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Special Issue "The Identification of the Genetic Components of Autism Spectrum Disorders 2017"

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 (28 February 2017)

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Guest Editor
Prof. Dr. Merlin G. Butler

Psychiatry & Behavioral Sciences and Pediatrics, The University of Kansas Medical Center, 3901 Rainbow Blvd., Mail Stop 4015, Kansas City, KS 66160, USA
Website | E-Mail
Interests: autism; Prader-Willi syndrome; fragile X syndrome; copy number and gene variants; microarray analysis; exome sequencing; genetics of syndromic and non-syndromic obesity; delineation of rare diseases; genotype-phenotype correlations; intellectual disabilities; 15q11-q13 chromosome rearrangements and Burnside-Butler syndrome

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

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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

Related Special Issues

Published Papers (18 papers)

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Research

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Open AccessArticle Variability of Creatine Metabolism Genes in Children with Autism Spectrum Disorder
Int. J. Mol. Sci. 2017, 18(8), 1665; https://doi.org/10.3390/ijms18081665
Received: 5 May 2017 / Revised: 19 July 2017 / Accepted: 25 July 2017 / Published: 31 July 2017
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Abstract
Creatine deficiency syndrome (CDS) comprises three separate enzyme deficiencies with overlapping clinical presentations: arginine:glycine amidinotransferase (GATM gene, glycine amidinotransferase), guanidinoacetate methyltransferase (GAMT gene), and creatine transporter deficiency (SLC6A8 gene, solute carrier family 6 member 8). CDS presents with developmental delays/regression,
[...] Read more.
Creatine deficiency syndrome (CDS) comprises three separate enzyme deficiencies with overlapping clinical presentations: arginine:glycine amidinotransferase (GATM gene, glycine amidinotransferase), guanidinoacetate methyltransferase (GAMT gene), and creatine transporter deficiency (SLC6A8 gene, solute carrier family 6 member 8). CDS presents with developmental delays/regression, intellectual disability, speech and language impairment, autistic behaviour, epileptic seizures, treatment-refractory epilepsy, and extrapyramidal movement disorders; symptoms that are also evident in children with autism. The objective of the study was to test the hypothesis that genetic variability in creatine metabolism genes is associated with autism. We sequenced GATM, GAMT and SLC6A8 genes in 166 patients with autism (coding sequence, introns and adjacent untranslated regions). A total of 29, 16 and 25 variants were identified in each gene, respectively. Four variants were novel in GATM, and 5 in SLC6A8 (not present in the 1000 Genomes, Exome Sequencing Project (ESP) or Exome Aggregation Consortium (ExAC) databases). A single variant in each gene was identified as non-synonymous, and computationally predicted to be potentially damaging. Nine variants in GATM were shown to have a lower minor allele frequency (MAF) in the autism population than in the 1000 Genomes database, specifically in the East Asian population (Fisher’s exact test). Two variants also had lower MAFs in the European population. In summary, there were no apparent associations of variants in GAMT and SLC6A8 genes with autism. The data implying there could be a lower association of some specific GATM gene variants with autism is an observation that would need to be corroborated in a larger group of autism patients, and with sub-populations of Asian ethnicities. Overall, our findings suggest that the genetic variability of creatine synthesis/transport is unlikely to play a part in the pathogenesis of autism spectrum disorder (ASD) in children. Full article
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Open AccessArticle Parents’ Attitudes toward Clinical Genetic Testing for Autism Spectrum Disorder—Data from a Norwegian Sample
Int. J. Mol. Sci. 2017, 18(5), 1078; https://doi.org/10.3390/ijms18051078
Received: 27 February 2017 / Revised: 12 May 2017 / Accepted: 13 May 2017 / Published: 18 May 2017
Cited by 3 | PDF Full-text (246 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Clinical genetic testing (CGT) of children with autism spectrum disorder (ASD) may have positive and negative effects. Knowledge about parents’ attitudes is needed to ensure good involvement of caregivers, which is crucial for accurate diagnosis and effective clinical management. This study aimed to
[...] Read more.
Clinical genetic testing (CGT) of children with autism spectrum disorder (ASD) may have positive and negative effects. Knowledge about parents’ attitudes is needed to ensure good involvement of caregivers, which is crucial for accurate diagnosis and effective clinical management. This study aimed to assess parents’ attitudes toward CGT for ASD. Parent members of the Norwegian Autism Society were given a previously untested questionnaire and 1455 answered. Linear regression analyses were conducted to evaluate contribution of parent and child characteristics to attitude statements. Provided it could contribute to a casual explanation of their child’s ASD, 76% would undergo CGT. If it would improve the possibilities for early interventions, 74% were positive to CGT. Between 49–67% agreed that CGT could have a negative impact on health insurance, increase their concern for the child’s future and cause family conflicts. Parents against CGT (9%) were less optimistic regarding positive effects, but not more concerned with negative impacts. The severity of the children’s ASD diagnosis had a weak positive association with parent’s positive attitudes to CGT (p-values range from <0.001 to 0.975). Parents prefer that CGT is offered to those having a child with ASD (65%), when the child’s development deviates from normal (48%), or before pregnancy (36%). A majority of the parents of children with ASD are positive to CGT due to possibilities for an etiological explanation. Full article
Open AccessArticle Examining the Overlap between Autism Spectrum Disorder and 22q11.2 Deletion Syndrome
Int. J. Mol. Sci. 2017, 18(5), 1071; https://doi.org/10.3390/ijms18051071
Received: 1 March 2017 / Revised: 4 May 2017 / Accepted: 5 May 2017 / Published: 18 May 2017
Cited by 5 | PDF Full-text (840 KB) | HTML Full-text | XML Full-text
Abstract
22q11.2 deletion syndrome (22q11.2DS) is a genomic disorder reported to associate with autism spectrum disorders (ASDs) in 15–50% of cases; however, others suggest that individuals with 22q11.2DS present psychiatric or behavioral features associated with ASDs, but do not meet full criteria for ASD
[...] Read more.
22q11.2 deletion syndrome (22q11.2DS) is a genomic disorder reported to associate with autism spectrum disorders (ASDs) in 15–50% of cases; however, others suggest that individuals with 22q11.2DS present psychiatric or behavioral features associated with ASDs, but do not meet full criteria for ASD diagnoses. Such wide variability in findings may arise in part due to methodological differences across studies. Our study sought to determine whether individuals with 22q11.2DS meet strict ASD diagnostic criteria using research-based guidelines from the Collaborative Programs of Excellence in Autism (CPEA), which required a gathering of information from three sources: the Autism Diagnostic Interview-Revised (ADI-R), the Autism Diagnostic Observational Schedule (ADOS), and a clinician’s best-estimate diagnosis. Our study examined a cohort of children, adolescents, and young adults (n = 56) with 22q11.2DS, who were ascertained irrespective of parents’ behavioral or developmental concerns, and found that 17.9% (n = 10) of the participants met CPEA criteria for an ASD diagnosis, and that a majority showed some level of social-communication impairment or the presence of repetitive behaviors. We conclude that strictly defined ASDs occur in a substantial proportion of individuals with 22q11.2DS, and recommend that all individuals with 22q11.2DS be screened for ASDs during early childhood. Full article
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Open AccessShort Note Unbalance between Excitation and Inhibition in Phenylketonuria, a Genetic Metabolic Disease Associated with Autism
Int. J. Mol. Sci. 2017, 18(5), 941; https://doi.org/10.3390/ijms18050941
Received: 28 February 2017 / Revised: 20 April 2017 / Accepted: 23 April 2017 / Published: 29 April 2017
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Abstract
Phenylketonuria (PKU) is the most common genetic metabolic disease with a well-documented association with autism spectrum disorders. It is characterized by the deficiency of the phenylalanine hydroxylase activity, causing plasmatic hyperphenylalaninemia and variable neurological and cognitive impairments. Among the potential pathophysiological mechanisms implicated
[...] Read more.
Phenylketonuria (PKU) is the most common genetic metabolic disease with a well-documented association with autism spectrum disorders. It is characterized by the deficiency of the phenylalanine hydroxylase activity, causing plasmatic hyperphenylalaninemia and variable neurological and cognitive impairments. Among the potential pathophysiological mechanisms implicated in autism spectrum disorders is the excitation/inhibition (E/I) imbalance which might result from alterations in excitatory/inhibitory synapse development, synaptic transmission and plasticity, downstream signalling pathways, and intrinsic neuronal excitability. Here, we investigated functional and molecular alterations in the prefrontal cortex (pFC) of BTBR-Pahenu2 (ENU2) mice, the animal model of PKU. Our data show higher frequency of inhibitory transmissions and significant reduced frequency of excitatory transmissions in the PKU-affected mice in comparison to wild type. Moreover, in the pFC of ENU2 mice, we reported higher levels of the post-synaptic cell-adhesion proteins neuroligin1 and 2. Altogether, our data point toward an imbalance in the E/I neurotransmission favouring inhibition in the pFC of ENU2 mice, along with alterations of the molecular components involved in the organization of cortical synapse. In addition to being the first evidence of E/I imbalance within cortical areas of a mouse model of PKU, our study provides further evidence of E/I imbalance in animal models of pathology associated with autism spectrum disorders. Full article
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Open AccessArticle Clock Genes and Altered Sleep–Wake Rhythms: Their Role in the Development of Psychiatric Disorders
Int. J. Mol. Sci. 2017, 18(5), 938; https://doi.org/10.3390/ijms18050938
Received: 19 October 2016 / Revised: 4 March 2017 / Accepted: 9 March 2017 / Published: 29 April 2017
Cited by 10 | PDF Full-text (533 KB) | HTML Full-text | XML Full-text
Abstract
In mammals, the circadian clocks network (central and peripheral oscillators) controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted
[...] Read more.
In mammals, the circadian clocks network (central and peripheral oscillators) controls circadian rhythms and orchestrates the expression of a range of downstream genes, allowing the organism to anticipate and adapt to environmental changes. Beyond their role in circadian rhythms, several studies have highlighted that circadian clock genes may have a more widespread physiological effect on cognition, mood, and reward-related behaviors. Furthermore, single nucleotide polymorphisms in core circadian clock genes have been associated with psychiatric disorders (such as autism spectrum disorder, schizophrenia, anxiety disorders, major depressive disorder, bipolar disorder, and attention deficit hyperactivity disorder). However, the underlying mechanisms of these associations remain to be ascertained and the cause–effect relationships are not clearly established. The objective of this article is to clarify the role of clock genes and altered sleep–wake rhythms in the development of psychiatric disorders (sleep problems are often observed at early onset of psychiatric disorders). First, the molecular mechanisms of circadian rhythms are described. Then, the relationships between disrupted circadian rhythms, including sleep–wake rhythms, and psychiatric disorders are discussed. Further research may open interesting perspectives with promising avenues for early detection and therapeutic intervention in psychiatric disorders. Full article
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Open AccessArticle Increased Force Variability Is Associated with Altered Modulation of the Motorneuron Pool Activity in Autism Spectrum Disorder (ASD)
Int. J. Mol. Sci. 2017, 18(4), 698; https://doi.org/10.3390/ijms18040698
Received: 21 February 2017 / Revised: 20 March 2017 / Accepted: 22 March 2017 / Published: 25 March 2017
Cited by 1 | PDF Full-text (2152 KB) | HTML Full-text | XML Full-text
Abstract
Force control deficits have been repeatedly documented in autism spectrum disorder (ASD). They are associated with worse social and daily living skill impairments in patients suggesting that developing a more mechanistic understanding of the central and peripheral processes that cause them may help
[...] Read more.
Force control deficits have been repeatedly documented in autism spectrum disorder (ASD). They are associated with worse social and daily living skill impairments in patients suggesting that developing a more mechanistic understanding of the central and peripheral processes that cause them may help guide the development of treatments that improve multiple outcomes in ASD. The neuromuscular mechanisms underlying force control deficits are not yet understood. Seventeen individuals with ASD and 14 matched healthy controls completed an isometric index finger abduction test at 60% of their maximum voluntary contraction (MVC) during recording of the first dorsal interosseous (FDI) muscle to determine the neuromuscular processes associated with sustained force variability. Central modulation of the motorneuron pool activation of the FDI muscle was evaluated at delta (0–4 Hz), alpha (4–10 Hz), beta (10–35 Hz) and gamma (35–60 Hz) frequency bands. ASD patients showed greater force variability than controls when attempting to maintain a constant force. Relative to controls, patients also showed increased central modulation of the motorneuron pool at beta and gamma bands. For controls, reduced force variability was associated with reduced delta frequency modulation of the motorneuron pool activity of the FDI muscle and increased modulation at beta and gamma bands. In contrast, delta, beta, and gamma frequency oscillations were not associated with force variability in ASD. These findings suggest that alterations of central mechanisms that control motorneuron pool firing may underlie the common and often impairing symptoms of ASD. Full article
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Open AccessArticle GeneAnalytics Pathway Analysis and Genetic Overlap among Autism Spectrum Disorder, Bipolar Disorder and Schizophrenia
Int. J. Mol. Sci. 2017, 18(3), 527; https://doi.org/10.3390/ijms18030527
Received: 18 January 2017 / Revised: 15 February 2017 / Accepted: 23 February 2017 / Published: 28 February 2017
Cited by 13 | PDF Full-text (623 KB) | HTML Full-text | XML Full-text
Abstract
Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway
[...] Read more.
Bipolar disorder (BPD) and schizophrenia (SCH) show similar neuropsychiatric behavioral disturbances, including impaired social interaction and communication, seen in autism spectrum disorder (ASD) with multiple overlapping genetic and environmental influences implicated in risk and course of illness. GeneAnalytics software was used for pathway analysis and genetic profiling to characterize common susceptibility genes obtained from published lists for ASD (792 genes), BPD (290 genes) and SCH (560 genes). Rank scores were derived from the number and nature of overlapping genes, gene-disease association, tissue specificity and gene functions subdivided into categories (e.g., diseases, tissues or functional pathways). Twenty-three genes were common to all three disorders and mapped to nine biological Superpathways including Circadian entrainment (10 genes, score = 37.0), Amphetamine addiction (five genes, score = 24.2), and Sudden infant death syndrome (six genes, score = 24.1). Brain tissues included the medulla oblongata (11 genes, score = 2.1), thalamus (10 genes, score = 2.0) and hypothalamus (nine genes, score = 2.0) with six common genes (BDNF, DRD2, CHRNA7, HTR2A, SLC6A3, and TPH2). Overlapping genes impacted dopamine and serotonin homeostasis and signal transduction pathways, impacting mood, behavior and physical activity level. Converging effects on pathways governing circadian rhythms support a core etiological relationship between neuropsychiatric illnesses and sleep disruption with hypoxia and central brain stem dysfunction. Full article
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Open AccessArticle Investigating Autism-Related Symptoms in Children with Prader-Willi Syndrome: A Case Study
Int. J. Mol. Sci. 2017, 18(3), 517; https://doi.org/10.3390/ijms18030517
Received: 21 January 2017 / Revised: 13 February 2017 / Accepted: 23 February 2017 / Published: 28 February 2017
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Abstract
Prader-Willi syndrome (PWS), a rare genetic disorder caused by the lack of expression of paternal genes from chromosome 15q11-13, has been investigated for autism spectrum disorder (ASD) symptomatology in various studies. However, previous findings have been variable, and no studies investigating ASD symptomatology
[...] Read more.
Prader-Willi syndrome (PWS), a rare genetic disorder caused by the lack of expression of paternal genes from chromosome 15q11-13, has been investigated for autism spectrum disorder (ASD) symptomatology in various studies. However, previous findings have been variable, and no studies investigating ASD symptomatology in PWS have exclusively studied children. We aimed to characterize social communication functioning and other ASD-related symptoms in children with PWS, and assessed agreement across measures and rates of ASD diagnosis. Measures included the Autism Diagnostic Observation Schedule-2 (ADOS-2), the Social Communication Questionnaire (SCQ), Social Responsiveness Scale-2 (SRS-2), Social Skills Improvement System-Rating Scales (SSIS-RS), and the Vineland Adaptive Behavioral Scales-II (VABS-II). General adaptive and intellectual skills were also assessed. Clinical best estimate (CBE) diagnosis was determined by an experienced developmental pediatrician, based on history and review of all available study measures, and taking into account overall developmental level. Participants included 10 children with PWS, aged 3 to 12 years. Three of the 10 children were male and genetic subtypes were two deletion (DEL) and eight uniparental disomy (UPD) (with a total of 6 female UPD cases). Although 8 of the 10 children exceeded cut-offs on at least one of the ASD assessments, agreement between parent questionnaires (SCQ, SRS-2, SSIS-RS) and observational assessment (ADOS-2) was very poor. None of the children were assigned a CBE diagnosis of ASD, with the caveat that the risk may have been lower because of the predominance of girls in the sample. The lack of agreement between the assessments emphasizes the complexity of interpreting ASD symptom measures in children with PWS. Full article
Open AccessArticle Chromosomal Microarray Analysis of Consecutive Individuals with Autism Spectrum Disorders Using an Ultra-High Resolution Chromosomal Microarray Optimized for Neurodevelopmental Disorders
Int. J. Mol. Sci. 2016, 17(12), 2070; https://doi.org/10.3390/ijms17122070
Received: 15 October 2016 / Revised: 29 November 2016 / Accepted: 4 December 2016 / Published: 9 December 2016
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Abstract
Copy number variants (CNVs) detected by chromosomal microarray analysis (CMA) significantly contribute to understanding the etiology of autism spectrum disorder (ASD) and other related conditions. In recognition of the value of CMA testing and its impact on medical management, CMA is in medical
[...] Read more.
Copy number variants (CNVs) detected by chromosomal microarray analysis (CMA) significantly contribute to understanding the etiology of autism spectrum disorder (ASD) and other related conditions. In recognition of the value of CMA testing and its impact on medical management, CMA is in medical guidelines as a first-tier test in the evaluation of children with these disorders. As CMA becomes adopted into routine care for these patients, it becomes increasingly important to report these clinical findings. This study summarizes the results of over 4 years of CMA testing by a CLIA-certified clinical testing laboratory. Using a 2.8 million probe microarray optimized for the detection of CNVs associated with neurodevelopmental disorders, we report an overall CNV detection rate of 28.1% in 10,351 consecutive patients, which rises to nearly 33% in cases without ASD, with only developmental delay/intellectual disability (DD/ID) and/or multiple congenital anomalies (MCA). The overall detection rate for individuals with ASD is also significant at 24.4%. The detection rate and pathogenic yield of CMA vary significantly with the indications for testing, age, and gender, as well as the specialty of the ordering doctor. We note discrete differences in the most common recurrent CNVs found in individuals with or without a diagnosis of ASD. Full article
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Open AccessArticle Association Analysis of Noncoding Variants in Neuroligins 3 and 4X Genes with Autism Spectrum Disorder in an Italian Cohort
Int. J. Mol. Sci. 2016, 17(10), 1765; https://doi.org/10.3390/ijms17101765
Received: 10 August 2016 / Revised: 5 October 2016 / Accepted: 12 October 2016 / Published: 22 October 2016
Cited by 7 | PDF Full-text (513 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the
[...] Read more.
Since involved in synaptic transmission and located on X-chromosome, neuroligins 3 and 4X have been studied as good positional and functional candidate genes for autism spectrum disorder pathogenesis, although contradictory results have been reported. Here, we performed a case-control study to assess the association between noncoding genetic variants in NLGN3 and NLGN4X genes and autism, in an Italian cohort of 202 autistic children analyzed by high-resolution melting. The results were first compared with data from 379 European healthy controls (1000 Genomes Project) and then with those from 1061 Italian controls genotyped by Illumina single nucleotide polymorphism (SNP) array 1M-duo. Statistical evaluations were performed using Plink v1.07, with the Omnibus multiple loci approach. According to both the European and the Italian control groups, a 6-marker haplotype on NLGN4X (rs6638575(G), rs3810688(T), rs3810687(G), rs3810686(C), rs5916269(G), rs1882260(T)) was associated with autism (odd ratio = 3.58, p-value = 2.58 × 10−6 for the European controls; odds ratio = 2.42, p-value = 6.33 × 10−3 for the Italian controls). Furthermore, several haplotype blocks at 5-, 4-, 3-, and 2-, including the first 5, 4, 3, and 2 SNPs, respectively, showed a similar association with autism. We provide evidence that noncoding polymorphisms on NLGN4X may be associated to autism, suggesting the key role of NLGN4X in autism pathophysiology and in its male prevalence. Full article
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Open AccessArticle Selection of Suitable Reference Genes for Analysis of Salivary Transcriptome in Non-Syndromic Autistic Male Children
Int. J. Mol. Sci. 2016, 17(10), 1711; https://doi.org/10.3390/ijms17101711
Received: 9 August 2016 / Revised: 29 September 2016 / Accepted: 30 September 2016 / Published: 12 October 2016
Cited by 1 | PDF Full-text (1340 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Childhood autism is a severe form of complex genetically heterogeneous and behaviorally defined set of neurodevelopmental diseases, collectively termed as autism spectrum disorders (ASD). Reverse transcriptase quantitative real-time PCR (RT-qPCR) is a highly sensitive technique for transcriptome analysis, and it has been frequently
[...] Read more.
Childhood autism is a severe form of complex genetically heterogeneous and behaviorally defined set of neurodevelopmental diseases, collectively termed as autism spectrum disorders (ASD). Reverse transcriptase quantitative real-time PCR (RT-qPCR) is a highly sensitive technique for transcriptome analysis, and it has been frequently used in ASD gene expression studies. However, normalization to stably expressed reference gene(s) is necessary to validate any alteration reported at the mRNA level for target genes. The main goal of the present study was to find the most stable reference genes in the salivary transcriptome for RT-qPCR analysis in non-syndromic male childhood autism. Saliva samples were obtained from nine drug naïve non-syndromic male children with autism and also sex-, age-, and location-matched healthy controls using the RNA-stabilizer kit from DNA Genotek. A systematic two-phased measurement of whole saliva mRNA levels for eight common housekeeping genes (HKGs) was carried out by RT-qPCR, and the stability of expression for each candidate gene was analyzed using two specialized algorithms, geNorm and NormFinder, in parallel. Our analysis shows that while the frequently used HKG ACTB is not a suitable reference gene, the combination of GAPDH and YWHAZ could be recommended for normalization of RT-qPCR analysis of salivary transcriptome in non-syndromic autistic male children. Full article
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Open AccessCommunication Association between IRS1 Gene Polymorphism and Autism Spectrum Disorder: A Pilot Case-Control Study in Korean Males
Int. J. Mol. Sci. 2016, 17(8), 1227; https://doi.org/10.3390/ijms17081227
Received: 11 May 2016 / Revised: 13 July 2016 / Accepted: 25 July 2016 / Published: 29 July 2016
Cited by 4 | PDF Full-text (208 KB) | HTML Full-text | XML Full-text
Abstract
The insulin-like growth factor (IGF) pathway is thought to play an important role in brain development. Altered levels of IGFs and their signaling regulators have been shown in autism spectrum disorder (ASD) patients. In this study, we investigated whether coding region single-nucleotide polymorphisms
[...] Read more.
The insulin-like growth factor (IGF) pathway is thought to play an important role in brain development. Altered levels of IGFs and their signaling regulators have been shown in autism spectrum disorder (ASD) patients. In this study, we investigated whether coding region single-nucleotide polymorphisms (cSNPs) of the insulin receptor substrates (IRS1 and IRS2), key mediators of the IGF pathway, were associated with ASD in Korean males. Two cSNPs (rs1801123 of IRS1, and rs4773092 of IRS2) were genotyped using direct sequencing in 180 male ASD patients and 147 male control subjects. A significant association between rs1801123 of IRS1 and ASD was shown in additive (p = 0.022, odds ratio (OR) = 0.66, 95% confidence interval (CI) = 0.46–0.95) and dominant models (p = 0.013, OR = 0.57, 95% CI = 0.37–0.89). Allele frequency analysis also showed an association between rs1801123 and ASD (p = 0.022, OR = 0.66, 95% CI = 0.46–0.94). These results suggest that IRS1 may contribute to the susceptibility of ASD in Korean males. Full article
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Open AccessArticle A Study of Single Nucleotide Polymorphisms of the SLC19A1/RFC1 Gene in Subjects with Autism Spectrum Disorder
Int. J. Mol. Sci. 2016, 17(5), 772; https://doi.org/10.3390/ijms17050772
Received: 19 February 2016 / Revised: 24 April 2016 / Accepted: 2 May 2016 / Published: 19 May 2016
Cited by 2 | PDF Full-text (591 KB) | HTML Full-text | XML Full-text
Abstract
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with complex genetic etiology. Recent studies have indicated that children with ASD may have altered folate or methionine metabolism, suggesting that the folate–methionine cycle may play a key role in the etiology of
[...] Read more.
Autism Spectrum Disorder (ASD) is a group of neurodevelopmental disorders with complex genetic etiology. Recent studies have indicated that children with ASD may have altered folate or methionine metabolism, suggesting that the folate–methionine cycle may play a key role in the etiology of ASD. SLC19A1, also referred to as reduced folate carrier 1 (RFC1), is a member of the solute carrier group of transporters and is one of the key enzymes in the folate metabolism pathway. Findings from multiple genomic screens suggest the presence of an autism susceptibility locus on chromosome 21q22.3, which includes SLC19A1. Therefore, we performed a case-control study in a Japanese population. In this study, DNA samples obtained from 147 ASD patients at the Kanazawa University Hospital in Japan and 150 unrelated healthy Japanese volunteers were examined by the sequence-specific primer-polymerase chain reaction method pooled with fluorescence correlation spectroscopy. p < 0.05 was considered to represent a statistically significant outcome. Of 13 single nucleotide polymorphisms (SNPs) examined, a significant p-value was obtained for AA genotype of one SNP (rs1023159, OR = 0.39, 95% CI = 0.16–0.91, p = 0.0394; Fisher’s exact test). Despite some conflicting results, our findings supported a role for the polymorphism rs1023159 of the SLC19A1 gene, alone or in combination, as a risk factor for ASD. However, the findings were not consistent after multiple testing corrections. In conclusion, although our results supported a role of the SLC19A1 gene in the etiology of ASD, it was not a significant risk factor for the ASD samples analyzed in this study. Full article
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Open AccessArticle Morphometric Analysis of Recognized Genes for Autism Spectrum Disorders and Obesity in Relationship to the Distribution of Protein-Coding Genes on Human Chromosomes
Int. J. Mol. Sci. 2016, 17(5), 673; https://doi.org/10.3390/ijms17050673
Received: 10 February 2016 / Revised: 11 April 2016 / Accepted: 28 April 2016 / Published: 5 May 2016
Cited by 1 | PDF Full-text (1477 KB) | HTML Full-text | XML Full-text
Abstract
Mammalian chromosomes are comprised of complex chromatin architecture with the specific assembly and configuration of each chromosome influencing gene expression and function in yet undefined ways by varying degrees of heterochromatinization that result in Giemsa (G) negative euchromatic (light) bands and G-positive heterochromatic
[...] Read more.
Mammalian chromosomes are comprised of complex chromatin architecture with the specific assembly and configuration of each chromosome influencing gene expression and function in yet undefined ways by varying degrees of heterochromatinization that result in Giemsa (G) negative euchromatic (light) bands and G-positive heterochromatic (dark) bands. We carried out morphometric measurements of high-resolution chromosome ideograms for the first time to characterize the total euchromatic and heterochromatic chromosome band length, distribution and localization of 20,145 known protein-coding genes, 790 recognized autism spectrum disorder (ASD) genes and 365 obesity genes. The individual lengths of G-negative euchromatin and G-positive heterochromatin chromosome bands were measured in millimeters and recorded from scaled and stacked digital images of 850-band high-resolution ideograms supplied by the International Society of Chromosome Nomenclature (ISCN) 2013. Our overall measurements followed established banding patterns based on chromosome size. G-negative euchromatic band regions contained 60% of protein-coding genes while the remaining 40% were distributed across the four heterochromatic dark band sub-types. ASD genes were disproportionately overrepresented in the darker heterochromatic sub-bands, while the obesity gene distribution pattern did not significantly differ from protein-coding genes. Our study supports recent trends implicating genes located in heterochromatin regions playing a role in biological processes including neurodevelopment and function, specifically genes associated with ASD. Full article
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Review

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Open AccessReview Delineating the Common Biological Pathways Perturbed by ASD’s Genetic Etiology: Lessons from Network-Based Studies
Int. J. Mol. Sci. 2017, 18(4), 828; https://doi.org/10.3390/ijms18040828
Received: 28 February 2017 / Revised: 3 April 2017 / Accepted: 6 April 2017 / Published: 14 April 2017
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Abstract
In recent decades it has become clear that Autism Spectrum Disorder (ASD) possesses a diverse and heterogeneous genetic etiology. Aberrations in hundreds of genes have been associated with ASD so far, which include both rare and common variations. While one may expect that
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In recent decades it has become clear that Autism Spectrum Disorder (ASD) possesses a diverse and heterogeneous genetic etiology. Aberrations in hundreds of genes have been associated with ASD so far, which include both rare and common variations. While one may expect that these genes converge on specific common molecular pathways, which drive the development of the core ASD characteristics, the task of elucidating these common molecular pathways has been proven to be challenging. Several studies have combined genetic analysis with bioinformatical techniques to uncover molecular mechanisms that are specifically targeted by autism-associated genetic aberrations. Recently, several analysis have suggested that particular signaling mechanisms, including the Wnt and Ca2+/Calmodulin-signaling pathways are often targeted by autism-associated mutations. In this review, we discuss several studies that determine specific molecular pathways affected by autism-associated mutations, and then discuss more in-depth into the biological roles of a few of these pathways, and how they may be involved in the development of ASD. Considering that these pathways may be targeted by specific pharmacological intervention, they may prove to be important therapeutic targets for the treatment of ASD. Full article
Open AccessReview Dysfunctional mTORC1 Signaling: A Convergent Mechanism between Syndromic and Nonsyndromic Forms of Autism Spectrum Disorder?
Int. J. Mol. Sci. 2017, 18(3), 659; https://doi.org/10.3390/ijms18030659
Received: 20 February 2017 / Revised: 13 March 2017 / Accepted: 14 March 2017 / Published: 18 March 2017
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Abstract
Whereas autism spectrum disorder (ASD) exhibits striking heterogeneity in genetics and clinical presentation, dysfunction of mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has been identified as a molecular feature common to several well-characterized syndromes with high prevalence of ASD. Additionally, recent
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Whereas autism spectrum disorder (ASD) exhibits striking heterogeneity in genetics and clinical presentation, dysfunction of mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway has been identified as a molecular feature common to several well-characterized syndromes with high prevalence of ASD. Additionally, recent findings have also implicated mTORC1 signaling abnormalities in a subset of nonsyndromic ASD, suggesting that defective mTORC1 pathway may be a potential converging mechanism in ASD pathology across different etiologies. However, the mechanistic evidence for a causal link between aberrant mTORC1 pathway activity and ASD neurobehavioral features varies depending on the ASD form involved. In this review, we first discuss six monogenic ASD-related syndromes, including both classical and potentially novel mTORopathies, highlighting their contribution to our understanding of the neurobiological mechanisms underlying ASD, and then we discuss existing evidence suggesting that aberrant mTORC1 signaling may also play a role in nonsyndromic ASD. Full article
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Open AccessReview Role of Genetics in the Etiology of Autistic Spectrum Disorder: Towards a Hierarchical Diagnostic Strategy
Int. J. Mol. Sci. 2017, 18(3), 618; https://doi.org/10.3390/ijms18030618
Received: 13 December 2016 / Revised: 17 February 2017 / Accepted: 20 February 2017 / Published: 12 March 2017
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Abstract
Progress in epidemiological, molecular and clinical genetics with the development of new techniques has improved knowledge on genetic syndromes associated with autism spectrum disorder (ASD). The objective of this article is to show the diversity of genetic disorders associated with ASD (based on
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Progress in epidemiological, molecular and clinical genetics with the development of new techniques has improved knowledge on genetic syndromes associated with autism spectrum disorder (ASD). The objective of this article is to show the diversity of genetic disorders associated with ASD (based on an extensive review of single-gene disorders, copy number variants, and other chromosomal disorders), and consequently to propose a hierarchical diagnostic strategy with a stepwise evaluation, helping general practitioners/pediatricians and child psychiatrists to collaborate with geneticists and neuropediatricians, in order to search for genetic disorders associated with ASD. The first step is a clinical investigation involving: (i) a child psychiatric and psychological evaluation confirming autism diagnosis from different observational sources and assessing autism severity; (ii) a neuropediatric evaluation examining neurological symptoms and developmental milestones; and (iii) a genetic evaluation searching for dysmorphic features and malformations. The second step involves laboratory and if necessary neuroimaging and EEG studies oriented by clinical results based on clinical genetic and neuropediatric examinations. The identification of genetic disorders associated with ASD has practical implications for diagnostic strategies, early detection or prevention of co-morbidity, specific treatment and follow up, and genetic counseling. Full article
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Open AccessReview Clinical Genetic Aspects of Autism Spectrum Disorders
Int. J. Mol. Sci. 2016, 17(2), 180; https://doi.org/10.3390/ijms17020180
Received: 9 December 2015 / Revised: 19 January 2016 / Accepted: 26 January 2016 / Published: 29 January 2016
Cited by 15 | PDF Full-text (383 KB) | HTML Full-text | XML Full-text | Correction
Abstract
Early presumptions opined that autism spectrum disorder (ASD) was related to the rearing of these children by emotionally-distant mothers. Advances in the 1960s and 1970s clearly demonstrated the biologic basis of autism with a high heritability. Recent advances have demonstrated that specific etiologic
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Early presumptions opined that autism spectrum disorder (ASD) was related to the rearing of these children by emotionally-distant mothers. Advances in the 1960s and 1970s clearly demonstrated the biologic basis of autism with a high heritability. Recent advances have demonstrated that specific etiologic factors in autism spectrum disorders can be identified in 30%–40% of cases. Based on early reports newer, emerging genomic technologies are likely to increase this diagnostic yield to over 50%. To date these investigations have focused on etiologic factors that are largely mono-factorial. The currently undiagnosed causes of ASDs will likely be found to have causes that are more complex. Epigenetic, multiple interacting loci, and four dimensional causes (with timing as a variable) are likely to be associated with the currently unidentifiable cases. Today, the “Why” is more important than ever. Understanding the causes of ASDs help inform families of important issues such as recurrence risk, prognosis, natural history, and predicting associated co-morbid medical conditions. In the current era of emerging efforts in “personalized medicine”, identifying an etiology will be critical in identifying endo-phenotypic groups and individual variations that will allow for tailored treatment for persons with ASD. Full article
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