Next Article in Journal
Three-Dimensional Morphological Changes of the True Cleft under Passive Presurgical Orthopaedics in Unilateral Cleft Lip and Palate: A Retrospective Cohort Study
Previous Article in Journal
The Glucocorticoid Receptor NR3C1 in Testicular Peritubular Cells is Developmentally Regulated and Linked to the Smooth Muscle-Like Cellular Phenotype
 
 
Review

Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder

Department of Stem Cell and Regenerative Biotechnology, KU Institute of Technology, Konkuk University, Seoul 05029, Korea
*
Author to whom correspondence should be addressed.
Authors with equal contribution.
J. Clin. Med. 2020, 9(4), 966; https://doi.org/10.3390/jcm9040966
Received: 28 February 2020 / Revised: 28 March 2020 / Accepted: 28 March 2020 / Published: 31 March 2020
(This article belongs to the Section Clinical Laboratory Medicine)

Abstract

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental disorder characterized by difficulties in social interaction, language development delays, repeated body movements, and markedly deteriorated activities and interests. Environmental factors, such as viral infection, parental age, and zinc deficiency, can be plausible contributors to ASD susceptibility. As ASD is highly heritable, genetic risk factors involved in neurodevelopment, neural communication, and social interaction provide important clues in explaining the etiology of ASD. Accumulated evidence also shows an important role of epigenetic factors, such as DNA methylation, histone modification, and noncoding RNA, in ASD etiology. In this review, we compiled the research published to date and described the genetic and epigenetic epidemiology together with environmental risk factors underlying the etiology of the different phenotypes of ASD.
Keywords: autism spectrum disorder; genetic; epigenetic; etiology autism spectrum disorder; genetic; epigenetic; etiology

1. Introduction

Autistic disorder or a broader form of autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by difficulties in social interaction, delayed development of communication and language, repeated body movements, and impaired intelligence development, first described by psychiatrist Leo Kanner in 1943 [1,2]. The prevalence of typical autism and ASD is approximately 5.5–20 and 18.7–60 per 10,000 individuals, respectively [3]. Moreover, ASD has increased steadily since the term was coined, with the prevalence of autism worldwide currently at 1%–2% [4,5,6,7]. This phenomenon is partly due to an increase in awareness and the development of the Mental Disorders Diagnosis and Statistical Manual (DSM) criteria, starting with schizophrenia which began in 1952, and the development of key diagnostics, which currently deal with various mental disorders [8]. In addition, about 31% of ASD patients showed intellectual disabilities [9] and 20%–37% of them were known to have epilepsy [10,11]. Moreover, ASD is often accompanied by psychiatric or other medical problems, including anxiety disorders, depression, attention deficit hyperactivity disorder, sleep disorders, and gastrointestinal problems [12,13,14]. So far, many theories about ASD etiology and pathogenesis have been proposed, but it is said to be related to the interaction of genetic and environmental factors [15,16]. The concordance rate of ASDs in monozygotic twins (92%) was much higher than that in dizygotic twins (10%), indicating that genetic factors are more likely to contribute to ASD than environmental factors [17]. Genome-wide association and microscopy analysis have identified many different loci and genes that are associated with the etiology of ASD. However, although many genetic and epigenetic risk factors have been suggested, no clear pathogenesis and specific diagnostic markers for ASD have been identified. Accumulated evidence has also demonstrated an important role of epigenetic factors, such as DNA methylation, in ASD etiology [18]. To better understand the molecular basis of ASD, we describe the genetic and epigenetic epidemiology along with the environmental risk factors underlying the etiology of ASD (Figure 1).

2. Environmental and Prenatal Factors that Cause ASD

2.1. Viral Infection

As ASD is a neurodevelopmental disorder, it is commonly considered a genetic disorder. However, there are many studies that support the idea that environmental factors can be a major cause of ASD. Most of these factors are due to the prenatal period, which can be affected by environmental changes within the parental body [19]. During pregnancy, the maternal body becomes immunosuppressed, which makes the mother and the developing embryo susceptible to many infectious agents [20]. Similarly, it has been consistently suggested that parental viral infections are associated with the development of autism in their offspring [21,22,23]. Among the infectious diseases, some have been specifically pointed out as contributing to infantile autism when infection occurs during the first trimester of pregnancy [24]. These diseases include rubella [21,25,26,27], measles, mumps [21,26,27], chicken pox [21,28], influenza [21,23], herpes simplex virus [29], pneumonia, syphilis, varicella zoster [30], and cytomegalovirus [27,31,32,33]. Of note, cytomegalovirus is known to cause permanent neurological damage in about 10%–20% newborns when the mother is infected [34]. Moreover, bacterial infection during the second trimester of pregnancy has also been suggested to cause autism of infants [21,22]. In some cases, autoimmune diseases of parents were shown to be related to infantile autism [35,36]. Animal model studies have also shown that maternal infections activated the immune system, which eventually affects fetal brain development [37,38].

2.2. Parental Age

We have shown that maternal infection is directly related to the fetal pathological status since the baby is developed and nourished within the maternal body [20]. Similarly, the age of pregnant women and paternity were suggested as one of the most plausible contributors to increasing the risk of autism [39,40,41,42,43,44,45]. Meta-analysis for the correlation between maternal age and autism was analyzed by Sandin et al. A maternal age < 20 showed a lower risk (the relative risk for autism was 0.76) for autism compared to a maternal age between 25 and 29. On the other hand, the relative risk for mothers aged 35 or over compared to mothers aged 25 to 29 was 1.52 [46]. Reichenberg et al. reported a population-based study showing that the risk for autism began to increase at the paternal age of 30 and continued to increase after the age of 50 [42]. Paternal ages above 55 had at least twice the risk to have a child with autism, compared with those below 50 [42]. Moreover, it is well known that the older the parents, the higher the chance of miscarriage [47,48,49,50], fetal death [47,51,52], childhood cancers [53,54], and schizophrenia [55,56,57,58]. This is thought to be due to an increase in de novo genetic mutation during germ cell development in the aging process [59,60]. The effect of parental age on various diseases has been supported by many studies, and the correlation between parental age and autism seems to be one of the most acceptable factors causing autism [47,53,55,59].

2.3. Zinc Deficiency

The physiological function of zinc was first identified in the study of carbonic anhydrase [61]. Currently, more than 300 zinc-related enzymes have been discovered, including isoenzymes [62]. Zinc, as a cofactor in metalloenzymes, plays a catalytic role mostly in the transformation of substrates by aiding the formation of hydroxide ions at neutral pH or through Lewis acid catalysis [63,64]. Zinc is now known to be an essential trace element that plays a role in the immune system, protein synthesis, and wound healing [65]. Moreover, zinc has been known to play a role in forming the zinc finger motif of proteins and binding them to DNA, suggesting that zinc is also involved in regulating gene expression [66]. Zinc also supports fetal growth and development during pregnancy and the development of children [67,68]. Therefore, prolonged deficiency of zinc during pregnancy might lead to diverse dysfunction of embryonic growth, especially neurodevelopment [69,70,71]. Research on the relationship between zinc and autism began with reports of the metal ion’s involvement in neurodegeneration and dysfunction [72,73,74,75,76,77]. Since metal toxicity was shown to cause damage to the central nervous system [71,72], it was expected that an excess of zinc could cause damage to the nervous system [78,79,80,81,82,83,84,85]. A recent study also suggests that a toxic metal uptake and deficiency of essential elements increase the risk of ASD [86]. It has been noted that zinc interacts with β-amyloid and its precursors, which are crucial factors for the degenerative process of the brain [73,85,87,88,89,90,91].
Synaptic morphology and function were associated with autism, schizophrenia, and Alzheimer’s disease. The normal function of synapses depends largely on the molecular setting of the synaptic proteins, including ProSAP/Shank proteins, which function as scaffolding molecules for protein–protein interaction at postsynaptic density. ProSAP/Shank localization to postsynaptic density is induced by increased levels of zinc [92,93,94]. Thus, zinc deficiency was shown to dysregulate ProSAP/Shank and postsynaptic density in vivo and in vitro [94]. Several reports suggested that mutation in ProSAP/Shank could lead to ASD [95,96,97]. Moreover, ProSAP/Shank proteins, including ProSAP1/Shank2 and ProSAP2/Shank3, have a C-terminal sterile alpha motif, to which zinc can bind [98]. Thus, a lack of zinc prevents the zinc-dependent ProSAP/Shank proteins from playing a normal role in the formation of the scaffold structure. This leads to synaptic defects and can also lead to autism [94,99]. Moreover, the relation of zinc uptake and the expression of Shank3 regarding autism has been studied recently [100]. This study only included participants with genetically confirmed diagnosis of Phelan McDermid Syndrome (PMDS) with deletion of Shank3 gene [100]. The study showed that low Shank3 levels resulted in abnormally low zinc transporter, which led to low zinc concentration [100]. Statistical data also suggests the close relationship between zinc deficiency and infantile autism [101]. Of children between 0 and 3 years of age with autism, 43.5% (251/577) were zinc deficient in males and 52.5% (62/118) in females [101]. Among autism children from 4 to 9 years old, high rates of zinc deficiency were still found in males (28.1%) and females (28.7%) [101]. An animal-based study of Shank3+/- and Shank-/- transgenic mouse compared with prenatal zinc-deficient autism mouse model, which are offspring from zinc-deficient diet fed mice, showed diverse brain region abnormalities in different models of ASD [102]. However, the role of zinc deficiency on autism is still controversial. Sweetman et al. tested blood sample of 74 ASD children and claimed that zinc deficiency was not related to ASD [103,104]. Another recent report also suggested that zinc deficiency may not be micronutrient deficiency during pregnancy but may be a compensatory mechanism to prevent exposure to air pollutants during fetal development [103,104].

3. Genetic Epidemiology

Because autism is a neurodevelopmental disorder, the genetic aspect of autism has continuously been studied along with other factors that affect neurodevelopment. Autism can be defined by three behavioral domains: social interaction, language communication and imaginative play, and range of interests and activities [105,106]. Therefore, studies have been conducted to find genes involved in each symptom of ASD and to identify how the genes are related to ASD pathogenesis. Due to various symptoms of ASD, ASD-related genes are also closely related to other neurodevelopmental syndromic disorders, such as fragile X syndrome and Rett syndrome [107].

3.1. Chromosome Loci that Affect ASD

The phenotype of ASD is very vague and the specific factors that cause the disease have not yet been clearly elucidated [108]. The diverse phenotypes of ASD may be due to the large number of genes or environmental factors involved in autism, resulting in different genetic variations that occur in each individual. Moreover, the diverse interaction between the various ASD-associated genes makes it difficult to interpret its pathogenesis [109]. Previous research has approached this uncertainty by identifying gene mutation or copy number variation (CNV) at specific chromosomal loci that are relevant to neurodevelopment among individuals and families [109,110,111,112]. Genes that have long been mentioned as involved in the causation of autism are FOXP2, RAY1/ST7, IMMP2L, and RELN genes at 7q22-q33 [109]. These genes are also involved in diagnosable diseases that are associated with autism such as neurofibromatosis, tuberous sclerosis complex, and fragile X syndrome [109]. Moreover, not only coding regions but also noncoding regions of risk genes were found to be related to the etiology of autism [113].

3.2. Candidate Genes on Chromosome 7

Some researchers have focused on the locus of chromosome 7, as many genes in this region seem to be related to autism [114,115,116] (Figure 2). An international study conducted by the International Molecular Genetic Study of Autism Consortium on 99 multiplex families was able to point out the most probable ASD-related regions on six different chromosomes (chromosomes 4, 7, 10, 16, 19, and 22), with chromosome 7 being the most significant [117]. Interestingly, a genome-wide study on the pedigree of the KE family have shown that the region implicated in language disabilities is localized to 7q31 [118]. Half of the KE family members struggled with serious language impairment. Genome-wide association studies found more specific loci concerning speech and language development and autism-related loci, such as SPCH1 and AUTS1 (autism susceptibility locus) [119,120]. Subsequent studies also reported increased allele sharing on 7q within the autism relative pair families [115,121,122].

3.2.1. FOXP2

Forkhead box P 2 (FOXP2) is the first known gene involved in oral movement and speech [123,124]. Heterozygous FOXP2 mutation causes severe speech and language disorders, while cognition and other aspects are relatively low in severity. FOXP2 is localized between 7q31.1 and 7q31.31, which are known to be associated with language impairment and mental retardation. Further research discovered that FOXP2, as a transcription factor, could regulate gene expression in the development of lung, cardiovascular, intestinal, and neural tissues [124,125]. The inheritance pattern of the three-generation pedigree of the KE family revealed that all affected family members had a point mutation in the forkhead domain of FOXP2, indicating a relevance of this gene to the speech and language deficits observed in ASD [123,126]. However, there are also contradictory views on the relationship between FOXP2 and ASD [127,128]. Case-control association study with Spanish ASD patients revealed that common variants of FOXP2 were not directly connected with ASD [127,129].

3.2.2. RAY1/ST7

The RAY1/ST7 gene was identified in an autistic individual carrying a translocation breakpoint on chromosome 7 [113]. RAY1, which spans more than 220 kb of DNA and is encoded by 16 exons by alternative splicing, is expressed in a variety of tissues with varying levels of expression [113]. However, any specific variants in the coding region were not found in 27 unrelated ASD individuals, indicating that there is no sequence associated with etiology of ASD in the coding sequence [113]. It was also suggested that long noncoding RNA (lnc RNA) called ST7 overlapping transcript antisense 1-4 (ST7OT1-4), which possibly regulates the expression of RAY1/ST7, could be associated with autism [130,131]. Moreover, no significant further studies have been conducted to provide solid evidence for the relationship between RAY1/ST7 and ASD since the study of Vincent et al. [131]. Therefore, further studies have to be made to verify the function of RAY1/ST7 and its implications in autism [131].

3.2.3. IMMP2L

IMP2 inner mitochondrial membrane protease-like (IMMP2L) was identified as the most frequently associated gene to autism through high-density SNP (single nucleotide polymorphism) analysis on chromosome 7 [132]. IMMP2L was originally known to be related to a complex neuropsychiatric disorder, Gilles de la Tourette syndrome, which demonstrated an overlapping phenotype with ASD [133]. A high-density association analysis study was conducted with 127 families and 188 gender-matched controls that focused on the locus autism, susceptibility to, 1 (AUTS1) of chromosome 7 [132]. This study screened more than 3000 SNPs in the conserved region and highlighted several genes including IMMP2L and dedicator of cytokinesis 4 (DOCK4) that required further research to determine their association with ASD [132]. Fabian et al. recently conducted an animal-based study using IMMP2L knockdown mice to study the effect of IMMP2L deficiency on behavioral domains. This study shows that IMMP2L deficiency induced behavioral effects, which was gene-dose and sex dependent [134]. However, IMMP2L may be not a common gene that causes ASD because coding mutation was not observed in ASD patients [135]. Another family-based association study focused on zinc finger protein 533 (ZNF533), DOCK4, and IMMP2L genes in the Chinese Han population showed that SNPs within ZNF533 and DOCK4 were related to autism, whereas IMMP2L was shown irrelevant [136].

3.2.4. RELN

Reelin (RELN) is a gene with 65 exons located in 7q22 that is necessary for the formation of brain structure by directing the migration of several neuronal cell types and the development of neural connections [137,138,139,140]. The signaling protein roles of RELN in the migration of neurons and neural connection could explain the RELN abnormalities in patients with ASD [141,142,143,144,145] along with Alzheimer’s disease [146,147], schizophrenia [148,149], lissencephaly [150,151], and bipolar disease [149]. One study showed that reduced blood levels of RELN might be the cause of autism [152]. In addition, to determine the association between ASD and single-locus markers and multi-locus haplotypes, family-based association analysis for 218 Caucasian families showed RELN as an important potential contributor to autism [143]. Moreover, a larger family-based RNA-SSCP and DNA sequencing data revealed the association and linkage that a polymorphic trinucleotide repeat (GGC) located in the 5′ untranslated region of the RELN gene may play a role in the transcriptional regulation, and longer GGC repeats are correlated with vulnerability to ASD [142]. Wang et al. reviewed and analyzed papers published in 2013 and concluded that rs362691 SNP in RELN contributed more to the ASD risk than rs736707 or GGC repeat variants [153].
According to the Simons Foundation Autism Research Initiative (SFARI) database [154], 913 genes and 17 recurrent CNV loci are suggested to be implicated with autism. Among these 17 CNV loci, only one CNV locus, 7q11.23, is known to exist within 7q22-33 region [155]. Moreover, based on the gene score database conducted by SFARI, RELN is the only gene which seems to have a strong association to autism on 7q [156,157]. Therefore, further studies are required to narrow down the potential genes that are associated with ASD.

3.3. Neurodevelopmental Disorders and ASD by CNV

In addition, recent studies have found that inherited and de novo CNV could contribute to ASD. Changes in genetic expression involved in neural development are the main genetic etiology of ASD, such as suppression of neurodevelopment, changes in brain size, synapse formation, and connectivity between brain regions. These gene dosage changes can be caused by CNV and can be confirmed by SNP analysis. CNVs are a phenomenon in which parts of the genome are repeated in various numbers from individual to individual by deletion, duplication, translocation, and reversal [158]. Seven percent of ASD families were found to be associated with de novo CNVs. For example, duplications in 16p11.2, 15q11-q13, 7q11.23, 1q21.1, 22q11.2, and 7q22-q31 and deletions in 16p11.2, 3q29, and 22q11.2 were found to be associated with ASD [159] (Table 1). Microdeletion of 16q24.3 is associated with ASD because it affects ankyrin repeat domain 11 (ANKRD11) and zinc finger protein 778 (ZNF778) genes, leading to cognitive impairment and brain abnormality [160]. Chromosomal deletion of ~593 kb or segmental duplication of ~147 kb in 16p11.2 affected the neural development of the brain, which caused ASD [161,162]. These 16p11.2 microdeletions and microduplications were found in approximately 1% of patients with ASD. Potassium channel tetramerization domain-containing 13 (KCTD13), which is one of the genes that encompasses the deletion regions in 16p11.2, is associated with neurodevelopmental phenotypes. KCTD13 encodes a polymerase delta-interacting protein 1 that interacts with polymerase δ in the nucleus of proliferating cells. Therefore, KCTD13 deletion resulted in a decrease in the proliferation of neuronal progenitors and an increase in cell death during brain development [163]. On the other hand, overexpression of KCTD13 with an increase in redundancy of 16p11.2 delayed brain development and caused microcephaly. The effect of KCTD13 suppression is still controversial. Golzio et al. argued that the deletion of 16p11.2 stimulated brain development, which evolved into macrocephaly [164]. This was rebutted by Escamilla et al., who showed no differences in embryonic nor adult brain size after KCTD13 deletion in mice [165].
The 5p14.1 region, which encompasses cadherin 10 (CDH10) and cadherin 9 (CDH9), encodes neuronal cell-adhesion molecules and was identified by a genome-wide association approach using 943 ASD families [169]. Although the 2.2 megabase intergenic region between CDH10 and CDH9 was not likely to be related to ASD, CDH10 deletion is one of the common variants that is implicated in ASD risk [159].
Arking et al. identified common variants that contribute to autism in contactin-associated protein-like 2 (CNTNAP2), a member of the neurexin superfamily [162,179,180]. Although rare, alterations in neurexin1 (NRXN1), which is located on chromosome 2p16.3 (which encodes presynaptic cell adhesion molecules) in ASD patients, including subtle sequence variants in the coding region could contribute to the susceptibility of ASD [162,179,180].
Deletion at the 17q12 region is a strong candidate for ASD, as well as schizophrenia and RCAD (renal cysts and diabetes syndrome). The loss of one or more of the 15 genes found in the 17q12 region causes ASD and schizophrenia, and the more genes that are deleted, the more brain development and function becomes affected [172]. The chromosomal CNV by 22q11 deletion, which causes 22q11.2 deletion syndromes, shows higher susceptibility for ASD than the general population at about 23%–50% [166].
Recently, Leblond et al. found notable ASD-related genes, including kalirin RhoGEF kinase (KALRN), phospholipase A2 group IVA (PLA2G4A), and regulating synaptic membrane exocytosis 4 (RIMS4), which are expressed in the nervous system during development and maturation [166]. KALRN encodes a guanine nucleotide exchange factor expressed in neural tissue [166,167]. KALRN, together with Huntingtin, regulates dendritic spine plasticity, and its de novo variant (3q21.2 duplication) was observed in ASD patients [181]. Both KALRN and PLA2G4A knockout mouse models showed abnormalities in neuronal maturation and long-term potentiation in the brain [168]. De novo CNV by stop truncation in RIMS4, which encodes presynaptic proteins during dendritic and axon morphogenesis, is likely to be associated with perturbed modulation of the releases of glutamate at the synapse and contribute to the development of autism [173].
Fragile X mental retardation protein (FMRP), which is associated with Fragile X Syndrome, is a selective RNA binding protein and regulates polyribosome-mediated translation at synapses [182]. Darnell et al. revealed that FMRP interacts with the transcripts involved in ASD [177]. Fmr1 knockout mice were defective in synaptic plasticity, which may be caused by blocking the translation of proteins with synaptic function [178].
Splicing factor nSR100/SRRM4 functions specifically in neuronal cells and regulates neural ‘microexons’ (3–15 nucleotides) through alternative splicing [171]. In ASD patients, neural microexons are frequently misregulated in the brain, which is associated with reduced levels of nSR100. Mirzaa et al. identified 23 variants of ZNF292 (zinc finger protein 292), which resulted from alternative splicing of the most terminal exon 8. These variants in ZNF292 were associated with neurodevelopmental disorders with or without ASD [170]. Deletion of 6q14.3 in ZNF292 also resulted in ASD symptoms, such as learning and intellectual disabilities and behavioral problems [183].
Ubiquitin-protein ligase E3A (UBE3A) is one of the most potent regulators involved in ASD pathology. UBE3A and neighboring ASD candidate gene gamma-aminobutyric acid receptor subunit beta-3 (GABRB3) were downregulated in MeCP2-deficient mice and ASD patients [184]. UBE3A is also reduced in Angelman syndrome, which is caused by maternal loss of chromosome 15q11-q13 and shows ASD features [185]. In addition, UBE3A is involved in the maintenance of synaptic plasticity and in dendritic spine density [186]. Smith et al. generated a mouse model expressing double and triple doses of UBE3A, which was reminiscent of ASD patients with maternal 15q11-13 duplication [187]. Like ASD patients, mice with increased dosage of UBE3A showed defective social interaction; they rarely communicated with other mice and did not emit ultrasonic vocalization when they encountered new mice of the same sex.
The deletion of 142 kb at intron 8 of SHANK3 of the paternal chromosome 22q13 (heterozygous mutation) can cause ASD [95,96,97]. On the other hand, an additional copy of 22q13/SHANK3 did not display ASD symptoms, such as language and social communication impairment [95,97,174,175]. In the postsynaptic density (PSD) complex, SHANK3 binds to neuroligins (NLGNs) to form glutamatergic synapses [97]. The representative NLGNs, NLGN3 and NLGN4, are essential for cell adhesion and synaptogenesis, and thus, deletion of the NLGN3 gene shows the same phenomenon as autism [176]. Therefore, these reports suggest that SHANK together with NLGNs are involved in the formation of the appropriate postsynaptic structure, which is required for the development of language and social communication.

4. Epigenetic Dysregulation Underlying ASD

Epigenetic mechanisms regulate chromatin structure and gene expression without altering the DNA sequence [188,189]. They play an important role in the fine-tuning of development-related genes and are involved in the development of the brain; thus, epigenetic dysregulation can cause neurodevelopmental disorders, including ASD.
Significant differences in expression levels of epigenetic-related genes were found in ASD patients but not in normal individuals, suggesting that epigenetic modifications play a pivotal role in the ASD phenotype [190,191,192]. Only recently, the etiological role of epigenetic dysregulation in ASD has been documented by finding a specific mutation in epigenetic-regulation-related genes in ASD patients. There are two major molecular epigenetic mechanisms involved in gene expression: DNA methylation and histone modification. Noncoding RNA is also a crucial player involved in regulating chromatin structure and gene expression (Table 2).

4.1. DNA Methylation

Since DNA methylation links between genes and environmental factors and can answer the complex pathogenesis of autism, most studies have investigated this epigenetic mechanism [206]. Although definitive biological markers or mechanisms underlying ASD have not yet been identified, researchers have been investigating the relationship of environmental exposure and DNA methylation with autism [207,208,209,210,211]. Wong et al. found variant DNA methylation patterns in ASD-discordant monozygotic twins, which is known to be the first epigenetic analysis in ASD patients [212]. They identified differentially methylated CpG sites that were likely to be associated with ASD by comparing ASD-discordant monozygotic twins. Top-ranked differentially methylated regions included GABRB3, AF4/FMR2 family member 2 (AFF2), NLGN2, jumonji domain-containing 1C (JMJD1C), small nuclear ribonucleoprotein polypeptide N (SNRPN), SNRPN upstream reading frame (SNURF), UBE3A, and potassium inwardly rectifying channel subfamily J member 10 (KCNJ10); some of these were known to be previously implicated in ASD. These findings indicate that DNA methylation as an epigenetic factor can provide an explanation for the etiology of ASD, which may otherwise be difficult to do using a genetic approach.
DNA methylation at the fifth carbon of the cytosine (5-methylcytosine, 5mC) can be converted to 5-hydroxy methylcytosine (5hmC) during the DNA demethylation process [213]. Interestingly, DNA hydroxymethylation has also been implicated in ASD [214,215]. This was supported by studies that used animal models with mutations in ASD-related genes. Chromatin remodelers AT-rich interaction domain 1B (Arid1b) and chromodomain helicase DNA-binding protein 8 (Chd8) [216,217,218,219,220,221], histone methyltransferase euchromatic histone lysine methyltransferase 1 (Ehmt1) [222,223], and transcriptional regulators Foxp1 and Foxp2 [224,225,226,227,228,229,230,231] were targeted to investigate ASD-like behavioral phenotypes in mutated mice. SET domain-containing 5 (Setd5) was suggested as one of the histone methyltransferase candidates [232], but methyltransferase activity of Setd5 was not accepted by the majority of other researchers [233,234].
Phenotypes of these mutant mice were characterized by sensory disorders, motor coordination disorders, hydrocephalus, and weight loss, as seen in ASD patients. In behavioral tests, they showed increased anxiety-like behavior, social deficits, and repetitive behaviors. In addition, studies have shown that 5hmC is found abundantly in many genes associated with neural development in ASD, including glutamic acid decarboxylase 67 (GAD1) and RELN [235]. Of note, DNA methylation at CpG and non-CpG sites has been suggested as a major factor identifying the causes of many other neurological disorders, including Alzheimer’s disease, Parkinson’s disease, Rett syndrome, fragile X syndrome, Huntington’s disease, and amyotrophic lateral sclerosis [211].

4.1.1. MeCP2

One of the best-studied epigenetic factors associated with ASD is methyl-CpG binding protein 2 (MeCP2). MeCP2 is an important epigenetic regulator of human brain development and is highly abundant in the central nervous system, particularly in GABAergic interneurons. Since the MeCP2 protein has the dual function of acting as both activator and repressor of transcription, the binding action of MeCP2 in healthy individuals has been shown to regulate many genes with synaptic functions, such as GABRB3, brain-derived neurotrophic factor (BDNF), distal-less homeobox 5 (DLX5), insulin-like growth-factor-binding protein 3 (IGFBP3), cyclin-dependent kinase-like 1 (CDKL1), protocadherin beta 1 (PCDHB1), protocadherin 7 (PCDH7), and lin-7 homolog A (LIN7A) [184,193]. Abnormal physiological levels of MeCP2 caused by overexpression via gene duplication or loss of expression by mutation, i.e., MeCP2 duplication syndrome or Rett syndrome, respectively, were known to exhibit social behavioral disorders similar to ASD [236]. Decreased expression of MeCP2 in the frontal cortex of ASD patients was associated with abnormal methylation on the promoter of MeCP2 [237]. This was further supported by Lu et al., demonstrating the important role of MeCP2 promoter methylation in ASD etiology by locus-specific methylation of the MeCP2 promotor using dCas9-based methylation targeting method [238]. Kuwano et al. analyzed peripheral blood to determine differentially expressed genes between ASD patients and gender-matched healthy controls. They found that MeCP2 overexpression (>1.5-fold) was observed in peripheral blood of idiopathic ASD patients [239]. MeCP2 proteins bind to their target genes and recruit other chromatin remodelers, which may repress the target genes [240]. Zhubi et al. showed that enhanced binding of MeCP2 to promoters of target genes was correlated with the increased ratio of 5-hydroxymethyl cytosine to 5-methyl cytosine (5hmC/5mC) at the regulatory regions [235]. They also found enhanced MeCP2 binding to the increased 5hmC/5mC promoter regions of GAD1 and RELN genes, which were known to be downregulated in postmortem brains of ASD patients [235]. GAD1 is an enzyme that catalyzes glutamate to the inhibitory neurotransmitter γ-aminobutyric acid (GABA) and thereby plays a pivotal role in maintaining an excitatory–inhibitory balance [241,242]. Reelin is a signaling protein that is involved in neural migration, development of neural connection, and modulating synaptic plasticity [243].

4.1.2. OXTR

Oxytocin receptors (OXTR) encode G-protein-coupled receptors that bind to the neurotransmitter peptide hormone oxytocin. OXTR is also involved in ASD etiology [194]. Genome-wide microarray and comparative genomic hybridizations on 119 proband of ASD families identified CNV (deletion) of the OXTR gene [244]. Interestingly, however, deletion at the OXTR region was not detected in the affected sibling of the proband, but aberrant gene silencing by increased DNA methylation at the regulatory region was observed instead. In-depth DNA methylation analysis showed that several CpG islands that regulate OXTR expression were hypermethylated in the temporal cortex of ASD patients [244]. This finding was supported by a study that observed hypermethylation at the OXTR region in a fetal membrane of preterm birth, which is also an ASD symptom [245]. In addition, adults with ASD showed higher levels of OXTR methylation in CpG 16 in the intron 1 region compared to neurotypical subjects. The researchers found that the methylation of CpG 16 was particularly correlated with social interaction and communication scores [246].

4.1.3. SHANK3

Mutations in the SH3 and multiple ankyrin repeat domains 3 (SHANK3) gene are associated with autism and affect the morphology of dendritic spines and synaptic transmission [196]. SHANK3 is a scaffolding protein in the postsynaptic density and functions in synapse formation and maintenance. Of interest, methylation of CpG island was shown as a strong regulator for SHANK3 expression. During mouse brain development, SHANK3 was upregulated two weeks after birth when the methylation rate in the CpG island was highly increased. Zhu et al. reported altered methylation patterns in SHANK3 by analyzing the DNA methylation profiles of five CpG island regions (CGI-1 to CGI-5) in postmortem brains of ASD patients and controls [247]. Significant increase in overall DNA methylation of CGI at CGI-2, CGI-3, and CGI-4 was found in ASD brain tissues. In addition, the SHANK3 knockout mouse model exhibits a rescued behavioral phenotype when treated with potent histone deacetylase inhibitor, which strengthens the role of epigenetics in ASD [195]. These reports strongly suggest that defects in DNA methylation and histone modification of ASD-related genes are the underlying mechanisms for the development or symptoms of ASD [195].

4.2. Histone Modification and Chromatin Remodeling

Dysregulation of proteins that control histone modifications are associated with ASD. In general, H3K4me3, the trimethylation on the fourth lysine residue of histone H3, plays an important role in the open chromatin formation and gene activation. Specifically, H3K4me3 recruits chromosome remodeling factors to the gene transcriptional start site and is involved in the regulation of the differentiation, growth, and plasticity required for learning and memory of the hippocampus [248,249]. Shulha et al. found that changes in H3K4me3 levels in neurons were related to autism through deep sequencing with anti-H3K4me3-ChIP using prefrontal cortex neurons isolated from postmortem tissue of 6 months to 70 years of age [250]. However, further studies on a larger population are needed to clearly identify and assess the role of H3K4me3 in autism pathophysiology [250]. Similarly, deficiency of lysine-specific demethylase 5C (KDM5C) alters the epigenetic state, which is associated with intellectual disability and frequent autistic behavior [197]. Duffney et al. also reported that depletion of linker histone H1.4, which is encoded by the histone cluster 1 H1 family member e (HIST1H1E) gene, is associated with the features of ASD and intellectual disorders [198]. They found a de novo mutation of HIST1H1E gene in a 10-year-old boy with ASD [198]. The main function of the H1 linker protein is to organize the higher-order chromatin structure and regulation of gene transcription.
In addition, many efforts have been made to identify autism-related genes using whole exome sequencing in ASD subjects [251]. Frequent mutations of chromodomain helicase DNA-binding protein (CHD) encoding the ATP-dependent helicase, which is typically involved in chromatin remodeling, occur in autistic individuals [251]. Autistic patients with CHD8 mutations often showed additional distinct phenotypes, including macrophage and gastrointestinal disorders [252]. CHD8 appeared to inhibit the target genes of Wnt/β-catenin, with many other CHD8 targets involving autism risk genes [199].
In addition to the CHD family, there are several more genes related to chromatin remodelers, including ARID1B, BAF chromatin-remodeling complex subunit BCL11A (BCL11A) and activity-dependent neuroprotector homeobox (ADNP) [201]. ARID1B, a component of the ATP-dependent human SWI/SNF (or BAF) chromatin-remodeling complex, is a gene that is frequently mutated in autism [15,200]. In addition, BCL11A and ADNP are known to encode proteins that interact directly with members of the SWI/SNF complex and have been found to be frequently mutated in autism [201]. Therefore, ADNP can be a SWI/SNF-related gene that is ASD-associated and may explain the etiology of about 0.17% of ASD patients [201]. Many other chromatin-remodeling factors, including HDAC4 and polycomb group protein EZH2, are often mutated in patients with intellectual disabilities and ASD, as chromatin regulators are functionally essential for neural progenitor self-renewal, neural differentiation, synaptogenesis, apoptosis, and neurological and cognitive development [253].

4.3. MicroRNAs

MicroRNAs (miRNAs) are short noncoding RNA molecules that range from 15 to 22 nucleotides. miRNAs are epigenetic regulators that control the expression of many genes at the level of post-transcription by blocking protein synthesis or inducing mRNA degradation [254]. It is well known that 50% of human genes are regulated by miRNAs and control all the functional pathways involved in cell differentiation, proliferation, development, and apoptosis [202]. To date, about half of all miRNAs identified in humans are expressed in the brain. Mor et al. utilized small RNA sequencing analysis to find unregulated miRNAs and correlated the results with genome-wide DNA methylation data. miRNAs significantly expressed in the ASD brains were associated with synaptic function [255]. Animal model studies also showed that deregulation of miRNA synthesis leads to neurodevelopmental disorders [202,203,204,205]. Abu-Elneel et al. identified 28 miRNAs (out of 466 miRNAs examined) that were differentially expressed between autism and control in a postmortem brain analysis [256]. The differential expression of miRNAs in autistic individuals was also examined in whole blood and lymphoblastoid cell samples [257,258].
The treatment of ASD using miRNA-based therapy is a promising strategy because miRNAs can be delivered into cells and not induce integration into the host genome. Overexpressed miRNA in ASD patients could be downregulated by miRNA antagonists, i.e., miRNA inhibition therapy [259], while miRNA replacement therapy using miRNA mimics can compensate for low-expressing miRNAs [259].

5. Social Interaction Genes Associated with ASD

As ASD causes defects in social interaction, communication, repetitive patterns of behavior, and lack of attention, it is classified as both a mental disorder and a neurodevelopmental disorder by the American Psychiatric Association. Thus, the prosocial hormone oxytocin has been implicated with the pathogenesis and treatment of ASD. Oxytocin and vasopressin systems were proposed as modulators of social behavior in vertebrates, including humans [260]. Significantly higher oxytocin and receptor binding was observed in the nucleus basalis of Meynert of the forebrain of ASD frozen specimens [261]. On the other hand, significantly lower binding of oxytocin to receptor was detected in the ventral pallidum (VP) of ASD brains compared to controls. VP is involved in the mesolimbic dopamine reward pathway, and lower oxytocin receptor binding levels may be interpreted as a reduced experience of oxytocin-mediated social reward in ASD patients [261]. Of note, ASD patients who inhaled a single dose of oxytocin displayed promoted social behavior [262].
Variation in the arginine vasopressin receptor 1a (AVPR1a) gene on chromosome 12q14–15, which encodes the V1a receptor, is also associated with a deficiency in social behavior. As stated above, vasopressin, a neuropeptide, has been implicated in the social adaptation of mammals, including humans [263]. In terms of ASD diagnosis, AVPR1a variation is correlated with the scores of autism quotients [264]. Independent reports suggest that microsatellites in the promoter region of AVPR1a are closely related to ASD [265]. Intravenous administration of RG7713, a V1a receptor antagonist, could improve deficiencies in social communication in ASD without intellectual disability [266].

6. Conclusion and Future Perspectives

ASD is a complex neurodevelopmental disorder with diverse symptoms and various aspects. Therefore, it is likely that various factors are involved in ASD, including environmental, genetic, and epigenetic. Presently, a genomic approach using patient samples may be the most appropriate method as ASD displayed the highest proportion of cases with a clinically relevant CNV [267]. However, since epigenetics is the underlying mechanism of regulating gene expression, it will be necessary to understand ASD from an epigenetic perspective, which will help to develop ASD therapies by controlling epigenetic states.
The human brain is a complex organ composed of various types of neurons, glia, microglia, neuroepithelial cells, neural stem/progenitor cells, etc., consisting of about 100 billion cells. Moreover, since human brains grow and change in proportion and composition throughout life, particularly early in life, it may be difficult to understand the exact etiology of ASD by studying postmortem samples. Thus, induced pluripotent stem cells (iPSCs) may be an alternative way to study the human brain or neurological disorders [268]. As iPSCs are pluripotent and can differentiate into all cell types of our body, patient-derived iPSCs can be used as starting material to generate disease model neurons or three-dimensional minibrain structures, i.e., brain organoids [269]. For example, Mariani et al. utilized brain organoids to identify the mechanism underlying ASD [270]. Brain organoids generated using ASD-patient-derived iPSCs showed accelerated cell cycles and an increased number of GABAergic neurons, which was controlled by forkhead box G1 (FOXG1). Therefore, FOXG1 could be a candidate gene for the etiology underlying ASD.
ASD manifests complex phenotypes and is usually accompanied by comorbidities. One of the comorbidities associated with ASD is gastrointestinal problems, which are closely affected by the gut microbiome [271]. Recent studies suggest that intestinal microbiome is involved in many neurological disorders, including Alzheimer’s disease and ASD, and have built upon the concept of the brain–gut axis, in which the brain and gastrointestinal tract communicate bidirectionally via signaling molecules [272]. Although much remains to be discovered about the brain–gut-microbiome axis, manipulating the gut microbiota composition in patients with ASD may be a potential therapy for treating gastrointestinal problems in ASD [271].
Another intriguing approach to ameliorate ASD symptoms is to use exosomes, which are suborganelles rich in DNA, RNA, and protein content [273]. Interestingly, the composition of exosomes secreted from mesenchymal stem cells could be manipulated by the treatment of several interleukins [274]. Recently, neuroinflammation induced by proinflammatory cytokines was suggested as a novel pathogenesis of ASD, particularly in irritability and socialization problems [275]. As a therapeutic approach, stem-cell-derived exosomes containing anti-inflammatory molecules could be used as efficient carriers for delivering anti-inflammatory molecules across the blood–brain barrier [276]. These attempts have already been made to alleviate the symptoms of Alzheimer’s disease [276].
Recent developments in bioengineering and stem cell technology will help to understand the pathophysiology and cure of neurological diseases, including ASD. Although much effort has been made to identify the pathogenesis of ASD, research using organoids is expected to be responsible for the future of medical science advancements. The combinatorial approach, by which several different tissue organoids from patient-derived iPSCs are cultured in microfluidic organ-on-a-chip system, has great potential in allowing the study of organ physiology and disease etiology in a simulated tissue–tissue interaction system [277].

Author Contributions

Conceptualization, S.H.Y., J.C., W.J.L., and J.T.D.; validation, J.T.D.; writing—original draft preparation, S.H.Y., J.C., W.J.L., and J.T.D.; writing—review and editing, J.T.D.; supervision, J.T.D.; funding acquisition, J.T.D. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) of the Republic of Korea (grant Nos. 2016M3A9B6946835 and 2015R1A5A1009701).

Conflicts of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. Quaak, I.; Brouns, M.R.; Van de Bor, M. The dynamics of autism spectrum disorders: How neurotoxic compounds and neurotransmitters interact. Int. J. Environ. Res. Public Health 2013, 10, 3384–3408. [Google Scholar] [CrossRef][Green Version]
  2. Kanner, L.J. Autistic disturbances of affective contact. Nerv. Child 1943, 2, 217–250. [Google Scholar]
  3. Fombonne, E. The epidemiology of autism: A review. Psychol. Med. 1999, 29, 769–786. [Google Scholar] [CrossRef]
  4. Kim, Y.S.; Leventhal, B.L.; Koh, Y.-J.; Fombonne, E.; Laska, E.; Lim, E.-C.; Cheon, K.-A.; Kim, S.-J.; Kim, Y.-K.; Lee, H.; et al. Prevalence of Autism Spectrum Disorders in a Total Population Sample. Am. J. Psychiatry 2011, 168, 904–912. [Google Scholar] [CrossRef][Green Version]
  5. Saemundsen, E.; Magnússon, P.; Georgsdóttir, I.; Egilsson, E.; Rafnsson, V. Prevalence of autism spectrum disorders in an Icelandic birth cohort. BMJ Open 2013, 3, e002748. [Google Scholar] [CrossRef][Green Version]
  6. Wan, Y.; Hu, Q.; Li, T.; Jiang, L.; Du, Y.; Feng, L.; Wong, J.C.-M.; Li, C.-B. Prevalence of autism spectrum disorders among children in China: A systematic review. Shanghai Arch. Psychiatry 2013, 25, 70–80. [Google Scholar]
  7. Russell, G.; Rodgers, L.R.; Ukoumunne, O.C.; Ford, T. Prevalence of Parent-Reported ASD and ADHD in the UK: Findings from the Millennium Cohort Study. J. Autism Dev. Disord. 2013, 44, 31–40. [Google Scholar] [CrossRef][Green Version]
  8. Zeldovich, L. The Evolution of ‘Autism’As a Diagnosis, Explained; Spectrum: New York, NY, USA, 2018. [Google Scholar]
  9. Baio, J.; Wiggins, L.; Christensen, D.L.; Maenner, M.J.; Daniels, J.; Warren, Z.; Kurzius-Spencer, M.; Zahorodny, W.; Robinson, C.; Rosenberg, C.R.; et al. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years—Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. Mmwr. Surveill. Summ. 2018, 67, 1–23. [Google Scholar] [CrossRef]
  10. Canitano, R. Epilepsy in autism spectrum disorders. Eur. Child Adolesc. Psychiatry 2006, 16, 61–66. [Google Scholar] [CrossRef]
  11. Yasuhara, A. Correlation between EEG abnormalities and symptoms of autism spectrum disorder (ASD). Brain Dev. 2010, 32, 791–798. [Google Scholar] [CrossRef]
  12. Valicenti-McDermott, M.; McVicar, K.A.; Rapin, I.; Wershil, B.K.; Cohen, H.; Shinnar, S. Frequency of Gastrointestinal Symptoms in Children with Autistic Spectrum Disorders and Association with Family History of Autoimmune Disease. J. Dev. Behav. Pediatr. 2006, 27, S128–S136. [Google Scholar] [CrossRef]
  13. Richdale, A.L.; Schreck, K.A. Sleep problems in autism spectrum disorders: Prevalence, nature, & possible biopsychosocial aetiologies. Sleep Med. Rev. 2009, 13, 403–411. [Google Scholar]
  14. White, S.; Oswald, D.; Ollendick, T.H.; Scahill, L. Anxiety in children and adolescents with autism spectrum disorders. Clin. Psychol. Rev. 2009, 29, 216–229. [Google Scholar] [CrossRef][Green Version]
  15. De Rubeis, S.; He, X.; Goldberg, A.P.; Poultney, C.S.; Samocha, K.; Cicek, A.E.; Kou, Y.; Liu, L.; Fromer, M.; Walker, S. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 2014, 515, 209–215. [Google Scholar] [CrossRef]
  16. Ng, M.; de Montigny, J.G.; Ofner, M.; Docé, M.T. Health promotion and Chronic Disease Prevention in Canada: Research, Practice. Environmental Factors Associated with Autism Spectrum Disorder: A Scoping Review for the Years 2003–2013. HPCDP 2017, 37, 1. [Google Scholar]
  17. Bailey, A.; Le Couteur, A.; Gottesman, I.; Bolton, P.; Simonoff, E.; Yuzda, E.; Rutter, M. Autism as a strongly genetic disorder: Evidence from a British twin study. Psychol. Med. 1995, 25, 63–77. [Google Scholar] [CrossRef]
  18. Ciernia, A.V.; LaSalle, J. The landscape of DNA methylation amid a perfect storm of autism aetiologies. Nat. Rev. Neurosci. 2016, 17, 411–423. [Google Scholar] [CrossRef][Green Version]
  19. Hultman, C.M.; Sparen, P.; Cnattingius, S. Perinatal risk factors for infantile autism. Epidemiology 2002, 13, 417–423. [Google Scholar] [CrossRef]
  20. Clemens, L.E.; Siiteri, P.K.; Stites, D.P. Mechanism of immunosuppression of progesterone on maternal lymphocyte activation during pregnancy. J. Immunol. 1979, 122, 1978–1985. [Google Scholar]
  21. Deykin, E.Y.; MacMahon, B. Viral exposure and autism. Am. J. Epidemiol. 1979, 109, 628–638. [Google Scholar] [CrossRef]
  22. Atladottir, H.O.; Thorsen, P.; Ostergaard, L.; Schendel, D.E.; Lemcke, S.; Abdallah, M.; Parner, E.T. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders. J. Autism. Dev. Disord. 2010, 40, 1423–1430. [Google Scholar] [CrossRef]
  23. Zerbo, O.; Qian, Y.; Yoshida, C.; Grether, J.K.; Van de Water, J.; Croen, L.A. Maternal Infection During Pregnancy and Autism Spectrum Disorders. J. Autism. Dev. Disord. 2015, 45, 4015–4025. [Google Scholar] [CrossRef][Green Version]
  24. Karimi, P.; Kamali, E.; Mousavi, S.M.; Karahmadi, M. Environmental factors influencing the risk of autism. J. Res. Med. Sci. 2017, 22, 27. [Google Scholar] [CrossRef]
  25. Chess, S. Follow-up report on autism in congenital rubella. J. Autism. Child Schizophr. 1977, 7, 69–81. [Google Scholar] [CrossRef]
  26. Madsen, K.M.; Hviid, A.; Vestergaard, M.; Schendel, D.; Wohlfahrt, J.; Thorsen, P.; Olsen, J.; Melbye, M. A population-based study of measles, mumps, and rubella vaccination and autism. N. Engl. J. Med. 2002, 347, 1477–1482. [Google Scholar] [CrossRef]
  27. Libbey, J.E.; Sweeten, T.L.; McMahon, W.M.; Fujinami, R.S. Autistic disorder and viral infections. J. Neurovirol. 2005, 11, 1–10. [Google Scholar] [CrossRef]
  28. Diav-Citrin, O.; Ornoy, A. Adverse environment and prevention of early pregnancy disorders. Early Pregnancy 2000, 4, 5–18. [Google Scholar]
  29. Mahic, M.; Mjaaland, S.; Bovelstad, H.M.; Gunnes, N.; Susser, E.; Bresnahan, M.; Oyen, A.S.; Levin, B.; Che, X.; Hirtz, D.; et al. Maternal Immunoreactivity to Herpes Simplex Virus 2 and Risk of Autism Spectrum Disorder in Male Offspring. mSphere 2017, 2. [Google Scholar] [CrossRef][Green Version]
  30. Gillberg, C.; Mary, C. The Biology of the Autistic Syndromes; Cambridge University Press: Cambridge, UK, 2000. [Google Scholar]
  31. Yamashita, Y.; Fujimoto, C.; Nakajima, E.; Isagai, T.; Matsuishi, T. Possible association between congenital cytomegalovirus infection and autistic disorder. J. Autism. Dev. Disord. 2003, 33, 455–459. [Google Scholar] [CrossRef]
  32. Sweeten, T.L.; Posey, D.J.; McDougle, C.J. Brief report: Autistic disorder in three children with cytomegalovirus infection. J. Autism. Dev. Disord. 2004, 34, 583–586. [Google Scholar] [CrossRef]
  33. Kawatani, M.; Nakai, A.; Okuno, T.; Kobata, R.; Moriuchi, M.; Moriuchi, H.; Tsukahara, H.; Mayumi, M. Detection of cytomegalovirus in preserved umbilical cord from a boy with autistic disorder. Pediatr. Int. 2010, 52, 304–307. [Google Scholar] [CrossRef] [PubMed]
  34. Malm, G.; Engman, M.L. Congenital cytomegalovirus infections. Semin. Fetal Neonatal Med. 2007, 12, 154–159. [Google Scholar] [CrossRef]
  35. Mouridsen, S.E.; Rich, B.; Isager, T.; Nedergaard, N.J. Autoimmune diseases in parents of children with infantile autism: A case-control study. Dev. Med. Child Neurol. 2007, 49, 429–432. [Google Scholar] [CrossRef] [PubMed]
  36. Keil, A.; Daniels, J.L.; Forssen, U.; Hultman, C.; Cnattingius, S.; Soderberg, K.C.; Feychting, M.; Sparen, P. Parental autoimmune diseases associated with autism spectrum disorders in offspring. Epidemiology 2010, 21, 805–808. [Google Scholar] [CrossRef][Green Version]
  37. Smith, S.E.; Li, J.; Garbett, K.; Mirnics, K.; Patterson, P.H. Maternal immune activation alters fetal brain development through interleukin-6. J. Neurosci. Off. 2007, 27, 10695–10702. [Google Scholar] [CrossRef][Green Version]
  38. Short, S.J.; Lubach, G.R.; Karasin, A.I.; Olsen, C.W.; Styner, M.; Knickmeyer, R.C.; Gilmore, J.H.; Coe, C.L. Maternal influenza infection during pregnancy impacts postnatal brain development in the rhesus monkey. Biol. Psychiatry 2010, 67, 965–973. [Google Scholar] [CrossRef][Green Version]
  39. Gillberg, C. Maternal age and infantile autism. J. Autism. Dev. Disord. 1980, 10, 293–297. [Google Scholar] [CrossRef]
  40. Glasson, E.J.; Bower, C.; Petterson, B.; de Klerk, N.; Chaney, G.; Hallmayer, J.F. Perinatal factors and the development of autism: A population study. Arch. Gen. Psychiatry 2004, 61, 618–627. [Google Scholar] [CrossRef][Green Version]
  41. Maimburg, R.D.; Vaeth, M. Perinatal risk factors and infantile autism. Acta Psychiatr. Scand. 2006, 114, 257–264. [Google Scholar] [CrossRef]
  42. Reichenberg, A.; Gross, R.; Weiser, M.; Bresnahan, M.; Silverman, J.; Harlap, S.; Rabinowitz, J.; Shulman, C.; Malaspina, D.; Lubin, G.; et al. Advancing paternal age and autism. Arch. Gen. Psychiatry 2006, 63, 1026–1032. [Google Scholar] [CrossRef]
  43. Croen, L.A.; Najjar, D.V.; Fireman, B.; Grether, J.K. Maternal and paternal age and risk of autism spectrum disorders. Arch. Pediatr. Adolesc. Med. 2007, 161, 334–340. [Google Scholar] [CrossRef] [PubMed][Green Version]
  44. Durkin, M.S.; Maenner, M.J.; Newschaffer, C.J.; Lee, L.C.; Cunniff, C.M.; Daniels, J.L.; Kirby, R.S.; Leavitt, L.; Miller, L.; Zahorodny, W.; et al. Advanced parental age and the risk of autism spectrum disorder. Am. J. Epidemiol. 2008, 168, 1268–1276. [Google Scholar] [CrossRef] [PubMed][Green Version]
  45. Reichenberg, A.; Gross, R.; Sandin, S.; Susser, E.S. Advancing paternal and maternal age are both important for autism risk. Am. J. Public Health 2010, 100, 772–773. [Google Scholar] [CrossRef]
  46. Sandin, S.; Hultman, C.M.; Kolevzon, A.; Gross, R.; MacCabe, J.H.; Reichenberg, A. Advancing maternal age is associated with increasing risk for autism: A review and meta-analysis. J. Am. Acad. Child Adolesc. Psychiatry 2012, 51, 477–486. [Google Scholar] [CrossRef]
  47. De la Rochebrochard, E.; Thonneau, P. Paternal age and maternal age are risk factors for miscarriage; results of a multicentre European study. Hum. Reprod. 2002, 17, 1649–1656. [Google Scholar] [CrossRef][Green Version]
  48. De La Rochebrochard, E.; Thonneau, P. Paternal age > or = 40 years: An important risk factor for infertility. Am. J. Obstet. Gynecol. 2003, 189, 901–905. [Google Scholar] [CrossRef]
  49. Kleinhaus, K.; Perrin, M.; Friedlander, Y.; Paltiel, O.; Malaspina, D.; Harlap, S. Paternal age and spontaneous abortion. Obstet. Gynecol. 2006, 108, 369–377. [Google Scholar] [CrossRef]
  50. Jaleel, R.; Khan, A. Paternal factors in spontaneous first trimester miscarriage. Pak. J. Med. Sci. 2013, 29, 748–752. [Google Scholar] [CrossRef]
  51. Nybo Andersen, A.M.; Hansen, K.D.; Andersen, P.K.; Davey Smith, G. Advanced paternal age and risk of fetal death: A cohort study. Am. J. Epidemiol. 2004, 160, 1214–1222. [Google Scholar] [CrossRef][Green Version]
  52. Slama, R.; Bouyer, J.; Windham, G.; Fenster, L.; Werwatz, A.; Swan, S.H. Influence of paternal age on the risk of spontaneous abortion. Am. J. Epidemiol. 2005, 161, 816–823. [Google Scholar] [CrossRef]
  53. Yip, B.H.; Pawitan, Y.; Czene, K. Parental age and risk of childhood cancers: A population-based cohort study from Sweden. Int. J. Epidemiol. 2006, 35, 1495–1503. [Google Scholar] [CrossRef] [PubMed][Green Version]
  54. Urhoj, S.K.; Raaschou-Nielsen, O.; Hansen, A.V.; Mortensen, L.H.; Andersen, P.K.; Nybo Andersen, A.M. Advanced paternal age and childhood cancer in offspring: A nationwide register-based cohort study. Int. J. Cancer 2017, 140, 2461–2472. [Google Scholar] [CrossRef] [PubMed][Green Version]
  55. Malaspina, D.; Harlap, S.; Fennig, S.; Heiman, D.; Nahon, D.; Feldman, D.; Susser, E.S. Advancing paternal age and the risk of schizophrenia. Arch. Gen. Psychiatry 2001, 58, 361–367. [Google Scholar] [CrossRef] [PubMed][Green Version]
  56. Brown, A.S.; Schaefer, C.A.; Wyatt, R.J.; Begg, M.D.; Goetz, R.; Bresnahan, M.A.; Harkavy-Friedman, J.; Gorman, J.M.; Malaspina, D.; Susser, E.S. Paternal age and risk of schizophrenia in adult offspring. Am. J. Psychiatry 2002, 159, 1528–1533. [Google Scholar] [CrossRef][Green Version]
  57. Zammit, S.; Allebeck, P.; Dalman, C.; Lundberg, I.; Hemmingson, T.; Owen, M.J.; Lewis, G. Paternal age and risk for schizophrenia. Br. J. Psychiatry J. Ment. Sci. 2003, 183, 405–408. [Google Scholar] [CrossRef][Green Version]
  58. Sipos, A.; Rasmussen, F.; Harrison, G.; Tynelius, P.; Lewis, G.; Leon, D.A.; Gunnell, D. Paternal age and schizophrenia: A population based cohort study. BMJ 2004, 329, 1070. [Google Scholar] [CrossRef][Green Version]
  59. Penrose, L.S. Parental age and mutation. Lancet 1955, 269, 312–313. [Google Scholar] [CrossRef]
  60. Jones, K.L.; Smith, D.W.; Harvey, M.A.; Hall, B.D.; Quan, L. Older paternal age and fresh gene mutation: Data on additional disorders. J. Pediatr. 1975, 86, 84–88. [Google Scholar] [CrossRef]
  61. Keilin, D.; Mann, T. Carbonic anhydrase. Purification and nature of the enzyme. Biochem. J. 1940, 34, 1163–1176. [Google Scholar] [CrossRef][Green Version]
  62. Vallee, B.L.; Falchuk, K.H. The biochemical basis of zinc physiology. Physiol. Rev. 1993, 73, 79–118. [Google Scholar] [CrossRef]
  63. Vallee, B.L.; Galdes, A. The metallobiochemistry of zinc enzymes. Adv. Enzymol. Relat. Areas Mol. Biol. 1984, 56, 283–430. [Google Scholar] [CrossRef] [PubMed]
  64. Choi, D.W.; Koh, J.Y. Zinc and brain injury. Annu. Rev. Neurosci. 1998, 21, 347–375. [Google Scholar] [CrossRef] [PubMed]
  65. Prasad, A.S. Zinc: An overview. Nutrition 1995, 11, 93–99. [Google Scholar] [PubMed]
  66. Vallee, B.L.; Coleman, J.E.; Auld, D.S. Zinc fingers, zinc clusters, and zinc twists in DNA-binding protein domains. Proc. Natl. Acad. Sci. USA 1991, 88, 999–1003. [Google Scholar] [CrossRef][Green Version]
  67. Simmer, K.; Thompson, R.P. Zinc in the fetus and newborn. Acta Paediatr. Scand. Suppl. 1985, 319, 158–163. [Google Scholar] [CrossRef]
  68. Fabris, N.; Mocchegiani, E. Zinc, human diseases and aging. Aging 1995, 7, 77–93. [Google Scholar] [CrossRef]
  69. Bhatnagar, S.; Taneja, S. Zinc and cognitive development. Br. J. Nutr. 2001, 85, S139–S145. [Google Scholar] [CrossRef][Green Version]
  70. Black, M.M. The evidence linking zinc deficiency with children’s cognitive and motor functioning. J. Nutr. 2003, 133, 1473S–1476S. [Google Scholar] [CrossRef]
  71. Black, M.M. Micronutrient deficiencies and cognitive functioning. J. Nutr. 2003, 133, 3927S–3931S. [Google Scholar] [CrossRef][Green Version]
  72. Clarkson, T.W. Metal toxicity in the central nervous system. Environ. Health Perspect. 1987, 75, 59–64. [Google Scholar] [CrossRef]
  73. Mantyh, P.W.; Ghilardi, J.R.; Rogers, S.; DeMaster, E.; Allen, C.J.; Stimson, E.R.; Maggio, J.E. Aluminum, iron, and zinc ions promote aggregation of physiological concentrations of beta-amyloid peptide. J. Neurochem. 1993, 61, 1171–1174. [Google Scholar] [CrossRef] [PubMed]
  74. Gaeta, A.; Hider, R.C. The crucial role of metal ions in neurodegeneration: The basis for a promising therapeutic strategy. Br. J. Pharmacol. 2005, 146, 1041–1059. [Google Scholar] [CrossRef] [PubMed][Green Version]
  75. Zatta, P.; Drago, D.; Bolognin, S.; Sensi, S.L. Alzheimer’s disease, metal ions and metal homeostatic therapy. Trends Pharmacol. Sci. 2009, 30, 346–355. [Google Scholar] [CrossRef]
  76. Karri, V.; Schuhmacher, M.; Kumar, V. Heavy metals (Pb, Cd, As and MeHg) as risk factors for cognitive dysfunction: A general review of metal mixture mechanism in brain. Environ. Toxicol. Pharmacol. 2016, 48, 203–213. [Google Scholar] [CrossRef][Green Version]
  77. Cristovao, J.S.; Santos, R.; Gomes, C.M. Metals and Neuronal Metal Binding Proteins Implicated in Alzheimer’s Disease. Oxidative Med. Cell. Longev. 2016, 2016, 9812178. [Google Scholar] [CrossRef][Green Version]
  78. Dexter, D.T.; Wells, F.R.; Lees, A.J.; Agid, F.; Agid, Y.; Jenner, P.; Marsden, C.D. Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson’s disease. J. Neurochem. 1989, 52, 1830–1836. [Google Scholar] [CrossRef]
  79. Wenstrup, D.; Ehmann, W.D.; Markesbery, W.R. Trace element imbalances in isolated subcellular fractions of Alzheimer’s disease brains. Brain Res. 1990, 533, 125–131. [Google Scholar] [CrossRef]
  80. Constantinidis, J. The hypothesis of zinc deficiency in the pathogenesis of neurofibrillary tangles. Med. Hypotheses 1991, 35, 319–323. [Google Scholar] [CrossRef]
  81. Jenner, P.; Dexter, D.T.; Sian, J.; Schapira, A.H.; Marsden, C.D. Oxidative stress as a cause of nigral cell death in Parkinson’s disease and incidental Lewy body disease. The Royal Kings and Queens Parkinson’s Disease Research Group. Ann. Neurol. 1992, 32, S82–S87. [Google Scholar] [CrossRef]
  82. Corrigan, F.M.; Reynolds, G.P.; Ward, N.I. Hippocampal tin, aluminum and zinc in Alzheimer’s disease. Biometals Int. J. Role Met. Ions Biol. Biochem. Med. 1993, 6, 149–154. [Google Scholar] [CrossRef]
  83. Andrasi, E.; Farkas, E.; Scheibler, H.; Reffy, A.; Bezur, L. Al, Zn, Cu, Mn and Fe levels in brain in Alzheimer’s disease. Arch. Gerontol. Geriatr. 1995, 21, 89–97. [Google Scholar] [CrossRef]
  84. Deibel, M.A.; Ehmann, W.D.; Markesbery, W.R. Copper, iron, and zinc imbalances in severely degenerated brain regions in Alzheimer’s disease: Possible relation to oxidative stress. J. Neurol. Sci. 1996, 143, 137–142. [Google Scholar] [CrossRef]
  85. Cuajungco, M.P.; Lees, G.J. Zinc metabolism in the brain: Relevance to human neurodegenerative disorders. Neurobiol. Dis. 1997, 4, 137–169. [Google Scholar] [CrossRef] [PubMed][Green Version]
  86. Arora, M.; Reichenberg, A.; Willfors, C.; Austin, C.; Gennings, C.; Berggren, S.; Lichtenstein, P.; Anckarsater, H.; Tammimies, K.; Bolte, S. Fetal and postnatal metal dysregulation in autism. Nat. Commun. 2017, 8, 15493. [Google Scholar] [CrossRef]
  87. Bush, A.I.; Multhaup, G.; Moir, R.D.; Williamson, T.G.; Small, D.H.; Rumble, B.; Pollwein, P.; Beyreuther, K.; Masters, C.L. A novel zinc(II) binding site modulates the function of the beta A4 amyloid protein precursor of Alzheimer’s disease. J. Biol. Chem. 1993, 268, 16109–16112. [Google Scholar]
  88. Bush, A.I.; Pettingell, W.H.; Multhaup, G.; d Paradis, M.; Vonsattel, J.P.; Gusella, J.F.; Beyreuther, K.; Masters, C.L.; Tanzi, R.E. Rapid induction of Alzheimer A beta amyloid formation by zinc. Science 1994, 265, 1464–1467. [Google Scholar] [CrossRef] [PubMed]
  89. Clements, A.; Allsop, D.; Walsh, D.M.; Williams, C.H. Aggregation and metal-binding properties of mutant forms of the amyloid A beta peptide of Alzheimer’s disease. J. Neurochem. 1996, 66, 740–747. [Google Scholar] [CrossRef]
  90. Esler, W.P.; Stimson, E.R.; Ghilardi, J.R.; Vinters, H.V.; Lee, J.P.; Mantyh, P.W.; Maggio, J.E. In vitro growth of Alzheimer’s disease beta-amyloid plaques displays first-order kinetics. Biochemistry 1996, 35, 749–757. [Google Scholar] [CrossRef]
  91. Strozyk, D.; Launer, L.J.; Adlard, P.A.; Cherny, R.A.; Tsatsanis, A.; Volitakis, I.; Blennow, K.; Petrovitch, H.; White, L.R.; Bush, A.I. Zinc and copper modulate Alzheimer Abeta levels in human cerebrospinal fluid. Neurobiol. Aging 2009, 30, 1069–1077. [Google Scholar] [CrossRef][Green Version]
  92. Naisbitt, S.; Kim, E.; Tu, J.C.; Xiao, B.; Sala, C.; Valtschanoff, J.; Weinberg, R.J.; Worley, P.F.; Sheng, M. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 1999, 23, 569–582. [Google Scholar] [CrossRef][Green Version]
  93. Boeckers, T.M.; Winter, C.; Smalla, K.H.; Kreutz, M.R.; Bockmann, J.; Seidenbecher, C.; Garner, C.C.; Gundelfinger, E.D. Proline-rich synapse-associated proteins ProSAP1 and ProSAP2 interact with synaptic proteins of the SAPAP/GKAP family. Biochem. Biophys. Res. Commun. 1999, 264, 247–252. [Google Scholar] [CrossRef] [PubMed]
  94. Grabrucker, S.; Jannetti, L.; Eckert, M.; Gaub, S.; Chhabra, R.; Pfaender, S.; Mangus, K.; Reddy, P.P.; Rankovic, V.; Schmeisser, M.J.; et al. Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders. Brain 2014, 137, 137–152. [Google Scholar] [CrossRef] [PubMed][Green Version]
  95. Durand, C.M.; Betancur, C.; Boeckers, T.M.; Bockmann, J.; Chaste, P.; Fauchereau, F.; Nygren, G.; Rastam, M.; Gillberg, I.C.; Anckarsater, H.; et al. Mutations in the gene encoding the synaptic scaffolding protein SHANK3 are associated with autism spectrum disorders. Nat. Genet. 2007, 39, 25–27. [Google Scholar] [CrossRef] [PubMed][Green Version]
  96. Moessner, R.; Marshall, C.R.; Sutcliffe, J.S.; Skaug, J.; Pinto, D.; Vincent, J.; Zwaigenbaum, L.; Fernandez, B.; Roberts, W.; Szatmari, P.; et al. Contribution of SHANK3 mutations to autism spectrum disorder. Am. J. Hum. Genet. 2007, 81, 1289–1297. [Google Scholar] [CrossRef][Green Version]
  97. Gauthier, J.; Spiegelman, D.; Piton, A.; Lafreniere, R.G.; Laurent, S.; St-Onge, J.; Lapointe, L.; Hamdan, F.F.; Cossette, P.; Mottron, L. Novel de novo SHANK3 mutation in autistic patients. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 2009, 150, 421–424. [Google Scholar] [CrossRef]
  98. Gundelfinger, E.D.; Boeckers, T.M.; Baron, M.K.; Bowie, J.U. A role for zinc in postsynaptic density asSAMbly and plasticity? Trends Biochem. Sci. 2006, 31, 366–373. [Google Scholar] [CrossRef]
  99. Grabrucker, A.M. A role for synaptic zinc in ProSAP/Shank PSD scaffold malformation in autism spectrum disorders. Dev. Neurobiol. 2014, 74, 136–146. [Google Scholar] [CrossRef][Green Version]
  100. Pfaender, S.; Sauer, A.K.; Hagmeyer, S.; Mangus, K.; Linta, L.; Liebau, S.; Bockmann, J.; Huguet, G.; Bourgeron, T.; Boeckers, T.M.; et al. Zinc deficiency and low enterocyte zinc transporter expression in human patients with autism related mutations in SHANK3. Sci. Rep. 2017, 7, 45190. [Google Scholar] [CrossRef][Green Version]
  101. Yasuda, H.; Yoshida, K.; Yasuda, Y.; Tsutsui, T. Infantile zinc deficiency: Association with autism spectrum disorders. Sci. Rep. 2011, 1, 129. [Google Scholar] [CrossRef]
  102. Schoen, M.; Asoglu, H.; Bauer, H.F.; Muller, H.P.; Abaei, A.; Sauer, A.K.; Zhang, R.; Song, T.J.; Bockmann, J.; Kassubek, J.; et al. Shank3 Transgenic and Prenatal Zinc-Deficient Autism Mouse Models Show Convergent and Individual Alterations of Brain Structures in MRI. Front. Neural. Circuits 2019, 13, 6. [Google Scholar] [CrossRef]
  103. Sweetman, D.U.; O’Donnell, S.M.; Lalor, A.; Grant, T.; Greaney, H. Zinc and vitamin A deficiency in a cohort of children with autism spectrum disorder. Child Care Health Dev. 2019, 45, 380–386. [Google Scholar] [CrossRef]
  104. Fluegge, K.J. Zinc and Copper Metabolism and Risk of Autism: A reply to Sayehmiri et al. Iran. J. Child Neurol. 2017, 11, 66. [Google Scholar]
  105. World Health Oganization. The ICD-10 Classification of Mental and Behavioral Disorders: Clinical Descriptions and Diagnostic Guidelines; World Health Oganization: Geneva, Switzerland, 1992. [Google Scholar]
  106. Association, A.P. Diagnostic Criteria from dsM-iV-tr; American Psychiatric Publishing, Inc.: Washington, DC, USA, 2000. [Google Scholar]
  107. Amir, R.E.; Van den Veyver, I.B.; Wan, M.; Tran, C.Q.; Francke, U.; Zoghbi, H.Y. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 1999, 23, 185–188. [Google Scholar] [CrossRef] [PubMed]
  108. Piven, J.; Palmer, P.; Jacobi, D.; Childress, D.; Arndt, S. Broader autism phenotype: Evidence from a family history study of multiple-incidence autism families. Am. J. Psychiatry 1997, 154, 185–190. [Google Scholar] [PubMed][Green Version]
  109. Muhle, R.; Trentacoste, S.V.; Rapin, I. The genetics of autism. Pediatrics 2004, 113, e472–e486. [Google Scholar] [CrossRef][Green Version]
  110. Neale, B.M.; Kou, Y.; Liu, L.; Ma’Ayan, A.; Samocha, K.E.; Sabo, A.; Lin, C.-F.; Stevens, C.; Wang, L.-S.; Makarov, V. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012, 485, 242–245. [Google Scholar] [CrossRef]
  111. Iossifov, I.; Ronemus, M.; Levy, D.; Wang, Z.; Hakker, I.; Rosenbaum, J.; Yamrom, B.; Lee, Y.-h.; Narzisi, G.; Leotta, A. De novo gene disruptions in children on the autistic spectrum. Neuron 2012, 74, 285–299. [Google Scholar] [CrossRef][Green Version]
  112. Iossifov, I.; O’roak, B.J.; Sanders, S.J.; Ronemus, M.; Krumm, N.; Levy, D.; Stessman, H.A.; Witherspoon, K.T.; Vives, L.; Patterson, K.E. The contribution of de novo coding mutations to autism spectrum disorder. Nature 2014, 515, 216–221. [Google Scholar] [CrossRef][Green Version]
  113. Vincent, J.B.; Herbrick, J.A.; Gurling, H.M.; Bolton, P.F.; Roberts, W.; Scherer, S.W. Identification of a novel gene on chromosome 7q31 that is interrupted by a translocation breakpoint in an autistic individual. Am. J. Hum. Genet. 2000, 67, 510–514. [Google Scholar] [CrossRef][Green Version]
  114. Lopreiato, J.O.; Wulfsberg, E.A. A complex chromosome rearrangement in a boy with autism. J. Dev. Behav. Pediatrics JDBP 1992, 13, 281–283. [Google Scholar] [CrossRef]
  115. Ashley-Koch, A.; Wolpert, C.M.; Menold, M.M.; Zaeem, L.; Basu, S.; Donnelly, S.L.; Ravan, S.A.; Powell, C.M.; Qumsiyeh, M.B.; Aylsworth, A. Genetic studies of autistic disorder and chromosome 7. Genomics 1999, 61, 227–236. [Google Scholar] [CrossRef] [PubMed]
  116. Warburton, P.; Baird, G.; Chen, W.; Morris, K.; Jacobs, B.W.; Hodgson, S.; Docherty, Z. Support for linkage of autism and specific language impairment to 7q3 from two chromosome rearrangements involving band 7q31. Am. J. Med Genet. 2000, 96, 228–234. [Google Scholar] [CrossRef]
  117. A full genome screen for autism with evidence for linkage to a region on chromosome 7q. International Molecular Genetic Study of Autism Consortium. Hum. Mol. Genet. 1998, 7, 571–578. [CrossRef]
  118. Hurst, J.A.; Baraitser, M.; Auger, E.; Graham, F.; Norell, S. An extended family with a dominantly inherited speech disorder. Dev. Med. Child Neurol. 1990, 32, 352–355. [Google Scholar] [CrossRef]
  119. Hutcheson, H.B.; Bradford, Y.; Folstein, S.E.; Gardiner, M.B.; Santangelo, S.L.; Sutcliffe, J.S.; Haines, J.L. Defining the autism minimum candidate gene region on chromosome 7. Am. J. Med Genet. Part B 2003, 117B, 90–96. [Google Scholar] [CrossRef] [PubMed]
  120. Shao, Y.; Wolpert, C.M.; Raiford, K.L.; Menold, M.M.; Donnelly, S.L.; Ravan, S.A.; Bass, M.P.; McClain, C.; von Wendt, L.; Vance, J.M.; et al. Genomic screen and follow-up analysis for autistic disorder. Am. J. Med. Genet. 2002, 114, 99–105. [Google Scholar] [CrossRef] [PubMed]
  121. Philippe, A.; Martinez, M.; Guilloud-Bataille, M.; Gillberg, C.; Råstam, M.; Sponheim, E.; Coleman, M.; Zappella, M.; Aschauer, H.; Van Maldergem, L. Genome-wide scan for autism susceptibility genes. Hum. Mol. Genet. 1999, 8, 805–812. [Google Scholar] [CrossRef][Green Version]
  122. Barrett, S.; Beck, J.C.; Bernier, R.; Bisson, E.; Braun, T.A.; Casavant, T.L.; Childress, D.; Folstein, S.E.; Garcia, M.; Gardiner, M.B. An autosomal genomic screen for autism. Collaborative linkage study of autism. Am. J. Med Genet. 1999, 88, 609–615. [Google Scholar] [PubMed]
  123. Lai, C.S.; Fisher, S.E.; Hurst, J.A.; Vargha-Khadem, F.; Monaco, A.P. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature 2001, 413, 519–523. [Google Scholar] [CrossRef]
  124. Lai, C.S.; Gerrelli, D.; Monaco, A.P.; Fisher, S.E.; Copp, A.J. FOXP2 expression during brain development coincides with adult sites of pathology in a severe speech and language disorder. Brain 2003, 126, 2455–2462. [Google Scholar] [CrossRef]
  125. Shu, W.; Yang, H.; Zhang, L.; Lu, M.M.; Morrisey, E.E. Characterization of a new subfamily of winged-helix/forkhead (Fox) genes that are expressed in the lung and act as transcriptional repressors. J. Biol. Chem. 2001, 276, 27488–27497. [Google Scholar] [CrossRef] [PubMed][Green Version]
  126. Fisher, S.E.; Vargha-Khadem, F.; Watkins, K.E.; Monaco, A.P.; Pembrey, M.E. Localisation of a gene implicated in a severe speech and language disorder. Nat. Genet. 1998, 18, 168–170. [Google Scholar] [CrossRef][Green Version]
  127. Newbury, D.F.; Bonora, E.; Lamb, J.A.; Fisher, S.E.; Lai, C.S.; Baird, G.; Jannoun, L.; Slonims, V.; Stott, C.M.; Merricks, M.J.; et al. FOXP2 is not a major susceptibility gene for autism or specific language impairment. Am. J. Hum. Genet. 2002, 70, 1318–1327. [Google Scholar] [CrossRef] [PubMed][Green Version]
  128. Tolosa, A.; Sanjuán, J.; Dagnall, A.M.; Moltó, M.D.; Herrero, N.; de Frutos, R.J. FOXP2 gene and language impairment in schizophrenia: Association and epigenetic studies. BMC Med. Genet. 2010, 11, 114. [Google Scholar] [CrossRef] [PubMed][Green Version]
  129. Toma, C.; Hervas, A.; Torrico, B.; Balmaña, N.; Salgado, M.; Maristany, M.; Vilella, E.; Martínez-Leal, R.; Planelles, M.I.; Cusco, I.; et al. Analysis of two language-related genes in autism. Psychiatr. Genet. 2013, 23, 82–85. [Google Scholar] [CrossRef] [PubMed][Green Version]
  130. Liyanage, V.R.B. Role of RNA methylation and non-coding RNAs in pathobiology of autism spectrum disorders. Biomed. Sci. 2016, 2, 24. [Google Scholar]
  131. Vincent, J.B.; Petek, E.; Thevarkunnel, S.; Kolozsvari, D.; Cheung, J.; Patel, M.; Scherer, S.W. The RAY1/ST7 tumor-suppressor locus on chromosome 7q31 represents a complex multi-transcript system. Genomics 2002, 80, 283–294. [Google Scholar] [CrossRef]
  132. Maestrini, E.; Pagnamenta, A.T.; Lamb, J.A.; Bacchelli, E.; Sykes, N.H.; Sousa, I.; Toma, C.; Barnby, G.; Butler, H.; Winchester, L.; et al. High-density SNP association study and copy number variation analysis of the AUTS1 and AUTS5 loci implicate the IMMP2L-DOCK4 gene region in autism susceptibility. Mol. Psychiatry 2010, 15, 954–968. [Google Scholar] [CrossRef][Green Version]
  133. Robertson, M.M. Annotation: Gilles de la Tourette syndrome—An update. J. Child Psychol. Psychiatry Allied Discip. 1994, 35, 597–611. [Google Scholar] [CrossRef]
  134. Kreilaus, F.; Chesworth, R.; Eapen, V.; Clarke, R.; Karl, T. First behavioural assessment of a novel Immp2l knockdown mouse model with relevance for Gilles de la Tourette syndrome and Autism spectrum disorder. Behav. Brain Res. 2019, 374, 112057. [Google Scholar] [CrossRef]
  135. Petek, E.; Schwarzbraun, T.; Noor, A.; Patel, M.; Nakabayashi, K.; Choufani, S.; Windpassinger, C.; Stamenkovic, M.; Robertson, M.M.; Aschauer, H.N.; et al. Molecular and genomic studies of IMMP2L and mutation screening in autism and Tourette syndrome. Mol. Genet. Genom. 2007, 277, 71–81. [Google Scholar] [CrossRef] [PubMed]
  136. Liang, S.; Wang, X.L.; Zou, M.Y.; Wang, H.; Zhou, X.; Sun, C.H.; Xia, W.; Wu, L.J.; Fujisawa, T.X.; Tomoda, A. Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population. J. Zhejiang Univ. Sci. B 2014, 15, 264–271. [Google Scholar] [CrossRef] [PubMed][Green Version]
  137. Ogawa, M.; Miyata, T.; Nakajimat, K.; Yagyu, K.; Seike, M.; Ikenaka, K.; Yamamoto, H.; Mikoshibat, K. The reeler gene-associated antigen on Cajal-Retzius neurons is a crucial molecule for laminar organization of cortical neurons. Neuron 1995, 14, 899–912. [Google Scholar] [CrossRef][Green Version]
  138. D’Arcangelo, G.; Miao, G.G.; Chen, S.-C.; Scares, H.D.; Morgan, J.I.; Curran, T. A protein related to extracellular matrix proteins deleted in the mouse mutant reeler. Nature 1995, 374, 719–723. [Google Scholar] [CrossRef]
  139. Yip, J.W.; Yip, Y.P.L.; Nakajima, K.; Capriotti, C. Reelin controls position of autonomic neurons in the spinal cord. Proc. Natl. Acad. Sci. USA 2000, 97, 8612–8616. [Google Scholar] [CrossRef][Green Version]
  140. Dulabon, L.; Olson, E.C.; Taglienti, M.G.; Eisenhuth, S.; McGrath, B.; Walsh, C.A.; Kreidberg, J.A.; Anton, E. Reelin binds α3β1 integrin and inhibits neuronal migration. Neuron 2000, 27, 33–44. [Google Scholar] [CrossRef][Green Version]
  141. Persico, A.; D’agruma, L.; Maiorano, N.; Totaro, A.; Militerni, R.; Bravaccio, C.; Wassink, T.; Schneider, C.; Melmed, R.; Trillo, S. Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Mol. Psychiatry 2001, 6, 150–159. [Google Scholar] [CrossRef][Green Version]
  142. Zhang, H.; Liu, X.; Zhang, C.; Mundo, E.; Macciardi, F.; Grayson, D.; Guidotti, A.; Holden, J. Reelin gene alleles and susceptibility to autism spectrum disorders. Mol. Psychiatry 2002, 7, 1012–1017. [Google Scholar] [CrossRef][Green Version]
  143. Skaar, D.; Shao, Y.; Haines, J.; Stenger, J.; Jaworski, J.; Martin, E.R.; DeLong, G.; Moore, J.; McCauley, J.L.; Sutcliffe, J. Analysis of the RELN gene as a genetic risk factor for autism. Mol. Psychiatry 2005, 10, 563–571. [Google Scholar] [CrossRef][Green Version]
  144. Fatemi, S.H.; Snow, A.V.; Stary, J.M.; Araghi-Niknam, M.; Reutiman, T.J.; Lee, S.; Brooks, A.I.; Pearce, D.A. Reelin signaling is impaired in autism. Biol. Psychiatry 2005, 57, 777–787. [Google Scholar] [CrossRef]
  145. Lammert, D.B.; Howell, B.W. RELN mutations in autism spectrum disorder. Front. Cell. Neurosci. 2016, 10, 84. [Google Scholar] [CrossRef] [PubMed][Green Version]
  146. Seripa, D.; Matera, M.G.; Franceschi, M.; Daniele, A.; Bizzarro, A.; Rinaldi, M.; Panza, F.; Fazio, V.M.; Gravina, C.; D’Onofrio, G.; et al. The RELN locus in Alzheimer’s disease. J. Alzheimer Dis. JAD 2008, 14, 335–344. [Google Scholar] [CrossRef] [PubMed]
  147. Kramer, P.L.; Xu, H.; Woltjer, R.L.; Westaway, S.K.; Clark, D.; Erten-Lyons, D.; Kaye, J.A.; Welsh-Bohmer, K.A.; Troncoso, J.C.; Markesbery, W.R.; et al. Alzheimer disease pathology in cognitively healthy elderly: A genome-wide study. Neurobiol. Aging 2011, 32, 2113–2122. [Google Scholar] [CrossRef] [PubMed][Green Version]
  148. Liu, Y.; Chen, P.L.; McGrath, J.; Wolyniec, P.; Fallin, D.; Nestadt, G.; Liang, K.Y.; Pulver, A.; Valle, D.; Avramopoulos, D. Replication of an association of a common variant in the Reelin gene (RELN) with schizophrenia in Ashkenazi Jewish women. Psychiatr. Genet. 2010, 20, 184–186. [Google Scholar] [CrossRef] [PubMed][Green Version]
  149. Ovadia, G.; Shifman, S. The genetic variation of RELN expression in schizophrenia and bipolar disorder. PLoS ONE 2011, 6, e19955. [Google Scholar] [CrossRef]
  150. Hong, S.E.; Shugart, Y.Y.; Huang, D.T.; Shahwan, S.A.; Grant, P.E.; Hourihane, J.O.; Martin, N.D.; Walsh, C.A. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat. Genet. 2000, 26, 93–96. [Google Scholar] [CrossRef]
  151. Chang, B.S.; Duzcan, F.; Kim, S.; Cinbis, M.; Aggarwal, A.; Apse, K.A.; Ozdel, O.; Atmaca, M.; Zencir, S.; Bagci, H.; et al. The role of RELN in lissencephaly and neuropsychiatric disease. Am. J. Med Genet. Part B 2007, 144B, 58–63. [Google Scholar] [CrossRef]
  152. Fatemi, S.H.; Stary, J.M.; Egan, E.A. Reduced blood levels of reelin as a vulnerability factor in pathophysiology of autistic disorder. Cell. Mol. Neurobiol. 2002, 22, 139–152. [Google Scholar] [CrossRef]
  153. Wang, Z.; Hong, Y.; Zou, L.; Zhong, R.; Zhu, B.; Shen, N.; Chen, W.; Lou, J.; Ke, J.; Zhang, T.; et al. Reelin gene variants and risk of autism spectrum disorders: An integrated meta-analysis. Am. J. Med Genet. Part B 2014, 165B, 192–200. [Google Scholar] [CrossRef]
  154. Abrahams, B.S.; Arking, D.E.; Campbell, D.B.; Mefford, H.C.; Morrow, E.M.; Weiss, L.A.; Menashe, I.; Wadkins, T.; Banerjee-Basu, S.; Packer, A. SFARI Gene 2.0: A community-driven knowledgebase for the autism spectrum disorders (ASDs). Mol. Autism 2013, 4, 36. [Google Scholar] [CrossRef][Green Version]
  155. Prontera, P.; Serino, D.; Caldini, B.; Scarponi, L.; Merla, G.; Testa, G.; Muti, M.; Napolioni, V.; Mazzotta, G.; Piccirilli, M.; et al. Brief Report: Functional MRI of a Patient with 7q11.23 Duplication Syndrome and Autism Spectrum Disorder. J. Autism Dev. Disord. 2014, 44, 2608–2613. [Google Scholar] [CrossRef] [PubMed]
  156. Lammert, D.; Middleton, F.A.; Pan, J.Q.; Olson, E.; Howell, B. The de novo autism spectrum disorder RELN R2290C mutation reduces Reelin secretion and increases protein disulfide isomerase expression. J. Neurochem. 2017, 142, 89–102. [Google Scholar] [CrossRef] [PubMed][Green Version]
  157. Lintas, C.; Sacco, R.; Persico, A.M. Differential methylation at the RELN gene promoter in temporal cortex from autistic and typically developing post-puberal subjects. J. Neurodev. Disord. 2016, 8, 18. [Google Scholar] [CrossRef] [PubMed][Green Version]
  158. Marshall, C.R.; Noor, A.; Vincent, J.B.; Lionel, A.C.; Feuk, L.; Skaug, J.; Shago, M.; Moessner, R.; Pinto, D.; Ren, Y.; et al. Structural variation of chromosomes in autism spectrum disorder. Am. J. Hum. Genet. 2008, 82, 477–488. [Google Scholar] [CrossRef][Green Version]
  159. Guo, H.; Peng, Y.; Hu, Z.; Li, Y.; Xun, G.; Ou, J.; Sun, L.; Xiong, Z.; Liu, Y.; Wang, T.; et al. Genome-wide copy number variation analysis in a Chinese autism spectrum disorder cohort. Sci. Rep. 2017, 7, 44155. [Google Scholar] [CrossRef][Green Version]
  160. Willemsen, M.H.; Fernandez, B.A.; Bacino, C.A.; Gerkes, E.; de Brouwer, A.P.; Pfundt, R.; Sikkema-Raddatz, B.; Scherer, S.W.; Marshall, C.R.; Potocki, L.; et al. Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome. Eur. J. Hum. Genet. EJHG 2010, 18, 429–435. [Google Scholar] [CrossRef][Green Version]
  161. Kumar, R.A.; KaraMohamed, S.; Sudi, J.; Conrad, D.F.; Brune, C.; Badner, J.A.; Gilliam, T.C.; Nowak, N.J.; Cook, E.H., Jr.; Dobyns, W.B.; et al. Recurrent 16p11.2 microdeletions in autism. Hum. Mol. Genet. 2008, 17, 628–638. [Google Scholar] [CrossRef][Green Version]
  162. Kim, H.-G.; Kishikawa, S.; Higgins, A.W.; Seong, I.-S.; Donovan, D.J.; Shen, Y.; Lally, E.; Weiss, L.A.; Najm, J.; Kutsche, K. Disruption of neurexin 1 associated with autism spectrum disorder. Am. J. Hum. Genet. 2008, 82, 199–207. [Google Scholar] [CrossRef][Green Version]
  163. He, H.; Tan, C.K.; Downey, K.M.; So, A.G. A tumor necrosis factor alpha- and interleukin 6-inducible protein that interacts with the small subunit of DNA polymerase delta and proliferating cell nuclear antigen. Proc. Natl. Acad. Sci. USA 2001, 98, 11979–11984. [Google Scholar] [CrossRef] [PubMed][Green Version]
  164. Golzio, C.; Willer, J.; Talkowski, M.E.; Oh, E.C.; Taniguchi, Y.; Jacquemont, S.; Reymond, A.; Sun, M.; Sawa, A.; Gusella, J.F.; et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 2012, 485, 363–367. [Google Scholar] [CrossRef]
  165. Escamilla, C.O.; Filonova, I.; Walker, A.K.; Xuan, Z.X.; Holehonnur, R.; Espinosa, F.; Liu, S.; Thyme, S.B.; Lopez-Garcia, I.A.; Mendoza, D.B.; et al. Kctd13 deletion reduces synaptic transmission via increased RhoA. Nature 2017, 551, 227–231. [Google Scholar] [CrossRef] [PubMed]
  166. Leblond, C.S.; Cliquet, F.; Carton, C.; Huguet, G.; Mathieu, A.; Kergrohen, T.; Buratti, J.; Lemiere, N.; Cuisset, L.; Bienvenu, T.; et al. Both rare and common genetic variants contribute to autism in the Faroe Islands. NPJ Genom. Med. 2019, 4, 1. [Google Scholar] [CrossRef] [PubMed][Green Version]
  167. Yan, Y.; Eipper, B.A.; Mains, R.E. Kalirin-9 and Kalirin-12 Play Essential Roles in Dendritic Outgrowth and Branching. Cereb. Cortex 2015, 25, 3487–3501. [Google Scholar] [CrossRef] [PubMed][Green Version]
  168. Qu, B.X.; Gong, Y.; Sinclair, D.; Fu, M.; Perl, D.; Diaz-Arrastia, R. cPLA2alpha knockout mice exhibit abnormalities in the architecture and synapses of cortical neurons. Brain Res. 2013, 1497, 101–105. [Google Scholar] [CrossRef]
  169. Wang, K.; Zhang, H.; Ma, D.; Bucan, M.; Glessner, J.T.; Abrahams, B.S.; Salyakina, D.; Imielinski, M.; Bradfield, J.P.; Sleiman, P.M.; et al. Common genetic variants on 5p14.1 associate with autism spectrum disorders. Nature 2009, 459, 528–533. [Google Scholar] [CrossRef]
  170. Mirzaa, G.M.; Chong, J.X.; Piton, A.; Popp, B.; Foss, K.; Guo, H.; Harripaul, R.; Xia, K.; Scheck, J.; Aldinger, K.A.; et al. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder. Genet. Med. Off. 2019. [Google Scholar] [CrossRef]
  171. Irimia, M.; Weatheritt, R.J.; Ellis, J.D.; Parikshak, N.N.; Gonatopoulos-Pournatzis, T.; Babor, M.; Quesnel-Vallieres, M.; Tapial, J.; Raj, B.; O’Hanlon, D.; et al. A highly conserved program of neuronal microexons is misregulated in autistic brains. Cell 2014, 159, 1511–1523. [Google Scholar] [CrossRef][Green Version]
  172. Sebat, J.; Lakshmi, B.; Malhotra, D.; Troge, J.; Lese-Martin, C.; Walsh, T.; Yamrom, B.; Yoon, S.; Krasnitz, A.; Kendall, J.; et al. Strong association of de novo copy number mutations with autism. Science 2007, 316, 445–449. [Google Scholar] [CrossRef][Green Version]
  173. Alvarez-Baron, E.; Michel, K.; Mittelstaedt, T.; Opitz, T.; Schmitz, F.; Beck, H.; Dietrich, D.; Becker, A.J.; Schoch, S. RIM3gamma and RIM4gamma are key regulators of neuronal arborization. J. Neurosci. Off. 2013, 33, 824–839. [Google Scholar] [CrossRef][Green Version]
  174. Ponson, L.; Gomot, M.; Blanc, R.; Barthelemy, C.; Roux, S.; Munnich, A.; Romana, S.; Aguillon-Hernandez, N.; Malan, V.; Bonnet-Brilhault, F. 22q13 deletion syndrome: Communication disorder or autism? Evidence from a specific clinical and neurophysiological phenotype. Transl. Psychiatry 2018, 8, 1–8. [Google Scholar] [CrossRef]
  175. Zhou, Y.; Sharma, J.; Ke, Q.; Landman, R.; Yuan, J.; Chen, H.; Hayden, D.S.; Fisher, J.W.; Jiang, M.; Menegas, W. Atypical behaviour and connectivity in SHANK3-mutant macaques. Nature 2019, 570, 326–331. [Google Scholar] [CrossRef] [PubMed]
  176. Jamain, S.; Quach, H.; Betancur, C.; Rastam, M.; Colineaux, C.; Gillberg, I.C.; Soderstrom, H.; Giros, B.; Leboyer, M.; Gillberg, C.; et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 2003, 34, 27–29. [Google Scholar] [CrossRef] [PubMed][Green Version]
  177. Darnell, J.C.; Van Driesche, S.J.; Zhang, C.; Hung, K.Y.; Mele, A.; Fraser, C.E.; Stone, E.F.; Chen, C.; Fak, J.J.; Chi, S.W.; et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 2011, 146, 247–261. [Google Scholar] [CrossRef] [PubMed][Green Version]
  178. Mirakian, R.; Ewan, P.W.; Durham, S.R.; Youlten, L.J.; Dugue, P.; Friedmann, P.S.; English, J.S.; Huber, P.A.; Nasser, S.M.; BSACI. BSACI guidelines for the management of drug allergy. Clin. Exp. Allergy 2009, 39, 43–61. [Google Scholar] [CrossRef] [PubMed]
  179. Arking, D.E.; Cutler, D.J.; Brune, C.W.; Teslovich, T.M.; West, K.; Ikeda, M.; Rea, A.; Guy, M.; Lin, S.; Cook, E.H., Jr. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am. J. Hum. Genet. 2008, 82, 160–164. [Google Scholar] [CrossRef] [PubMed][Green Version]
  180. Morrow, E.M.; Yoo, S.-Y.; Flavell, S.W.; Kim, T.-K.; Lin, Y.; Hill, R.S.; Mukaddes, N.M.; Balkhy, S.; Gascon, G.; Hashmi, A. Identifying autism loci and genes by tracing recent shared ancestry. Science 2008, 321, 218–223. [Google Scholar] [CrossRef][Green Version]
  181. Yuan, H.; Meng, Z.; Zhang, L.; Luo, X.; Liu, L.; Chen, M.; Li, X.; Zhao, W.; Liang, L. A rare de novo interstitial duplication of 15q15.3q21.2 in a boy with severe short stature, hypogonadism, global developmental delay and intellectual disability. Mol. Cytogenet. 2016, 9, 2. [Google Scholar] [CrossRef][Green Version]
  182. Bassell, G.J.; Warren, S.T. Fragile X syndrome: Loss of local mRNA regulation alters synaptic development and function. Neuron 2008, 60, 201–214. [Google Scholar] [CrossRef][Green Version]
  183. Engwerda, A.; Frentz, B.; den Ouden, A.L.; Flapper, B.C.T.; Swertz, M.A.; Gerkes, E.H.; Plantinga, M.; Dijkhuizen, T.; van Ravenswaaij-Arts, C.M.A. The phenotypic spectrum of proximal 6q deletions based on a large cohort derived from social media and literature reports. Eur. J. Hum. Genet. EJHG 2018, 26, 1478–1489. [Google Scholar] [CrossRef][Green Version]
  184. Samaco, R.C.; Hogart, A.; LaSalle, J.M. Epigenetic overlap in autism-spectrum neurodevelopmental disorders: MECP2 deficiency causes reduced expression of UBE3A and GABRB3. Hum. Mol. Genet. 2004, 14, 483–492. [Google Scholar] [CrossRef][Green Version]
  185. Steffenburg, S.; Gillberg, C.L.; Steffenburg, U.; Kyllerman, M. Autism in Angelman syndrome: A population-based study. Pediatr. Neurol. 1996, 14, 131–136. [Google Scholar] [CrossRef]
  186. Yashiro, K.; Riday, T.T.; Condon, K.H.; Roberts, A.C.; Bernardo, D.R.; Prakash, R.; Weinberg, R.J.; Ehlers, M.D.; Philpot, B.D. Ube3a is required for experience-dependent maturation of the neocortex. Nat. Neurosci. 2009, 12, 777–783. [Google Scholar] [CrossRef][Green Version]
  187. Smith, S.E.; Zhou, Y.D.; Zhang, G.; Jin, Z.; Stoppel, D.C.; Anderson, M.P. Increased gene dosage of Ube3a results in autism traits and decreased glutamate synaptic transmission in mice. Sci. Transl. Med. 2011, 3. [Google Scholar] [CrossRef] [PubMed][Green Version]
  188. Adalsteinsson, B.T.; Ferguson-Smith, A.C. Epigenetic control of the genome—Lessons from genomic imprinting. Genes 2014, 5, 635–655. [Google Scholar] [CrossRef][Green Version]
  189. Schiele, M.; Domschke, K. Epigenetics at the crossroads between genes, environment and resilience in anxiety disorders. Genes Brain Behav. 2018, 17, e12423. [Google Scholar] [CrossRef][Green Version]
  190. Ben-David, E.; Shifman, S. Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism. Mol. Psychiatry 2013, 18, 1054. [Google Scholar] [CrossRef][Green Version]
  191. Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium. Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24. 32 and a significant overlap with schizophrenia. Mol. Autism 2017, 8, 1–17.
  192. Waye, M.M.; Cheng, H.Y. Genetics and epigenetics of autism: A Review. Psychiatry Clin. Neurosci. 2018, 72, 228–244. [Google Scholar] [CrossRef]
  193. Kubota, T.; Mochizuki, K. Epigenetic effect of environmental factors on autism spectrum disorders. Int. J. Environ. Res. Public Health 2016, 13, 504. [Google Scholar] [CrossRef][Green Version]
  194. LoParo, D.; Waldman, I. The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: A meta-analysis. Mol. Psychiatry 2015, 20, 640–646. [Google Scholar] [CrossRef]
  195. Qin, L.; Ma, K.; Wang, Z.-J.; Hu, Z.; Matas, E.; Wei, J.; Yan, Z. Social deficits in Shank3-deficient mouse models of autism are rescued by histone deacetylase (HDAC) inhibition. Nat. Neurosci. 2018, 21, 564. [Google Scholar] [CrossRef] [PubMed]
  196. Uchino, S.; Waga, C. SHANK3 as an autism spectrum disorder-associated gene. Brain Dev. 2013, 35, 106–110. [Google Scholar] [CrossRef] [PubMed]
  197. Goncalves, T.F.; Goncalves, A.P.; Fintelman Rodrigues, N.; dos Santos, J.M.; Pimentel, M.M.; Santos-Reboucas, C.B. KDM5C mutational screening among males with intellectual disability suggestive of X-Linked inheritance and review of the literature. Eur. J. Med. Genet. 2014, 57, 138–144. [Google Scholar] [CrossRef] [PubMed]
  198. Duffney, L.J.; Valdez, P.; Tremblay, M.W.; Cao, X.; Montgomery, S.; McConkie-Rosell, A.; Jiang, Y.h. Epigenetics and autism spectrum disorder: A report of an autism case with mutation in H1 linker histone HIST1H1E and literature review. Am. J. Med Genet. Part B 2018, 177, 426–433. [Google Scholar] [CrossRef] [PubMed]
  199. Cotney, J.; Muhle, R.A.; Sanders, S.J.; Liu, L.; Willsey, A.J.; Niu, W.; Liu, W.; Klei, L.; Lei, J.; Yin, J. The autism-associated chromatin modifier CHD8 regulates other autism risk genes during human neurodevelopment. Nat. Commun. 2015, 6, 6404. [Google Scholar] [CrossRef]
  200. Hamdan, F.F.; Srour, M.; Capo-Chichi, J.-M.; Daoud, H.; Nassif, C.; Patry, L.; Massicotte, C.; Ambalavanan, A.; Spiegelman, D.; Diallo, O. De novo mutations in moderate or severe intellectual disability. PLoS Genet. 2014, 10, e1004772. [Google Scholar] [CrossRef] [PubMed][Green Version]
  201. Helsmoortel, C.; Vulto-van Silfhout, A.T.; Coe, B.P.; Vandeweyer, G.; Rooms, L.; Van Den Ende, J.; Schuurs-Hoeijmakers, J.H.; Marcelis, C.L.; Willemsen, M.H.; Vissers, L.E. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat. Genet. 2014, 46, 380. [Google Scholar] [CrossRef][Green Version]
  202. Bernstein, E.; Kim, S.Y.; Carmell, M.A.; Murchison, E.P.; Alcorn, H.; Li, M.Z.; Mills, A.A.; Elledge, S.J.; Anderson, K.V.; Hannon, G.J. Dicer is essential for mouse development. Nat. Genet. 2003, 35, 215–217. [Google Scholar] [CrossRef]
  203. Hébert, S.S.; De Strooper, B. miRNAs in neurodegeneration. Science 2007, 317, 1179–1180. [Google Scholar] [CrossRef]
  204. Davis, T.H.; Cuellar, T.L.; Koch, S.M.; Barker, A.J.; Harfe, B.D.; McManus, M.T.; Ullian, E.M. Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus. J. Neurosci. 2008, 28, 4322–4330. [Google Scholar] [CrossRef][Green Version]
  205. Kawase-Koga, Y.; Otaegi, G.; Sun, T. Different timings of Dicer deletion affect neurogenesis and gliogenesis in the developing mouse central nervous system. Dev. Dyn. Off. 2009, 238, 2800–2812. [Google Scholar] [CrossRef] [PubMed][Green Version]
  206. LaSalle, J.M. Epigenomic strategies at the interface of genetic and environmental risk factors for autism. J. Hum. Genet. 2013, 58, 396–401. [Google Scholar] [CrossRef][Green Version]
  207. James, S.J.; Cutler, P.; Melnyk, S.; Jernigan, S.; Janak, L.; Gaylor, D.W.; Neubrander, J.A. Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. Am. J. Clin. Nutr. 2004, 80, 1611–1617. [Google Scholar] [CrossRef] [PubMed][Green Version]
  208. Dolinoy, D.C.; Weidman, J.R.; Jirtle, R.L. Epigenetic gene regulation: Linking early developmental environment to adult disease. Reprod. Toxicol. 2007, 23, 297–307. [Google Scholar] [CrossRef] [PubMed]
  209. Jirtle, R.L.; Skinner, M.K. Environmental epigenomics and disease susceptibility. Nat. Rev. Genet. 2007, 8, 253–262. [Google Scholar] [CrossRef]
  210. Rusiecki, J.A.; Baccarelli, A.; Bollati, V.; Tarantini, L.; Moore, L.E.; Bonefeld-Jorgensen, E.C. Global DNA hypomethylation is associated with high serum-persistent organic pollutants in Greenlandic Inuit. Environ. Health Perspect. 2008, 116, 1547–1552. [Google Scholar] [CrossRef]
  211. Jang, H.S.; Shin, W.J.; Lee, J.E.; Do, J.T. CpG and Non-CpG Methylation in Epigenetic Gene Regulation and Brain Function. Genes 2017, 8, 148. [Google Scholar] [CrossRef][Green Version]
  212. Wong, C.; Meaburn, E.L.; Ronald, A.; Price, T.; Jeffries, A.R.; Schalkwyk, L.; Plomin, R.; Mill, J. Methylomic analysis of monozygotic twins discordant for autism spectrum disorder and related behavioural traits. Mol. Psychiatry 2014, 19, 495. [Google Scholar] [CrossRef]
  213. Tahiliani, M.; Koh, K.P.; Shen, Y.; Pastor, W.A.; Bandukwala, H.; Brudno, Y.; Agarwal, S.; Iyer, L.M.; Liu, D.R.; Aravind, L. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 2009, 324, 930–935. [Google Scholar] [CrossRef][Green Version]
  214. Shcheglovitov, A.; Shcheglovitova, O.; Yazawa, M.; Portmann, T.; Shu, R.; Sebastiano, V.; Krawisz, A.; Froehlich, W.; Bernstein, J.A.; Hallmayer, J.F. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature 2013, 503, 267–271. [Google Scholar] [CrossRef][Green Version]
  215. Yi, F.; Danko, T.; Botelho, S.C.; Patzke, C.; Pak, C.; Wernig, M.; Südhof, T.C. Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons. Science 2016, 352, aaf2669. [Google Scholar] [CrossRef] [PubMed][Green Version]
  216. Katayama, Y.; Nishiyama, M.; Shoji, H.; Ohkawa, Y.; Kawamura, A.; Sato, T.; Suyama, M.; Takumi, T.; Miyakawa, T.; Nakayama, K.I. CHD8 haploinsufficiency results in autistic-like phenotypes in mice. Nature 2016, 537, 675–679. [Google Scholar] [CrossRef] [PubMed]
  217. Celen, C.; Chuang, J.-C.; Luo, X.; Nijem, N.; Walker, A.K.; Chen, F.; Zhang, S.; Chung, A.S.; Nguyen, L.H.; Nassour, I. Arid1b haploinsufficient mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment. Elife 2017, 6, e25730. [Google Scholar] [CrossRef]
  218. Jung, E.-M.; Moffat, J.J.; Liu, J.; Dravid, S.M.; Gurumurthy, C.B.; Kim, W.-Y. Arid1b haploinsufficiency disrupts cortical interneuron development and mouse behavior. Nat. Neurosci. 2017, 20, 1694–1707. [Google Scholar] [CrossRef]
  219. Shibutani, M.; Horii, T.; Shoji, H.; Morita, S.; Kimura, M.; Terawaki, N.; Miyakawa, T.; Hatada, I. Arid1b haploinsufficiency causes abnormal brain gene expression and autism-related behaviors in mice. Int. J. Mol. Sci. 2017, 18, 1872. [Google Scholar] [CrossRef][Green Version]
  220. Jung, H.; Park, H.; Choi, Y.; Kang, H.; Lee, E.; Kweon, H.; Roh, J.D.; Ellegood, J.; Choi, W.; Kang, J. Sexually dimorphic behavior, neuronal activity, and gene expression in Chd8-mutant mice. Nat. Neurosci. 2018, 21, 1218–1228. [Google Scholar] [CrossRef]
  221. Suetterlin, P.; Hurley, S.; Mohan, C.; Riegman, K.L.; Pagani, M.; Caruso, A.; Ellegood, J.; Galbusera, A.; Crespo-Enriquez, I.; Michetti, C. Altered neocortical gene expression, brain overgrowth and functional over-connectivity in Chd8 haploinsufficient mice. Cereb. Cortex 2018, 28, 2192–2206. [Google Scholar] [CrossRef]
  222. Schaefer, A.; Sampath, S.C.; Intrator, A.; Min, A.; Gertler, T.S.; Surmeier, D.J.; Tarakhovsky, A.; Greengard, P. Control of cognition and adaptive behavior by the GLP/G9a epigenetic suppressor complex. Neuron 2009, 64, 678–691. [Google Scholar] [CrossRef][Green Version]
  223. Balemans, M.C.; Huibers, M.M.; Eikelenboom, N.W.; Kuipers, A.J.; van Summeren, R.C.; Pijpers, M.M.; Tachibana, M.; Shinkai, Y.; van Bokhoven, H.; Van der Zee, C.E. Reduced exploration, increased anxiety, and altered social behavior: Autistic-like features of euchromatin histone methyltransferase 1 heterozygous knockout mice. Behav. Brain Res. 2010, 208, 47–55. [Google Scholar] [CrossRef]
  224. Shu, W.; Cho, J.Y.; Jiang, Y.; Zhang, M.; Weisz, D.; Elder, G.A.; Schmeidler, J.; De Gasperi, R.; Sosa, M.A.G.; Rabidou, D. Altered ultrasonic vocalization in mice with a disruption in the Foxp2 gene. Proc. Natl. Acad. Sci. USA 2005, 102, 9643–9648. [Google Scholar] [CrossRef][Green Version]
  225. Araujo, D.J.; Anderson, A.G.; Berto, S.; Runnels, W.; Harper, M.; Ammanuel, S.; Rieger, M.A.; Huang, H.-C.; Rajkovich, K.; Loerwald, K.W. FoxP1 orchestration of ASD-relevant signaling pathways in the striatum. Genes Dev. 2015, 29, 2081–2096. [Google Scholar] [CrossRef] [PubMed][Green Version]
  226. Bacon, C.; Schneider, M.; Le Magueresse, C.; Froehlich, H.; Sticht, C.; Gluch, C.; Monyer, H.; Rappold, G. Brain-specific Foxp1 deletion impairs neuronal development and causes autistic-like behaviour. Mol. Psychiatry 2015, 20, 632–639. [Google Scholar] [CrossRef] [PubMed][Green Version]
  227. Chen, Y.-C.; Kuo, H.-Y.; Bornschein, U.; Takahashi, H.; Chen, S.-Y.; Lu, K.-M.; Yang, H.-Y.; Chen, G.-M.; Lin, J.-R.; Lee, Y.-H. Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c. Nat. Neurosci. 2016, 19, 1513–1522. [Google Scholar] [CrossRef] [PubMed]
  228. Araujo, D.J.; Toriumi, K.; Escamilla, C.O.; Kulkarni, A.; Anderson, A.G.; Harper, M.; Usui, N.; Ellegood, J.; Lerch, J.P.; Birnbaum, S.G. Foxp1 in forebrain pyramidal neurons controls gene expression required for spatial learning and synaptic plasticity. J. Neurosci. 2017, 37, 10917–10931. [Google Scholar] [CrossRef] [PubMed][Green Version]
  229. Usui, N.; Araujo, D.J.; Kulkarni, A.; Ellegood, J.; Harper, M.; Toriumi, K.; Lerch, J.P.; Konopka, G. Foxp1 regulation of neonatal vocalizations via cortical development. Genes Dev. 2017, 31, 2039–2055. [Google Scholar] [CrossRef][Green Version]
  230. Medvedeva, V.P.; Rieger, M.A.; Vieth, B.; Mombereau, C.; Ziegenhain, C.; Ghosh, T.; Cressant, A.; Enard, W.; Granon, S.; Dougherty, J.D. Altered social behavior in mice carrying a cortical Foxp2 deletion. Hum. Mol. Genet. 2019, 28, 701–717. [Google Scholar] [CrossRef]
  231. French, C.A.; Veloz, M.F.V.; Zhou, K.; Peter, S.; Fisher, S.E.; Costa, R.M.; De Zeeuw, C.I. Differential effects of Foxp2 disruption in distinct motor circuits. Mol. Psychiatry 2019, 24, 447–462. [Google Scholar] [CrossRef]
  232. Sessa, A.; Fagnocchi, L.; Mastrototaro, G.; Massimino, L.; Zaghi, M.; Indrigo, M.; Cattaneo, S.; Martini, D.; Gabellini, C.; Pucci, C.J.N. SETD5 regulates chromatin methylation state and preserves global transcriptional fidelity during brain development and neuronal wiring. Neuron 2019, 104, 271–289. [Google Scholar] [CrossRef]
  233. Deliu, E.; Arecco, N.; Morandell, J.; Dotter, C.P.; Contreras, X.; Girardot, C.; Käsper, E.-L.; Kozlova, A.; Kishi, K.; Chiaradia, I. Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition. Nat. Neurosci. 2018, 21, 1717–1727. [Google Scholar] [CrossRef]
  234. Osipovich, A.; Gangula, R.; Vianna, P.G.; Magnuson, M. Setd5 is essential for mammalian development and the co-transcriptional regulation of histone acetylation. Development 2016, 143, 4595–4607. [Google Scholar] [CrossRef][Green Version]
  235. Zhubi, A.; Chen, Y.; Dong, E.; Cook, E.; Guidotti, A.; Grayson, D. Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum. Transl. Psychiatry 2014, 4, e349. [Google Scholar] [CrossRef] [PubMed][Green Version]
  236. Peters, S.U.; Hundley, R.J.; Wilson, A.K.; Warren, Z.; Vehorn, A.; Carvalho, C.M.; Lupski, J.R.; Ramocki, M.B. The Behavioral Phenotype in MECP 2 Duplication Syndrome: A Comparison With Idiopathic Autism. Autism Res. 2013, 6, 42–50. [Google Scholar] [CrossRef] [PubMed][Green Version]
  237. Nagarajan, R.; Hogart, A.; Gwye, Y.; Martin, M.R.; LaSalle, J.M. Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics 2006, 1, 172–182. [Google Scholar] [CrossRef][Green Version]
  238. Lu, Z.; Liu, Z.; Mao, W.; Wang, X.; Zheng, X.; Chen, S.; Cao, B.; Huang, S.; Zhang, X.; Zhou, T.; et al. Locus-specific DNA methylation of Mecp2 promoter leads to autism-like phenotypes in mice. Cell Death Dis. 2020, 11, 85–111. [Google Scholar] [CrossRef][Green Version]
  239. Kuwano, Y.; Kamio, Y.; Kawai, T.; Katsuura, S.; Inada, N.; Takaki, A.; Rokutan, K. Autism-associated gene expression in peripheral leucocytes commonly observed between subjects with autism and healthy women having autistic children. PLoS ONE 2011, 6, e24723. [Google Scholar] [CrossRef][Green Version]
  240. Gonzales, M.L.; Adams, S.; Dunaway, K.W.; LaSalle, J.M. Phosphorylation of distinct sites in MeCP2 modifies cofactor associations and the dynamics of transcriptional regulation. Mol. Cell. Biol. 2012, 32, 2894–2903. [Google Scholar] [CrossRef][Green Version]
  241. Yip, J.; Soghomonian, J.-J.; Blatt, G.J. Decreased GAD67 mRNA levels in cerebellar Purkinje cells in autism: Pathophysiological implications. Acta Neuropathol. 2007, 113, 559–568. [Google Scholar] [CrossRef]
  242. Yip, J.; Soghomonian, J.J.; Blatt, G.J. Increased GAD67 mRNA expression in cerebellar interneurons in autism: Implications for Purkinje cell dysfunction. J. Neurosci. Res. 2008, 86, 525–530. [Google Scholar] [CrossRef]
  243. Bosch, C.; Muhaisen, A.; Pujadas, L.; Soriano, E.; Martinez, A. Reelin Exerts Structural, Biochemical and Transcriptional Regulation Over Presynaptic and Postsynaptic Elements in the Adult Hippocampus. Front. Cell. Neurosci. 2016, 10, 138. [Google Scholar] [CrossRef][Green Version]
  244. Gregory, S.G.; Connelly, J.J.; Towers, A.J.; Johnson, J.; Biscocho, D.; Markunas, C.A.; Lintas, C.; Abramson, R.K.; Wright, H.H.; Ellis, P. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism. BMC Med. 2009, 7, 62. [Google Scholar] [CrossRef][Green Version]
  245. Behnia, F.; Parets, S.E.; Kechichian, T.; Yin, H.; Dutta, E.H.; Saade, G.R.; Smith, A.K.; Menon, R. Fetal DNA methylation of autism spectrum disorders candidate genes: Association with spontaneous preterm birth. Am. J. Obstet. Gynecol. 2015, 212, e531–e533. [Google Scholar]
  246. Andari, E.; Nishitani, S.; Kaundinya, G.; Caceres, G.A.; Morrier, M.J.; Ousley, O.; Smith, A.K.; Cubells, J.F.; Young, L.J. Epigenetic modification of the oxytocin receptor gene: implications for autism symptom severity and brain functional connectivity. Neuropsychopharmacol. 2020, 1–10. [Google Scholar] [CrossRef] [PubMed]
  247. Zhu, L.; Wang, X.; Li, X.L.; Towers, A.; Cao, X.; Wang, P.; Bowman, R.; Yang, H.; Goldstein, J.; Li, Y.J.; et al. Epigenetic dysregulation of SHANK3 in brain tissues from individuals with autism spectrum disorders. Hum. Mol. Genet. 2014, 23, 1563–1578. [Google Scholar] [CrossRef] [PubMed][Green Version]
  248. Shilatifard, A. Molecular implementation and physiological roles for histone H3 lysine 4 (H3K4) methylation. Curr. Opin. Cell Biol. 2008, 20, 341–348. [Google Scholar] [CrossRef][Green Version]
  249. Gupta, S.; Kim, S.Y.; Artis, S.; Molfese, D.L.; Schumacher, A.; Sweatt, J.D.; Paylor, R.E.; Lubin, F.D. Histone methylation regulates memory formation. J. Neurosci. Off. 2010, 30, 3589–3599. [Google Scholar] [CrossRef]
  250. Shulha, H.P.; Cheung, I.; Whittle, C.; Wang, J.; Virgil, D.; Lin, C.L.; Guo, Y.; Lessard, A.; Akbarian, S.; Weng, Z. Epigenetic signatures of autism: Trimethylated H3K4 landscapes in prefrontal neurons. Arch. Gen. Psychiatry 2012, 69, 314–324. [Google Scholar] [CrossRef]
  251. Sanders, S.J.; He, X.; Willsey, A.J.; Ercan-Sencicek, A.G.; Samocha, K.E.; Cicek, A.E.; Murtha, M.T.; Bal, V.H.; Bishop, S.L.; Dong, S. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 2015, 87, 1215–1233. [Google Scholar] [CrossRef][Green Version]
  252. Bernier, R.; Golzio, C.; Xiong, B.; Stessman, H.A.; Coe, B.P.; Penn, O.; Witherspoon, K.; Gerdts, J.; Baker, C.; Vulto-van Silfhout, A.T. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 2014, 158, 263–276. [Google Scholar] [CrossRef][Green Version]
  253. Ronan, J.L.; Wu, W.; Crabtree, G.R. From neural development to cognition: Unexpected roles for chromatin. Nat. Rev. Genet. 2013, 14, 347–359. [Google Scholar] [CrossRef]
  254. Fregeac, J.; Colleaux, L.; Nguyen, L.S. The emerging roles of MicroRNAs in autism spectrum disorders. Neurosci. Biobehav. Rev. 2016, 71, 729–738. [Google Scholar] [CrossRef]
  255. Mor, M.; Nardone, S.; Sams, D.S.; Elliott, E. Hypomethylation of miR-142 promoter and upregulation of microRNAs that target the oxytocin receptor gene in the autism prefrontal cortex. Mol. Autism 2015, 6, 46. [Google Scholar] [CrossRef][Green Version]
  256. Abu-Elneel, K.; Liu, T.; Gazzaniga, F.S.; Nishimura, Y.; Wall, D.P.; Geschwind, D.H.; Lao, K.; Kosik, K.S. Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics 2008, 9, 153–161. [Google Scholar] [CrossRef] [PubMed]
  257. Seno, M.M.G.; Hu, P.; Gwadry, F.G.; Pinto, D.; Marshall, C.R.; Casallo, G.; Scherer, S.W. Gene and miRNA expression profiles in autism spectrum disorders. Brain Res. 2011, 1380, 85–97. [Google Scholar] [CrossRef] [PubMed]
  258. Popov, N.T.; Stoyanova, V.K.; Madzhirova, N.P.; Vachev, T.I. Epigenetic aspects in schizophrenia etiology and pathogenesis. Folia Med. 2012, 54, 12–16. [Google Scholar] [CrossRef] [PubMed][Green Version]
  259. Zhang, Y.; Wang, Z.; Gemeinhart, R.A. Progress in microRNA delivery. J. Control. Release 2013, 172, 962–974. [Google Scholar] [CrossRef] [PubMed][Green Version]
  260. Johnson, Z.V.; Young, L.J. Oxytocin and vasopressin neural networks: Implications for social behavioral diversity and translational neuroscience. Neurosci. Biobehav. Rev. 2017, 76, 87–98. [Google Scholar] [CrossRef][Green Version]
  261. Freeman, S.M.; Palumbo, M.C.; Lawrence, R.H.; Smith, A.L.; Goodman, M.M.; Bales, K.L. Effect of age and autism spectrum disorder on oxytocin receptor density in the human basal forebrain and midbrain. Transl. Psychiatry 2018, 8, 257. [Google Scholar] [CrossRef]
  262. Andari, E.; Duhamel, J.R.; Zalla, T.; Herbrecht, E.; Leboyer, M.; Sirigu, A. Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc. Natl. Acad. Sci. USA 2010, 107, 4389–4394. [Google Scholar] [CrossRef][Green Version]
  263. Donaldson, Z.R.; Young, L.J. Oxytocin, vasopressin, and the neurogenetics of sociality. Science 2008, 322, 900–904. [Google Scholar] [CrossRef][Green Version]
  264. Procyshyn, T.L.; Hurd, P.L.; Crespi, B.J. Association testing of vasopressin receptor 1a microsatellite polymorphisms in non-clinical autism spectrum phenotypes. Autism Res. 2017, 10, 750–756. [Google Scholar] [CrossRef]
  265. Yirmiya, N.; Rosenberg, C.; Levi, S.; Salomon, S.; Shulman, C.; Nemanov, L.; Dina, C.; Ebstein, R.P. Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: Mediation by socialization skills. Mol. Psychiatry 2006, 11, 488–494. [Google Scholar] [CrossRef] [PubMed][Green Version]
  266. Umbricht, D.; Del Valle Rubido, M.; Hollander, E.; McCracken, J.T.; Shic, F.; Scahill, L.; Noeldeke, J.; Boak, L.; Khwaja, O.; Squassante, L.; et al. A Single Dose, Randomized, Controlled Proof-Of-Mechanism Study of a Novel Vasopressin 1a Receptor Antagonist (RG7713) in High-Functioning Adults with Autism Spectrum Disorder. Neuropsychopharmacol. Off. 2017, 42, 1914–1923. [Google Scholar] [CrossRef] [PubMed]
  267. Zarrei, M.; Burton, C.L.; Engchuan, W.; Young, E.J.; Higginbotham, E.J.; MacDonald, J.R.; Trost, B.; Chan, A.J.S.; Walker, S.; Lamoureux, S.; et al. A large data resource of genomic copy number variation across neurodevelopmental disorders. NPJ Genom. Med. 2019, 4, 26. [Google Scholar] [CrossRef][Green Version]
  268. Hong, Y.J.; Do, J.T. Neural Lineage Differentiation From Pluripotent Stem Cells to Mimic Human Brain Tissues. Front. Bioeng. Biotechnol. 2019, 7, 400. [Google Scholar] [CrossRef][Green Version]
  269. Russo, F.B.; Brito, A.; de Freitas, A.M.; Castanha, A.; de Freitas, B.C.; Beltrao-Braga, P.C.B. The use of iPSC technology for modeling Autism Spectrum Disorders. Neurobiol. Dis. 2019, 130, 104483. [Google Scholar] [CrossRef]
  270. Mariani, J.; Coppola, G.; Zhang, P.; Abyzov, A.; Provini, L.; Tomasini, L.; Amenduni, M.; Szekely, A.; Palejev, D.; Wilson, M.; et al. FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. Cell 2015, 162, 375–390. [Google Scholar] [CrossRef][Green Version]
  271. Saurman, V.; Margolis, K.G.; Luna, R.A. Autism Spectrum Disorder as a Brain-Gut-Microbiome Axis Disorder. Dig. Dis. Sci. 2020. [Google Scholar] [CrossRef][Green Version]
  272. Collins, S.M.; Surette, M.; Bercik, P. The interplay between the intestinal microbiota and the brain. Nat. Rev. Microbiol. 2012, 10, 735–742. [Google Scholar] [CrossRef]
  273. Alessio, N.; Brigida, A.L.; Peluso, G.; Antonucci, N.; Galderisi, U.; Siniscalco, D. Stem Cell-Derived Exosomes in Autism Spectrum Disorder. Int. J. Environ. Res. Public Health 2020, 17, 944. [Google Scholar] [CrossRef][Green Version]
  274. Li, Q.; Wang, H.; Peng, H.; Huyan, T.; Cacalano, N.A. Exosomes: Versatile Nano Mediators of Immune Regulation. Cancers 2019, 11, 1557. [Google Scholar] [CrossRef][Green Version]
  275. Matta, S.M.; Hill-Yardin, E.L.; Crack, P.J. The influence of neuroinflammation in Autism Spectrum Disorder. Brain Behav. Immun. 2019, 79, 75–90. [Google Scholar] [CrossRef] [PubMed]
  276. Wang, H.; Sui, H.; Zheng, Y.; Jiang, Y.; Shi, Y.; Liang, J.; Zhao, L. Curcumin-primed exosomes potently ameliorate cognitive function in AD mice by inhibiting hyperphosphorylation of the Tau protein through the AKT/GSK-3beta pathway. Nanoscale 2019, 11, 7481–7496. [Google Scholar] [CrossRef] [PubMed]
  277. Bhatia, S.N.; Ingber, D.E. Microfluidic organs-on-chips. Nat. Biotechnol. 2014, 32, 760–772. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Comprehensive overview of the diverse etiology of autism spectrum disorder (ASD). Although definitive etiology and pathogenesis underlying ASD have not yet been identified, accumulated evidence has identified various risk factors, including environmental, genetic, and epigenetic factors.
Figure 1. Comprehensive overview of the diverse etiology of autism spectrum disorder (ASD). Although definitive etiology and pathogenesis underlying ASD have not yet been identified, accumulated evidence has identified various risk factors, including environmental, genetic, and epigenetic factors.
Jcm 09 00966 g001
Figure 2. Loci on chromosome 7 responsible for autism spectrum disorder (ASD). Chromosome 7 contains more ASD-related regions than other chromosomes. Genome-wide association studies found SPCH1 and AUTS1 (autism susceptibility locus), which encompass RELN, IMMP2L, FOXP2, and RAY1/ST7, to be the specific loci responsible for the defect in speech and language development in ASD patients.
Figure 2. Loci on chromosome 7 responsible for autism spectrum disorder (ASD). Chromosome 7 contains more ASD-related regions than other chromosomes. Genome-wide association studies found SPCH1 and AUTS1 (autism susceptibility locus), which encompass RELN, IMMP2L, FOXP2, and RAY1/ST7, to be the specific loci responsible for the defect in speech and language development in ASD patients.
Jcm 09 00966 g002
Table 1. Chromosome locus associated with ASD.
Table 1. Chromosome locus associated with ASD.
LocusFunctionGenesVariationReference
3q21.1
-
3q21.2
Abnormalities in neuronal maturation and long-term potentiation in the brain,
macrocephaly, intellectual disability facial dysmorphism
KALRNDuplication[166,167,168]
5p14.1Neuronal cell-adhesion moleculesCadherin 10 (CDH10) Cadherin 9 (CDH9)Deletion[159,169]
6q14.3Learning problems, intellectual disability, behavioral problemsZNF292
(zinc finger protein 292)
Deletion[170]
12q24.23Neuronal cells and misregulated neural ‘microexons’ in the brainsnSR100/SRRM4 [171]
16p11.2
Reduced proliferation of neuronal progenitors, the increased cell death during the brain development, microcephalyKCTD13
Deletion
Duplication
[161,162,163,164,165]
16q24.3Cognitive impairment, brain abnormalityANKRD11
ZNF778
Microdeletion[160]
17q12Macrocephaly, neurocognitive impairmentHNF1BDeletion[172]
20q13.12Releases of glutamate at the synapseRIMS4 [166,173]
22q11.2Physical, behavioral, social communication,
neurocognitive impairments
Deletion[166]
22q13Cognitive deficits, behavioral autistic symptoms,
language and social communication problems
SHANK3Deletion[96,97,174,175,176]
Xq27.3Synaptic function in the brainFMR1 [166,177,178]
Table 2. Epigenetic factors implicated in ASD.
Table 2. Epigenetic factors implicated in ASD.
Epigenetic FactorsGenesFunctionPossible Epigenetic MechanismsReference
DNA methylationMeCP2Encodes a methyl binding protein that binds to the methylated region of DNA and silence the gene. Has a role in synaptic development and long-term synaptic plasticity.MeCP2 regulation of other genes via epigenetics: recruitment of co-repressors, chromatin looping.[184,193]
UBE3AKnown for its role in Angelman syndrome.Loss of imprinting of one copy, and production of antisense RNA that binds to UBE3A and mRNA Prevents translation.[185,186]
OXTRG-protein coupled receptor for oxytocin. Modulates: stress, anxiety, social memory, maternal-offspring behavior, etc.Hypermethylation and silencing.Decreased OXTR expression.[194,195]
SHANK3Effect on the morphology of dendritic spine and synaptic transmissionExpression of SHANK3 was strongly regulated by methylated CpG island.[195,196]
Histone modificationKDM5CAlters the epigenetic state, which is associated with intellectual disability and frequent autistic behavior.Involved in the regulation of transcription and chromatin remodeling.[197]
HIST1H1EAssociated with the features of ASD and intellectual disorders.To organize the higher-order chromatin structure and regulation of gene transcription.[198]
CHD8Inhibit the target genes of Wnt/β-catenin, and many of the genes in CHD8 targets included autism risk genes.Encode ATP-dependent helicases that are typically involved in chromatin remodeling.[199]
ARID1BA component of the ATP-dependent human SWI/SNF chromatin-remodeling complex.Involved in chromatin remodeling.[15,200]
BCL11AEncode proteins that interact directly with members of the SWI/SNF.Involved in chromatin remodeling.[201]
ADNPEncode proteins that interact directly with members of the SWI/SNF.Involved in chromatin remodeling.[201]
Micro RNA Deregulation of miRNA synthesis leads to neurodevelopmental disorders.Epigenetic regulator that control the expression of many genes at the level of post-transcription by blocking protein synthesis or mRNA degradation.[202,203,204,205]
Back to TopTop