP1–BP2 Microdeletion Syndrome: A Review
Int. J. Mol. Sci. 2015, 16(2), 4068-4082; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms16024068 - 13 Feb 2015
Cited by 89 | Viewed by 10058
Abstract
Patients with the 15q11.2 BP1–BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen. The 15q11.2 BP1–BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, [...] Read more.
Patients with the 15q11.2 BP1–BP2 microdeletion can present with developmental and language delay, neurobehavioral disturbances and psychiatric problems. Autism, seizures, schizophrenia and mild dysmorphic features are less commonly seen. The 15q11.2 BP1–BP2 microdeletion involving four genes (i.e., TUBGCP5, CYFIP1, NIPA1, NIPA2) is emerging as a recognized syndrome with a prevalence ranging from 0.57%–1.27% of patients presenting for microarray analysis which is a two to four fold increase compared with controls. Review of clinical features from about 200 individuals were grouped into five categories and included developmental (73%) and speech (67%) delays; dysmorphic ears (46%) and palatal anomalies (46%); writing (60%) and reading (57%) difficulties, memory problems (60%) and verbal IQ scores ≤75 (50%); general behavioral problems, unspecified (55%) and abnormal brain imaging (43%). Other clinical features noted but not considered as common were seizures/epilepsy (26%), autism spectrum disorder (27%), attention deficit disorder (ADD)/attention deficit hyperactivity disorder (ADHD) (35%), schizophrenia/paranoid psychosis (20%) and motor delay (42%). Not all individuals with the deletion are clinically affected, yet the collection of findings appear to share biological pathways and presumed genetic mechanisms. Neuropsychiatric and behavior disturbances and mild dysmorphic features are associated with genomic imbalances of the 15q11.2 BP1–BP2 region, including microdeletions, but with an apparent incomplete penetrance and variable expressivity. Full article
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