1. Breuss MW, Gleeson JG. {{When size matters: CHD8 in autism}}. {Nat Neurosci};2016 (Oct 26);19(11):1430-1432.
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2. Caubit X, Gubellini P, Andrieux J, Roubertoux PL, Metwaly M, Jacq B, Fatmi A, Had-Aissouni L, Kwan KY, Salin P, Carlier M, Lieden A, Rudd E, Shinawi M, Vincent-Delorme C, Cuisset JM, Lemaitre MP, Abderrehamane F, Duban B, Lemaitre JF, Woolf AS, Bockenhauer D, Severac D, Dubois E, Zhu Y, Sestan N, Garratt AN, Kerkerian-Le Goff L, Fasano L. {{TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons}}. {Nat Genet};2016 (Nov);48(11):1359-1369.
TSHZ3, which encodes a zinc-finger transcription factor, was recently positioned as a hub gene in a module of the genes with the highest expression in the developing human neocortex, but its functions remained unknown. Here we identify TSHZ3 as the critical region for a syndrome associated with heterozygous deletions at 19q12-q13.11, which includes autism spectrum disorder (ASD). In Tshz3-null mice, differentially expressed genes include layer-specific markers of cerebral cortical projection neurons (CPNs), and the human orthologs of these genes are strongly associated with ASD. Furthermore, mice heterozygous for Tshz3 show functional changes at synapses established by CPNs and exhibit core ASD-like behavioral abnormalities. These findings highlight essential roles for Tshz3 in CPN development and function, whose alterations can account for ASD in the newly defined TSHZ3 deletion syndrome.
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3. Chan HL, Liu WS, Hsieh YH, Lin CF, Ling TS, Huang YS. {{Screening for attention deficit and hyperactivity disorder, autism spectrum disorder, and developmental delay in Taiwanese aboriginal preschool children}}. {Neuropsychiatr Dis Treat};2016;12:2521-2526.
OBJECTIVES: This study aimed to estimate the percentages of attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in Taiwanese aboriginal preschool children. Child development level was compared between the two groups. METHODS: Teachers completed screening questionnaires for ADHD, ASD, and development level for 36- to 72-month-old children in kindergartens in Taiwan. The questionnaire results were compared between the aboriginal and nonaboriginal children. One child psychiatrist then interviewed the aboriginal preschool children to determine if they had ADHD and/or ASD. RESULTS: We collected 93 questionnaires from the aboriginal group and 60 from the nonaboriginal group. In the aboriginal group, 5.37% of the children were identified to have ADHD, while 1.08% were identified to have ASD. Significantly fewer aboriginal children had developmental delays for situation comprehension and personal-social development (P=0.012 and 0.002, respectively) than nonaboriginal children. CONCLUSION: Aboriginal children in Taiwan had typical percentages of ADHD and ASD compared to those published in the literature. Aboriginal children showed relative strengths in situation comprehension and personal-social skills. Further studies are required to understand the learning styles of the aboriginal children and to develop effective screening and intervention strategies for ADHD and ASD.
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4. Cope EC, Briones BA, Brockett AT, Martinez S, Vigneron PA, Opendak M, Wang SS, Gould E. {{Immature Neurons and Radial Glia, But Not Astrocytes or Microglia, Are Altered in Adult Cntnap2 and Shank3 Mice, Models of Autism}}. {eNeuro};2016 (Sep-Oct);3(5)
Autism spectrum disorder (ASD) is often associated with cognitive deficits and excessive anxiety. Neuroimaging studies have shown atypical structure and neural connectivity in the hippocampus, medial prefrontal cortex (mPFC), and striatum, regions associated with cognitive function and anxiety regulation. Adult hippocampal neurogenesis is involved in many behaviors that are disrupted in ASD, including cognition, anxiety, and social behaviors. Additionally, glial cells, such as astrocytes and microglia, are important for modulating neural connectivity during development, and glial dysfunction has been hypothesized to be a key contributor to the development of ASD. Cells with astroglial characteristics are known to serve as progenitor cells in the developing and adult brain. Here, we examined adult neurogenesis in the hippocampus, as well as astroglia and microglia in the hippocampus, mPFC, and striatum of two models that display autism-like phenotypes, Cntnap2-/- and Shank3+/DeltaC transgenic mice. We found a substantial decrease in the number of immature neurons and radial glial progenitor cells in the ventral hippocampus of both transgenic models compared with wild-type controls. No consistent differences were detected in the number or size of astrocytes or microglia in any other brain region examined. Future work is needed to explore the functional contribution of adult neurogenesis to autism-related behaviors as well as to temporally characterize glial plasticity as it is associated with ASD.
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5. Frazier TW, Krishna J, Klingemier E, Beukemann M, Nawabit R, Ibrahim S. {{A Randomized, Crossover Trial of a Novel Sound-to-Sleep Mattress Technology in Children with Autism and Sleep Difficulties}}. {J Clin Sleep Med};2016 (Oct 20)
STUDY OBJECTIVES: This preliminary study investigated the tolerability and efficacy of a novel mattress technology – the Sound-To-Sleep (STS) system – in the treatment of sleep problems in children with autism. METHODS: After screening, 45 children, ages 2.5 to 12.9 years, were randomized to order of mattress technology use (On-Off vs. Off-On). Treatment conditions (On vs. Off) lasted two weeks with immediate crossover. Tolerability, including study discontinuation and parent-report of mattress tolerance and ease of use, was tracked throughout the study. Efficacy assessments were obtained at baseline, prior to crossover, and end of study and included measures of autism traits, other psychopathology symptoms, sensory abnormalities, communication difficulties, quality of life, sleep diary parameters, and single-blinded actigraphy-derived sleep parameters. Statistical analyses evaluated differences in tolerability and efficacy when the STS system was on versus off. RESULTS: STS system use was well tolerated (n = 2, 4.4% dropout) and resulted in parent-reported sleep quality improvements (STS off M = 4.3, 95%CI = 4.05-4.54 vs. on M = 4.9, 95%CI = 4.67-5.14). The technology was described by parents as very easy to use and child tolerance was rated as good. Parent-diary outcomes indicated improvements in falling asleep and reduced daytime challenging behavior. Actigraphy-derived sleep parameters indicated improved sleep duration and sleep efficiency. Improvements in child and family quality of life were identified on parent questionnaires. CONCLUSIONS: A future large sample phase 2 trial of the STS system is warranted and would benefit from extended study duration, an objective primary efficacy outcome, and careful attention to methodological issues that promote compliance with the intervention and study procedures.
6. Graber A. {{Autism, intellectual disability, and a challenge to our understanding of proxy consent}}. {Med Health Care Philos};2016 (Oct 26)
This paper focuses on a hypothetical case that represents an intervention request familiar to those who work with individuals with intellectual disability. Stacy has autism and moderate intellectual disability. Her parents have requested treatment for her hand flapping. Stacy is not competent to make her own treatment decisions; proxy consent is required. There are three primary justifications for proxy consent: the right to an open future, substituted judgment, and the best interest standard. The right to an open future justifies proxy consent on the assumption of future autonomy whereas substituted judgment justifies proxy consent via reference to past autonomy. Neither applies. Stacy has not been, nor will she be, competent to make her own treatment decisions. The best interest standard justifies proxy consent on the grounds of beneficence. It is unlikely that hand flapping harms Stacy. None of the three primary means of justifying proxy consent apply to Stacy’s case.
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7. Ha S, Park H, Mahmood U, Ra JC, Suh YH, Chang KA. {{Human adipose-derived stem cells ameliorate repetitive behavior, social deficit and anxiety in a VPA-induced autism mouse model}}. {Behav Brain Res};2016 (Oct 4);317:479-484.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder characterized by impairments in social interaction and communication, and patients often display co-occurring repetitive behaviors. Although the global prevalence of ASD has increased over time, the etiology and treatments for ASD are poorly understood. Recently, some researchers have suggested that stem cells have therapeutic potential for ASD. Thus, in the present study, we investigated the therapeutic effects of human adipose-derived stem cells (hASCs), a kind of autologous mesenchymal stem cells (MSCs) isolated from adipose tissue, on valproic acid (VPA)-induced autism model mice. Human ASCs were injected into the neonatal pups (P2 or P3) intraventricularly and then we evaluated major behavior symptoms of ASD. VPA-treated mice showed increased repetitive behaviors, decreased social interactions and increased anxiety but these autistic behaviors were ameliorated through transplantation of hASCs. In addition, hASCs transplantation restored the alteration of phosphatase and tensin homolog (PTEN) expression and p-AKT/AKT ratio in the brains of VPA-induced ASD model mice. The decreased level of vascular endothelial growth factor (VEGF) and interleukin 10 (IL-10) by VPA were rescued in the brains of the hASC-injected VPA mice. With these results, we experimentally found hASCs’ therapeutic effects on autistic phenotypes in a ASD model mice for the first time. This animal model system can be used to elucidate further mechanisms of therapeutic effects of hASCs in ASD.
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8. Harris JC. {{The origin and natural history of autism spectrum disorders}}. {Nat Neurosci};2016 (Oct 26);19(11):1390-1391.
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9. Ide-Okochi A, Tadaka E. {{A hybrid concept analysis of children of concern: Japanese healthcare professionals’ views of children at a high risk of developmental disability}}. {BMC Pediatr};2016 (Oct 28);16(1):171.
BACKGROUND: The new Diagnostic and Statistical Manual of Mental Disorders (fifth edition, DSM-5) redefined the boundaries of autism as a spectrum. It has been reported that the number of schoolchildren with undiagnosed developmental disorders (DDs) has risen in Japan. Such children referred to as kininaru-kodomo (KK, « children of concern ») by healthcare professionals fall into a gray area. Therefore, KK are often overlooked at infant medical checkups. This leaves KK without necessary medical care and special needs education. It is urgent to explore the KK concept to enable professionals to properly assess and provide for the healthcare needs of these children at a high risk of DD, ideally with early intervention. METHODS: A hybrid model of concept analysis was conducted. Working definitions were obtained from a systematic literature review in the theoretical phase. Subsequent in-depth personal interviews initiated in the fieldwork phase corroborated and refined the concept. These qualitative data were integrated in the final analytical phase to yield the practice-based real definition of KK in clinical settings. RESULTS: Three themes emerged regarding KK children: children who require special care, children whose special healthcare needs are owing to both individual and environmental factors, and children waiting for the development of a new support system for them or their parents. CONCLUSIONS: This study implies that KK are children who require special support because of individual and environmental factors. The concept of KK is considered useful for keeping children with undiagnosed DDs and/or other healthcare needs connected with support networks. It is strongly recommended that a screening tool be developed that reflects the concept of children at a high risk of DD so that children in this gray area may receive necessary support even before diagnosis.
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10. Keenan BM, Newman LK, Gray KM, Rinehart NJ. {{A qualitative study of attachment relationships in ASD during middle childhood}}. {Attach Hum Dev};2016 (Oct 28):1-21.
Although research has indicated that children with Autism Spectrum Disorder (ASD) display normative attachment behaviours, to date there has been limited qualitative research exploring these relationships. This study aimed to describe qualitative features of the child-caregiver attachment relationship in children with ASD. Primary caregivers to 26 children with ASD (aged 7-14 years) and 23 typically developing children (aged 7-13 years) were administered the Disturbances of Attachment Interview (Smyke & Zeanah, 1999) to elicit descriptions of children’s attachment behaviours. Thematic analysis of interview transcripts indicated that while children with ASD demonstrated a range of normative attachment behaviours, they displayed impairments in the use of the caregiver as a secure base and co-regulating agent. ASD-associated impairments in emotion processing, sharing/reciprocity, and emotion co-regulation, as well as the caregiver’s experience, were important in understanding attachment relationships in ASD. Findings highlight the need to consider the bidirectional nature of the attachment relationship in ASD.
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11. Khalfallah O, Jarjat M, Davidovic L, Nottet N, Cestele S, Mantegazza M, Bardoni B. {{Depletion of the Fragile X Mental Retardation Protein in Embryonic Stem Cells Alters the Kinetics of Neurogenesis}}. {Stem Cells};2016 (Sep 24)
Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and a leading cause of autism. FXS is due to the silencing of the Fragile X Mental Retardation Protein (FMRP), an RNA binding protein mainly involved in translational control, dendritic spine morphology and synaptic plasticity. Despite extensive studies, there is currently no cure for FXS. With the purpose to decipher the initial molecular events leading to this pathology, we developed a stem-cell-based disease model by knocking-down the expression of Fmr1 in mouse embryonic stem cells (ESCs). Repressing FMRP in ESCs increased the expression of amyloid precursor protein (APP) and Ascl1. When inducing neuronal differentiation, betaIII-tubulin, p27kip1 , NeuN, and NeuroD1 were upregulated, leading to an accelerated neuronal differentiation that was partially compensated at later stages. Interestingly, we observed that neurogenesis is also accelerated in the embryonic brain of Fmr1-knockout mice, indicating that our cellular model recapitulates the molecular alterations present in vivo. Importantly, we rescued the main phenotype of the Fmr1 knockdown cell line, not only by reintroducing FMRP but also by pharmacologically targeting APP processing, showing the role of this protein in the pathophysiology of FXS during the earliest steps of neurogenesis. Our work allows to define an early therapeutic window but also to identify more effective molecules for treating this disorder. Stem Cells 2016.
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12. Kinard JL, Sideris J, Watson LR, Baranek GT, Crais ER, Wakeford L, Turner-Brown L. {{Predictors of Parent Responsiveness to 1-Year-Olds At-Risk for Autism Spectrum Disorder}}. {J Autism Dev Disord};2016 (Oct 26)
Parent responsiveness is critical for child development of cognition, social-communication, and self-regulation. Parents tend to respond more frequently when children at-risk for autism spectrum disorder (ASD) demonstrate stronger social-communication; however, it is unclear how responsiveness is associated with sensory characteristics of children at-risk for ASD. To address this issue, we examined the extent to which child social-communication and sensory reactivity patterns (i.e., hyper- and hypo-reactivity) predicted parent responsiveness to 1-year-olds at-risk for ASD in a community sample of 97 parent-infant pairs. A combination of child social-communication and sensory hypo-reactivity consistently predicted how parents played and talked with their 1-year-old at-risk for ASD. Parents tended to talk less and use more play actions when infants communicated less and demonstrated stronger hypo-reactivity.
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13. Krishnan A, Zhang R, Yao V, Theesfeld CL, Wong AK, Tadych A, Volfovsky N, Packer A, Lash A, Troyanskaya OG. {{Genome-wide prediction and functional characterization of the genetic basis of autism spectrum disorder}}. {Nat Neurosci};2016 (Nov);19(11):1454-1462.
Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with a strong genetic basis. Yet, only a small fraction of potentially causal genes-about 65 genes out of an estimated several hundred-are known with strong genetic evidence from sequencing studies. We developed a complementary machine-learning approach based on a human brain-specific gene network to present a genome-wide prediction of autism risk genes, including hundreds of candidates for which there is minimal or no prior genetic evidence. Our approach was validated in a large independent case-control sequencing study. Leveraging these genome-wide predictions and the brain-specific network, we demonstrated that the large set of ASD genes converges on a smaller number of key pathways and developmental stages of the brain. Finally, we identified likely pathogenic genes within frequent autism-associated copy-number variants and proposed genes and pathways that are likely mediators of ASD across multiple copy-number variants. All predictions and functional insights are available at http://asd.princeton.edu.
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14. Mody M, Shui AM, Nowinski LA, Golas SB, Ferrone C, O’Rourke JA, McDougle CJ. {{Communication Deficits and the Motor System: Exploring Patterns of Associations in Autism Spectrum Disorder (ASD)}}. {J Autism Dev Disord};2016 (Oct 26)
Many children with autism spectrum disorder (ASD) have notable difficulties in motor, speech and language domains. The connection between motor skills (oral-motor, manual-motor) and speech and language deficits reported in other developmental disorders raises important questions about a potential relationship between motor skills and speech-language deficits in ASD. To this end, we examined data from children with ASD (n = 1781), 2-17 years of age, enrolled in the Autism Speaks-Autism Treatment Network (AS-ATN) registry who completed a multidisciplinary evaluation that included diagnostic, physical, cognitive and behavioral assessments as part of a routine standard of care protocol. After adjusting for age, non-verbal IQ, Attention Deficit Hyperactivity Disorder (ADHD) medication use, and muscle tone, separate multiple linear regression analyses revealed significant positive associations of fine motor skills (FM) with both expressive language (EL) and receptive language (RL) skills in an impaired FM subgroup; in contrast, the impaired gross motor (GM) subgroup showed no association with EL but a significant negative association with RL. Similar analyses between motor skills and interpersonal relationships across the sample found both GM skills and FM skills to be associated with social interactions. These results suggest potential differences in the contributions of fine versus gross motor skills to autistic profiles and may provide another lens with which to view communication differences across the autism spectrum for use in treatment interventions.
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15. Pirrone A, Dickinson A, Gomez R, Stafford T, Milne E. {{Understanding Perceptual Judgment in Autism Spectrum Disorder Using the Drift Diffusion Model}}. {Neuropsychology};2016 (Oct 10)
Objective: Two-alternative forced-choice tasks are widely used to gain insight into specific areas of enhancement or impairment in individuals with autism spectrum disorder (ASD). Data arising from these tasks have been used to support myriad theories regarding the integrity, or otherwise, of particular brain areas or cognitive processes in ASD. The drift diffusion model (DDM) provides an account of the underlying processes which give rise to accuracy and reaction time (RT) distributions, and parameterizes these processes in terms which have direct psychological interpretation. Importantly, the DDM provides further insight into the origin of potential group differences in task performance. Here, for the first time, we used the DDM to investigate perceptual decision making in ASD. Method: Adults with (N = 25) and without ASD (N = 32) performed an orientation discrimination task. A drift diffusion model was applied to the full RT distributions. Results: Participants with ASD responded more slowly than controls, the groups did not differ in accuracy. Modeled parameters indicated that: (a) participants with ASD were more cautious than controls (wider boundary separation); (b) nondecision time was increased in ASD; and (c) the quality of evidence extracted from the stimulus (drift rate) did not vary between groups. Conclusions: Taking the behavioral data in isolation would suggest reduced perceptual sensitivity in ASD. However, DDM results indicated that despite response slowing, there was no evidence of differential perceptual sensitivity between participants with and without ASD. Future use of the DDM in investigations of perception and cognition in ASD is highly recommended. (PsycINFO Database Record
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16. Skalny AV, Simashkova NV, Klyushnik TP, Grabeklis AR, Radysh IV, Skalnaya MG, Tinkov AA. {{Analysis of Hair Trace Elements in Children with Autism Spectrum Disorders and Communication Disorders}}. {Biol Trace Elem Res};2016 (Oct 26)
The primary objective of the present study is analysis of hair trace elements content in children with communication disorder (CD) and autism spectrum disorder (ASD). A total of 99 children from control, CD, and ASD groups (n = 33) were examined. All children were additionally divided into two subgroups according to age. Hair levels of trace elements were assessed using inductively coupled plasma mass spectrometry. The difference was considered significant at p < 0.01. The obtained data demonstrate that children with CD are characterized by significantly increased hair lithium (Li) (96 %; p = 0.008), selenium (Se) (66 %; p < 0.001), arsenic (As) (96 %; p = 0.005), beryllium (Be) (150 %; p < 0.001), and cadmium (Cd) (72 %; p = 0.007) content, being higher than the respective control values. In the ASD group, hair copper (Cu), iodine (I), and Be levels tended to be lower than the control values. In turn, the scalp hair content of Se significantly exceeded the control values (33 %; p = 0.004), whereas the level of iron (Fe) and aluminum (Al) tended to increase. After gradation for age, the most prominent differences in children with CD were detected in the elder group (5-8 years), whereas in the case of ASD-in the younger group (3-4 years old). Taking into account the role of hair as excretory mechanism for certain elements including the toxic ones, it can be proposed that children suffering from ASD are characterized by more profound alteration of metal handling and excretion in comparison to CD. Lien vers le texte intégral (Open Access ou abonnement)
17. Sztainberg Y, Zoghbi HY. {{Lessons learned from studying syndromic autism spectrum disorders}}. {Nat Neurosci};2016 (Oct 26);19(11):1408-1417.
Syndromic autism spectrum disorders represent a group of childhood neurological conditions, typically associated with chromosomal abnormalities or mutations in a single gene. The discovery of their genetic causes has increased our understanding of the molecular pathways critical for normal cognitive and social development. Human studies have revealed that the brain is particularly sensitive to changes in dosage of various proteins from transcriptional and translational regulators to synaptic proteins. Investigations of these disorders in animals have shed light on previously unknown pathogenic mechanisms leading to the identification of potential targets for therapeutic intervention. The demonstration of reversibility of several phenotypes in adult mice is encouraging, and brings hope that with novel therapies, skills and functionality might improve in affected children and young adults. As new research reveals points of convergence between syndromic and nonsyndromic autism spectrum disorders, we believe there will be opportunities for shared therapeutics for this class of conditions.
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18. Torjesen I. {{Early intervention may limit severity of autism symptoms}}. {BMJ};2016 (Oct 26);355:i5776.
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19. Wang Y, Picard M, Gu Z. {{Genetic Evidence for Elevated Pathogenicity of Mitochondrial DNA Heteroplasmy in Autism Spectrum Disorder}}. {PLoS Genet};2016 (Oct);12(10):e1006391.
Increasing clinical and biochemical evidence implicate mitochondrial dysfunction in the pathophysiology of Autism Spectrum Disorder (ASD), but little is known about the biological basis for this connection. A possible cause of ASD is the genetic variation in the mitochondrial DNA (mtDNA) sequence, which has yet to be thoroughly investigated in large genomic studies of ASD. Here we evaluated mtDNA variation, including the mixture of different mtDNA molecules in the same individual (i.e., heteroplasmy), using whole-exome sequencing data from mother-proband-sibling trios from simplex families (n = 903) where only one child is affected by ASD. We found that heteroplasmic mutations in autistic probands were enriched at non-polymorphic mtDNA sites (P = 0.0015), which were more likely to confer deleterious effects than heteroplasmies at polymorphic mtDNA sites. Accordingly, we observed a ~1.5-fold enrichment of nonsynonymous mutations (P = 0.0028) as well as a ~2.2-fold enrichment of predicted pathogenic mutations (P = 0.0016) in autistic probands compared to their non-autistic siblings. Both nonsynonymous and predicted pathogenic mutations private to probands conferred increased risk of ASD (Odds Ratio, OR[95% CI] = 1.87[1.14-3.11] and 2.55[1.26-5.51], respectively), and their influence on ASD was most pronounced in families with probands showing diminished IQ and/or impaired social behavior compared to their non-autistic siblings. We also showed that the genetic transmission pattern of mtDNA heteroplasmies with high pathogenic potential differed between mother-autistic proband pairs and mother-sibling pairs, implicating developmental and possibly in utero contributions. Taken together, our genetic findings substantiate pathogenic mtDNA mutations as a potential cause for ASD and synergize with recent work calling attention to their unique metabolic phenotypes for diagnosis and treatment of children with ASD.
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20. Wu YE, Parikshak NN, Belgard TG, Geschwind DH. {{Genome-wide, integrative analysis implicates microRNA dysregulation in autism spectrum disorder}}. {Nat Neurosci};2016 (Nov);19(11):1463-1476.
Genetic variants conferring risk for autism spectrum disorder (ASD) have been identified, but the role of post-transcriptional mechanisms in ASD is not well understood. We performed genome-wide microRNA (miRNA) expression profiling in post-mortem brains from individuals with ASD and controls and identified miRNAs and co-regulated modules that were perturbed in ASD. Putative targets of these ASD-affected miRNAs were enriched for genes that have been implicated in ASD risk. We confirmed regulatory relationships between several miRNAs and their putative target mRNAs in primary human neural progenitors. These include hsa-miR-21-3p, a miRNA of unknown CNS function that is upregulated in ASD and that targets neuronal genes downregulated in ASD, and hsa_can_1002-m, a previously unknown, primate-specific miRNA that is downregulated in ASD and that regulates the epidermal growth factor receptor and fibroblast growth factor receptor signaling pathways involved in neural development and immune function. Our findings support a role for miRNA dysregulation in ASD pathophysiology and provide a rich data set and framework for future analyses of miRNAs in neuropsychiatric diseases.
