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Papers of the Week

  • 1) Cell Rep. 2014 Oct 1. pii: S2211-1247(14)00760-8. doi: 10.1016/j.celrep.2014.08.068. [Epub ahead of print]

    De Novo Insertions and Deletions of Predominantly Paternal Origin Are Associated with Autism Spectrum Disorder.

    Dong S(1), Walker MF(2), Carriero NJ(3), DiCola M(4), Willsey AJ(5), Ye AY(6),
    Waqar Z(7), Gonzalez LE(7), Overton JD(8), Frahm S(4), Keaney JF 3rd(9), Teran
    NA(7), Dea J(2), Mandell JD(2), Hus Bal V(2), Sullivan CA(7), DiLullo NM(7),
    Khalil RO(10), Gockley J(11), Yuksel Z(12), Sertel SM(13), Ercan-Sencicek AG(14),
    Gupta AR(15), Mane SM(16), Sheldon M(17), Brooks AI(4), Roeder K(18), Devlin
    B(19), State MW(20), Wei L(21), Sanders SJ(22).
    
    Author information: 
    (1)Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene
    Research, School of Life Sciences, Peking University, Beijing 100871, People's
    Republic of China; Department of Genetics, Yale University School of Medicine,
    New Haven, CT 06520, USA.
    (2)Department of Psychiatry, University of California, San Francisco, San Francisco,
    CA 94158, USA.
    (3)Biomedical High Performance Computing Center, W.M. Keck Biotechnology Resource
    Laboratory, Department of Computer Science, Yale University, New Haven, CT 06520,
    USA.
    (4)Bionomics Research and Technology, Environmental and Occupational Health Sciences
    Institute, Rutgers University, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA.
    (5)Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, 
    USA; Department of Psychiatry, University of California, San Francisco, San
    Francisco, CA 94158, USA.
    (6)Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene
    Research, School of Life Sciences, Peking University, Beijing 100871, People's
    Republic of China; National Institute of Biological Sciences, Beijing 102206,
    People's Republic of China.
    (7)Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA.
    (8)Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, 
    CT 06520, USA; Regeneron Genetics Center, 777 Old Saw Mill River Road, Tarrytown,
    NY 10591, USA.
    (9)Department of Chronic Disease Epidemiology, Yale School of Public Health, New
    Haven, CT 06520, USA.
    (10)Department of Psychiatry, University of California, San Francisco, San Francisco,
    CA 94158, USA; Department of Research on Children with Special Needs, National
    Research Center, Cairo 11787, Egypt.
    (11)Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, 
    USA.
    (12)Department of Medical Genetics, Gulhane Military Medical Academy, Ankara 06010,
    Turkey.
    (13)Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800,
    Turkey.
    (14)Department of Neurosurgery, Yale Neurogenetics Program, Yale University School of
    Medicine, New Haven, CT 06520, USA.
    (15)Child Study Center, Yale University School of Medicine, New Haven, CT 06520, USA;
    Department of Pediatrics, Yale University School of Medicine, New Haven, CT
    06520, USA.
    (16)Yale Center for Genomic Analysis, Yale University School of Medicine, New Haven, 
    CT 06520, USA.
    (17)Department of Genetics and the Human Genetics Institute, Rutgers University, 145 
    Bevier Road, Room 136, Piscataway, NJ 08854, USA.
    (18)Department of Statistics, Carnegie Mellon University, Pittsburgh, PA 15213, USA; 
    Ray and Stephanie Lane Center for Computational Biology, Carnegie Mellon
    University, Pittsburgh, PA 15213, USA.
    (19)Department of Psychiatry, University of Pittsburgh School of Medicine,
    Pittsburgh, PA 15213, USA.
    (20)Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, 
    USA; Department of Psychiatry, University of California, San Francisco, San
    Francisco, CA 94158, USA; Child Study Center, Yale University School of Medicine,
    New Haven, CT 06520, USA; Department of Psychiatry, Yale University School of
    Medicine, New Haven, CT 06520, USA. Electronic address: matthew.state@ucsf.edu.
    (21)Center for Bioinformatics, State Key Laboratory of Protein and Plant Gene
    Research, School of Life Sciences, Peking University, Beijing 100871, People's
    Republic of China; National Institute of Biological Sciences, Beijing 102206,
    People's Republic of China. Electronic address: weilp@mail.cbi.pku.edu.cn.
    (22)Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, 
    USA; Department of Psychiatry, University of California, San Francisco, San
    Francisco, CA 94158, USA. Electronic address: stephan.sanders@ucsf.edu.
    
    Whole-exome sequencing (WES) studies have demonstrated the contribution of de
    novo loss-of-function single-nucleotide variants (SNVs) to autism spectrum
    disorder (ASD). However, challenges in the reliable detection of de novo
    insertions and deletions (indels) have limited inclusion of these variants in
    prior analyses. By applying a robust indel detection method to WES data from 787 
    ASD families (2,963 individuals), we demonstrate that de novo frameshift indels
    contribute to ASD risk (OR = 1.6; 95% CI = 1.0-2.7; p = 0.03), are more common in
    female probands (p = 0.02), are enriched among genes encoding FMRP targets (p =
    6 × 10(-9)), and arise predominantly on the paternal chromosome (p < 0.001). On
    the basis of mutation rates in probands versus unaffected siblings, we conclude
    that de novo frameshift indels contribute to risk in approximately 3% of
    individuals with ASD. Finally, by observing clustering of mutations in unrelated 
    probands, we uncover two ASD-associated genes: KMT2E (MLL5), a chromatin
    regulator, and RIMS1, a regulator of synaptic vesicle release.
    
    Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    
    PMID: 25284784  [PubMed - as supplied by publisher]
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  • 2) J Child Psychol Psychiatry. 2014 Oct 4. doi: 10.1111/jcpp.12334. [Epub ahead of print]

    Asperger syndrome in males over two decades: stability and predictors of diagnosis.

    Helles A(1), Gillberg CI, Gillberg C, Billstedt E.
    
    Author information: 
    (1)Gillberg Neuropsychiatry Centre, Institute of Neuroscience and Physiology,
    Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.
    
    OBJECTIVE: To examine the diagnostic stability of a childhood diagnosis of
    Asperger Syndrome (AS) into adulthood in a prospective longitudinal study, and
    identify the predictors of stability.
    METHODS: One hundred males with AS diagnosed in childhood (T0) according to
    Gillberg's AS criteria, were followed up prospectively into adulthood over an
    average of 19 years (range 13-26 years). Fifty males (mean age 30 years)
    participated in this second follow-up (T2) of the cohort. Seventy-six had
    participated in a previous follow-up (T1) at mean age 22 years (47 participated
    in both follow-ups). Diagnosis at T2 was assessed using three sets of diagnostic 
    criteria (Gillberg's AS criteria, DSM-IV Pervasive Developmental Disorder (PDD)
    and DSM-5 Autism Spectrum Disorder (ASD) criteria) and compared to previous
    assessments. Background predictors of diagnostic stability were analyzed. General
    functioning at T2 was assessed and compared to T1.
    RESULTS: There was a decline in the stability of AS diagnosis over time, the rate
    dropping from 82% at T1 to 44% at T2, when using the Gillberg criteria. There was
    also a significant decrease in the rate of cases fulfilling any PDD diagnosis
    according to the DSM-IV, from 91% at T1 to 76% at T2 in the 47 cases followed up 
    twice. Severity of autism spectrum symptoms at T1 was the main predictor of
    diagnostic stability at T2. Twenty percent of those meeting criteria for a PDD
    diagnosis according to DSM-IV, did not meet DSM-5 ASD criteria although they had 
    marked difficulties in everyday life.
    CONCLUSION: Asperger Syndrome, when considered as an ASD/PDD diagnosis, was
    fairly stable into adulthood, but there was a significant increase over time in
    cases no longer meeting criteria for an ASD diagnosis according to the DSM-IV, or
    AS according to the Gillberg criteria. Cases with a stable diagnosis showed
    significantly more core ASD symptoms in adolescence/young adulthood.
    
    © 2014 Association for Child and Adolescent Mental Health.
    
    PMID: 25283685  [PubMed - as supplied by publisher]
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  • 3) Transl Psychiatry. 2014 Oct 7;4:e460. doi: 10.1038/tp.2014.87.

    Elevated 5-hydroxymethylcytosine in the Engrailed-2 (EN-2) promoter is associated with increased gene expression and decreased MeCP2 binding in autism cerebellum.

    James SJ(1), Shpyleva S(1), Melnyk S(1), Pavliv O(1), Pogribny IP(2).
    
    Author information: 
    (1)Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas
    Children's Hospital Research Institute, Little Rock, AR, USA.
    (2)Division of Biochemical Toxicology, National Center for Toxicological Research,
    Jefferson, AR, USA.
    
    Epigenetic mechanisms regulate programmed gene expression during prenatal
    neurogenesis and serve as a mediator between genetics and environment in
    postnatal life. The recent discovery of 5-hydroxymethylcytosine (5-hmC), with
    highest concentration in the brain, has added a new dimension to epigenetic
    regulation of neurogenesis and the development of complex behavior disorders.
    Here, we take a candidate gene approach to define the role 5-hmC in Engrailed-2
    (EN-2) gene expression in the autism cerebellum. The EN-2 homeobox transcription 
    factor, previously implicated in autism, is essential for normal cerebellar
    patterning and development. We previously reported EN-2 overexpression associated
    with promoter DNA hypermethylation in the autism cerebellum but because
    traditional DNA methylation methodology cannot distinguish 5-methylcytosine
    (5-mC) from 5-hmC, we now extend our investigation by quantifying global and
    gene-specific 5-mC and 5-hmC. Globally, 5-hmC was significantly increased in the 
    autism cerebellum and accompanied by increases in the expression of de novo
    methyltransferases DNMT3A and DNMT3B, ten-eleven translocase genes TET1 and TET3,
    and in 8-oxo-deoxyguanosine (8-oxo-dG) content, a marker of oxidative DNA damage.
    Within the EN-2 promoter, there was a significant positive correlation between
    5-hmC content and EN-2 gene expression. Based on reports of reduced MeCP2
    affinity for 5-hmC, MeCP2 binding studies in the EN-2 promoter revealed a
    significant decrease in repressive MeCP2 binding that may contribute to the
    aberrant overexpression of EN-2. Because normal cerebellar development depends on
    perinatal EN-2 downregulation, the sustained postnatal overexpression suggests
    that a critical window of cerebellar development may have been missed in some
    individuals with autism with downstream developmental consequences. Epigenetic
    regulation of the programmed on-off switches in gene expression that occur at
    birth and during early brain development warrants further investigation.
    
    PMID: 25290267  [PubMed - as supplied by publisher]
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  • 4) Dev Neurorehabil. 2014 Oct 7:1-10. [Epub ahead of print]

    The Millennium child with autism: Early childhood trajectories for health, education and economic wellbeing.

    Dillenburger K(1), Jordan JA, McKerr L, Keenan M.
    
    Author information: 
    (1)Centre for Behaviour Analysis, School of Education, Queen's University Belfast , 
    Belfast , UK and.
    
    Abstract Objective: Most of what we know about children with autism spectrum
    disorder (ASD) is based on post-diagnostic, retrospective, self-select studies.
    Oftentimes, there is no direct comparison between trajectories of children with
    ASD and children without ASD. Methods: To circumvent both of these problems, the 
    present secondary data analysis utilised a large-scale longitudinal general
    population survey of children born in the year 2000 (i.e. the Millennium Cohort
    Study; MCS; n = 18 522). Bi-annual MCS data were available from five data sweeps 
    (children aged 9 months to 11 years of age). Results: Pre-diagnostic data showed 
    early health problems differentiated children later diagnosed with autism from
    non-diagnosed peers. Prevalence was much higher than previously estimated (3.5%
    for 11-year olds). Post-diagnosis, trajectories deteriorated significantly for
    the children with ASD and their families in relation to education, health and
    economic wellbeing. Conclusion: These findings raise many issues for service
    delivery and the rights of persons with disabilities and their families.
    
    PMID: 25289682  [PubMed - as supplied by publisher]
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  • 5) Proc Natl Acad Sci U S A. 2014 Oct 6. pii: 201416797. [Epub ahead of print]

    Autism as a disorder of prediction.

    Sinha P(1), Kjelgaard MM(2), Gandhi TK(3), Tsourides K(4), Cardinaux AL(4),
    Pantazis D(4), Diamond SP(4), Held RM(1).
    
    Author information: 
    (1)Department of Brain and Cognitive Sciences, Massachusetts Institute of
    Technology, Cambridge, MA 02139; heldd@neco.edu psinha@mit.edu.
    (2)Department of Brain and Cognitive Sciences, Massachusetts Institute of
    Technology, Cambridge, MA 02139; Department of Communication Sciences and
    Disorders, Massachusetts General Hospital Institute of Health Professions,
    Boston, MA 02129; and.
    (3)Department of Brain and Cognitive Sciences, Massachusetts Institute of
    Technology, Cambridge, MA 02139; Department of Biomedical Engineering, Defense
    Institute of Physiology and Allied Sciences, New Delhi, India DL 110054.
    (4)Department of Brain and Cognitive Sciences, Massachusetts Institute of
    Technology, Cambridge, MA 02139;
    
    A rich collection of empirical findings accumulated over the past three decades
    attests to the diversity of traits that constitute the autism phenotypes. It is
    unclear whether subsets of these traits share any underlying causality. This lack
    of a cohesive conceptualization of the disorder has complicated the search for
    broadly effective therapies, diagnostic markers, and neural/genetic correlates.
    In this paper, we describe how theoretical considerations and a review of
    empirical data lead to the hypothesis that some salient aspects of the autism
    phenotype may be manifestations of an underlying impairment in predictive
    abilities. With compromised prediction skills, an individual with autism inhabits
    a seemingly "magical" world wherein events occur unexpectedly and without cause. 
    Immersion in such a capricious environment can prove overwhelming and compromise 
    one's ability to effectively interact with it. If validated, this hypothesis has 
    the potential of providing unifying insights into multiple aspects of autism,
    with attendant benefits for improving diagnosis and therapy.
    
    PMID: 25288765  [PubMed - as supplied by publisher]
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  • 6) Proc Natl Acad Sci U S A. 2014 Oct 6. pii: 201409204. [Epub ahead of print]

    Autism spectrum disorder severity reflects the average contribution of de novo and familial influences.

    Robinson EB(1), Samocha KE(2), Kosmicki JA(3), McGrath L(4), Neale BM(5), Perlis 
    RH(6), Daly MJ(5).
    
    Author information: 
    (1)Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts
    General Hospital and Harvard Medical School, Boston, MA 02114; Stanley Center for
    Psychiatric Research and Program in Medical and Population Genetics, Broad
    Institute of Harvard and MIT, Cambridge, MA 02142;
    erobinson@atgu.mgh.harvard.edu.
    (2)Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts
    General Hospital and Harvard Medical School, Boston, MA 02114; Stanley Center for
    Psychiatric Research and Program in Medical and Population Genetics, Broad
    Institute of Harvard and MIT, Cambridge, MA 02142; Program in Genetics and
    Genomics, Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 
    02114;
    (3)Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts
    General Hospital and Harvard Medical School, Boston, MA 02114; Stanley Center for
    Psychiatric Research and Program in Medical and Population Genetics, Broad
    Institute of Harvard and MIT, Cambridge, MA 02142; Center for Biomedical
    Informatics, Harvard Medical School, Boston, MA 02115;
    (4)School of Education, Teaching, and Health, American University, Washington, DC
    20016; and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human
    Genetic Research and Department of Psychiatry, Massachusetts General Hospital and
    Harvard Medical School, Boston, MA 02114.
    (5)Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts
    General Hospital and Harvard Medical School, Boston, MA 02114; Stanley Center for
    Psychiatric Research and Program in Medical and Population Genetics, Broad
    Institute of Harvard and MIT, Cambridge, MA 02142;
    (6)Stanley Center for Psychiatric Research and Program in Medical and Population
    Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142; Psychiatric
    and Neurodevelopmental Genetics Unit, Center for Human Genetic Research and
    Department of Psychiatry, Massachusetts General Hospital and Harvard Medical
    School, Boston, MA 02114.
    
    Autism spectrum disorders (ASDs) are a highly heterogeneous group of
    conditions-phenotypically and genetically-although the link between phenotypic
    variation and differences in genetic architecture is unclear. This study aimed to
    determine whether differences in cognitive impairment and symptom severity
    reflect variation in the degree to which ASD cases reflect de novo or familial
    influences. Using data from more than 2,000 simplex cases of ASD, we examined the
    relationship between intelligence quotient (IQ), behavior and language
    assessments, and rate of de novo loss of function (LOF) mutations and family
    history of broadly defined psychiatric disease (depressive disorders, bipolar
    disorder, and schizophrenia; history of psychiatric hospitalization). Proband IQ 
    was negatively associated with de novo LOF rate (P = 0.03) and positively
    associated with family history of psychiatric disease (P = 0.003). Female cases
    had a higher frequency of sporadic genetic events across the severity
    distribution (P = 0.01). High rates of LOF mutation and low frequencies of family
    history of psychiatric illness were seen in individuals who were unable to
    complete a traditional IQ test, a group with the greatest degree of language and 
    behavioral impairment. These analyses provide strong evidence that familial risk 
    for neuropsychiatric disease becomes more relevant to ASD etiology as cases
    become higher functioning. The findings of this study reinforce that there are
    many routes to the diagnostic category of autism and could lead to genetic
    studies with more specific insights into individual cases.
    
    PMID: 25288738  [PubMed - as supplied by publisher]
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  • 7) Autism Res. 2014 Oct 6. doi: 10.1002/aur.1423. [Epub ahead of print]

    Autism Research Funding Allocation: Can Economics Tell Us If We Have Got It Right?

    Zwicker JD(1), Emery JC.
    
    Author information: 
    (1)School of Public Policy, University of Calgary, Calgary, Alberta, Canada.
    
    There is a concern that the allocation of autism spectrum disorder (ASD) research
    funding may be misallocating resources, overemphasizing basic science at the
    expense of translational and clinical research. Anthony Bailey has proposed that 
    an economic evaluation of autism research funding allocations could be beneficial
    for funding agencies by identifying under- or overfunded areas of research. In
    response to Bailey, we illustrate why economics cannot provide an objective,
    technical solution for identifying the "best" allocation of research resources.
    Economic evaluation has its greatest power as a late-stage research tool for
    interventions with identified objectives, outcomes, and data. This is not the
    case for evaluating whether research areas are over- or underfunded. Without an
    understanding of how research funding influences the likelihood and value of a
    discovery, or without a statement of the societal objectives for ASD research and
    level of risk aversion, economic analysis cannot provide a useful normative
    evaluation of ASD research. Autism Res 2014, ●●: ●●-●●. © 2014 International
    Society for Autism Research, Wiley Periodicals, Inc.
    
    © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
    
    PMID: 25288440  [PubMed - as supplied by publisher]
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  • 8) Mol Psychiatry. 2014 Oct 7. doi: 10.1038/mp.2014.125. [Epub ahead of print]

    Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism.

    Frazier TW(1), Embacher R(2), Tilot AK(3), Koenig K(4), Mester J(3), Eng C(3).
    
    Author information: 
    (1)1] Center for Autism, Pediatric Institute, The Cleveland Clinic, Cleveland, OH,
    USA [2] Genomic Medicine Institute, The Cleveland Clinic, Cleveland, OH, USA.
    (2)Center for Autism, Pediatric Institute, The Cleveland Clinic, Cleveland, OH, USA.
    (3)Genomic Medicine Institute, The Cleveland Clinic, Cleveland, OH, USA.
    (4)Neurological Institute, Cleveland Clinic, Cleveland, OH, USA.
    
    PTEN is a tumor suppressor associated with an inherited cancer syndrome and an
    important regulator of ongoing neural connectivity and plasticity. The present
    study examined molecular and phenotypic characteristics of individuals with
    germline heterozygous PTEN mutations and autism spectrum disorder (ASD)
    (PTEN-ASD), with the aim of identifying pathophysiologic markers that
    specifically associate with PTEN-ASD and that may serve as targets for future
    treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic
    (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly
    (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated
    for PTEN pathway protein expression levels, global and regional structural brain 
    volumes and cortical thickness measures, neurocognition and adaptive behavior.
    RNA expression patterns and brain characteristics of a murine model of Pten
    mislocalization were used to further evaluate abnormalities observed in human
    PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and
    showed reduced PTEN protein levels. Compared with the other groups, prominent
    white-matter and cognitive abnormalities were specifically associated with
    PTEN-ASD patients, with strong reductions in processing speed and working memory.
    White-matter abnormalities mediated the relationship between PTEN protein
    reductions and reduced cognitive ability. The Pten(m3m4) murine model had
    differential expression of genes related to myelination and increased corpus
    callosum. Processing speed and working memory deficits and white-matter
    abnormalities may serve as useful features that signal clinicians that PTEN is
    etiologic and prompting referral to genetic professionals for gene testing,
    genetic counseling and cancer risk management; and could reveal treatment targets
    in trials of treatments for PTEN-ASD.Molecular Psychiatry advance online
    publication, 7 October 2014; doi:10.1038/mp.2014.125.
    
    PMID: 25288137  [PubMed - as supplied by publisher]
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  • 9) Proc Natl Acad Sci U S A. 2014 Oct 7. pii: 201405266. [Epub ahead of print]

    CHD8 regulates neurodevelopmental pathways associated with autism spectrum disorder in neural progenitors.

    Sugathan A(1), Biagioli M(2), Golzio C(3), Erdin S(4), Blumenthal I(4), Manavalan
    P(5), Ragavendran A(4), Brand H(1), Lucente D(5), Miles J(6), Sheridan SD(1),
    Stortchevoi A(4), Kellis M(7), Haggarty SJ(8), Katsanis N(9), Gusella JF(10),
    Talkowski ME(11).
    
    Author information: 
    (1)Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics
    Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, 
    MA 02114; Departments of Neurology and.
    (2)Molecular Neurogenetics Unit and Departments of Neurology and.
    (3)Center for Human Disease Modeling and.
    (4)Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics
    Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, 
    MA 02114;
    (5)Molecular Neurogenetics Unit and.
    (6)Departments of Pediatrics, Medical Genetics, and Pathology, The Thompson Center
    for Autism and Neurodevelopmental Disorders, University of Missouri Hospitals and
    Clinics, Columbia, MO 65201;
    (7)Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute 
    of Technology, Cambridge, MA 02139; and Broad Institute of M.I.T. and Harvard,
    Cambridge, MA 02142.
    (8)Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics
    Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, 
    MA 02114; Departments of Neurology and Broad Institute of M.I.T. and Harvard,
    Cambridge, MA 02142.
    (9)Center for Human Disease Modeling and Department of Cell Biology, Duke
    University, Durham, NC 27710;
    (10)Molecular Neurogenetics Unit and Broad Institute of M.I.T. and Harvard,
    Cambridge, MA 02142 Genetics, Harvard Medical School, Boston, MA 02115;
    (11)Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics
    Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, 
    MA 02114; Departments of Neurology and Broad Institute of M.I.T. and Harvard,
    Cambridge, MA 02142 talkowski@chgr.mgh.harvard.edu.
    
    Truncating mutations of chromodomain helicase DNA-binding protein 8 (CHD8), and
    of many other genes with diverse functions, are strong-effect risk factors for
    autism spectrum disorder (ASD), suggesting multiple mechanisms of pathogenesis.
    We explored the transcriptional networks that CHD8 regulates in neural progenitor
    cells (NPCs) by reducing its expression and then integrating transcriptome
    sequencing (RNA sequencing) with genome-wide CHD8 binding (ChIP sequencing).
    Suppressing CHD8 to levels comparable with the loss of a single allele caused
    altered expression of 1,756 genes, 64.9% of which were up-regulated. CHD8 showed 
    widespread binding to chromatin, with 7,324 replicated sites that marked 5,658
    genes. Integration of these data suggests that a limited array of direct
    regulatory effects of CHD8 produced a much larger network of secondary expression
    changes. Genes indirectly down-regulated (i.e., without CHD8-binding sites)
    reflect pathways involved in brain development, including synapse formation,
    neuron differentiation, cell adhesion, and axon guidance, whereas CHD8-bound
    genes are strongly associated with chromatin modification and transcriptional
    regulation. Genes associated with ASD were strongly enriched among indirectly
    down-regulated loci (P < 10(-8)) and CHD8-bound genes (P = 0.0043), which align
    with previously identified coexpression modules during fetal development. We also
    find an intriguing enrichment of cancer-related gene sets among CHD8-bound genes 
    (P < 10(-10)). In vivo suppression of chd8 in zebrafish produced macrocephaly
    comparable to that of humans with inactivating mutations. These data indicate
    that heterozygous disruption of CHD8 precipitates a network of gene-expression
    changes involved in neurodevelopmental pathways in which many ASD-associated
    genes may converge on shared mechanisms of pathogenesis.
    
    PMID: 25294932  [PubMed - as supplied by publisher]
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  • 10) J Autism Dev Disord. 2014 Oct 8. [Epub ahead of print]

    Applying Machine Learning to Facilitate Autism Diagnostics: Pitfalls and Promises.

    Bone D(1), Goodwin MS, Black MP, Lee CC, Audhkhasi K, Narayanan S.
    
    Author information: 
    (1)Signal Analysis & Interpretation Laboratory (SAIL), University of Southern
    California, 3710 McClintock Ave., Los Angeles, CA, 90089, USA, dbone@usc.edu.
    
    Machine learning has immense potential to enhance diagnostic and intervention
    research in the behavioral sciences, and may be especially useful in
    investigations involving the highly prevalent and heterogeneous syndrome of
    autism spectrum disorder. However, use of machine learning in the absence of
    clinical domain expertise can be tenuous and lead to misinformed conclusions. To 
    illustrate this concern, the current paper critically evaluates and attempts to
    reproduce results from two studies (Wall et al. in Transl Psychiatry 2(4):e100,
    2012a; PloS One 7(8), 2012b) that claim to drastically reduce time to diagnose
    autism using machine learning. Our failure to generate comparable findings to
    those reported by Wall and colleagues using larger and more balanced data
    underscores several conceptual and methodological problems associated with these 
    studies. We conclude with proposed best-practices when using machine learning in 
    autism research, and highlight some especially promising areas for collaborative 
    work at the intersection of computational and behavioral science.
    
    PMID: 25294649  [PubMed - as supplied by publisher]
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  • 11) PLoS One. 2014 Oct 9;9(10):e109527. doi: 10.1371/journal.pone.0109527. eCollection 2014.

    Anaplerotic Triheptanoin Diet Enhances Mitochondrial Substrate Use to Remodel the Metabolome and Improve Lifespan, Motor Function, and Sociability in MeCP2-Null Mice.

    Park MJ(1), Aja S(1), Li Q(1), Degano AL(2), Penati J(3), Zhuo J(3), Roe CR(1),
    Ronnett GV(4).
    
    Author information: 
    (1)The Center for Metabolism and Obesity Research, The Johns Hopkins University,
    School of Medicine, Baltimore, MD, United States of America; Department of
    Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD,
    United States of America.
    (2)The Center for Metabolism and Obesity Research, The Johns Hopkins University,
    School of Medicine, Baltimore, MD, United States of America; Department of
    Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD,
    United States of America; Departamento de Química Biológica, CIQUIBIC-CONICET,
    Universidad Nacional de Córdoba, Córdoba, Argentina.
    (3)Department of Neuroscience, The Johns Hopkins University, School of Medicine,
    Baltimore, MD, United States of America.
    (4)The Center for Metabolism and Obesity Research, The Johns Hopkins University,
    School of Medicine, Baltimore, MD, United States of America; Department of
    Neuroscience, The Johns Hopkins University, School of Medicine, Baltimore, MD,
    United States of America; Department of Neurology, The Johns Hopkins University, 
    School of Medicine, Baltimore, MD, United States of America; Department of
    Biological Chemistry, The Johns Hopkins University, School of Medicine,
    Baltimore, MD, United States of America; Department of Brain Sciences, DGIST,
    Daegu, South Korea.
    
    Rett syndrome (RTT) is an autism spectrum disorder (ASD) caused by mutations in
    the X-linked MECP2 gene that encodes methyl-CpG binding protein 2 (MeCP2).
    Symptoms range in severity and include psychomotor disabilities, seizures,
    ataxia, and intellectual disability. Symptom onset is between 6-18 months of age,
    a critical period of brain development that is highly energy-dependent. Notably, 
    patients with RTT have evidence of mitochondrial dysfunction, as well as abnormal
    levels of the adipokines leptin and adiponectin, suggesting overall metabolic
    imbalance. We hypothesized that one contributor to RTT symptoms is energy
    deficiency due to defective nutrient substrate utilization by the TCA cycle. This
    energy deficit would lead to a metabolic imbalance, but would be treatable by
    providing anaplerotic substrates to the TCA cycle to enhance energy production.
    We show that dietary therapy with triheptanoin significantly increased longevity 
    and improved motor function and social interaction in male mice hemizygous for
    Mecp2 knockout. Anaplerotic therapy in Mecp2 knockout mice also improved
    indicators of impaired substrate utilization, decreased adiposity, increased
    glucose tolerance and insulin sensitivity, decreased serum leptin and insulin,
    and improved mitochondrial morphology in skeletal muscle. Untargeted metabolomics
    of liver and skeletal muscle revealed increases in levels of TCA cycle
    intermediates with triheptanoin diet, as well as normalizations of glucose and
    fatty acid biochemical pathways consistent with the improved metabolic phenotype 
    in Mecp2 knockout mice on triheptanoin. These results suggest that an approach
    using dietary supplementation with anaplerotic substrate is effective in
    improving symptoms and metabolic health in RTT.
    
    PMID: 25299635  [PubMed - in process]
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  • 12) PLoS One. 2014 Oct 10;9(10):e109946. doi: 10.1371/journal.pone.0109946. eCollection 2014.

    Views on Researcher-Community Engagement in Autism Research in the United Kingdom: A Mixed-Methods Study.

    Pellicano E(1), Dinsmore A(2), Charman T(3).
    
    Author information: 
    (1)Centre for Research in Autism and Education (CRAE), Department of Psychology and 
    Human Development, Institute of Education, University of London, London, United
    Kingdom.
    (2)Centre for Research in Autism and Education (CRAE), Department of Psychology and 
    Human Development, Institute of Education, University of London, London, United
    Kingdom; Wellcome Trust, Strategic Planning & Policy Unit, London, United
    Kingdom.
    (3)Department of Psychology, King's College London, Institute of Psychiatry, London,
    United Kingdom.
    
    There has been a substantial increase in research activity on autism during the
    past decade. Research into effective ways of responding to the immediate needs of
    autistic people is, however, less advanced, as are efforts at translating basic
    science research into service provision. Involving community members in research 
    is one potential way of reducing this gap. This study therefore investigated the 
    views of community involvement in autism research both from the perspectives of
    autism researchers and of community members, including autistic adults, family
    members and practitioners. Results from a large-scale questionnaire study
    (n = 1,516) showed that researchers perceive themselves to be engaged with the
    autism community but that community members, most notably autistic people and
    their families, did not share this view. Focus groups/interviews with 72
    participants further identified the potential benefits and remaining challenges
    to involvement in research, especially regarding the distinct perspectives of
    different stakeholders. Researchers were skeptical about the possibilities of
    dramatically increasing community engagement, while community members themselves 
    spoke about the challenges to fully understanding and influencing the research
    process. We suggest that the lack of a shared approach to community engagement in
    UK autism research represents a key roadblock to translational endeavors.
    
    PMID: 25303222  [PubMed - as supplied by publisher]
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  • 13) Science. 2014 Oct 10;346(6206):176. doi: 10.1126/science.1256009.

    Response to Comment on "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring".

    Eftekhari S(1), Shahrokhi A(2), Tsintsadze V(3), Nardou R(4), Brouchoud C(3),
    Conesa M(4), Burnashev N(3), Ferrari DC(4), Ben-Ari Y(5).
    
    Author information: 
    (1)Mediterranean Institute of Neurobiology (INMED), U901, INSERM, Marseille, France.
    UMR 901, Aix-Marseille University, Marseille, France. Neurochlore, Campus
    Scientifique de Luminy, 163 Route de Luminy, Marseille, France. On leave from
    Iran University of Medical Sciences, Tehran, Iran.
    (2)Mediterranean Institute of Neurobiology (INMED), U901, INSERM, Marseille, France.
    UMR 901, Aix-Marseille University, Marseille, France. Neurochlore, Campus
    Scientifique de Luminy, 163 Route de Luminy, Marseille, France. On leave from
    Tehran University of Medical Sciences, Tehran, Iran.
    (3)Mediterranean Institute of Neurobiology (INMED), U901, INSERM, Marseille, France.
    UMR 901, Aix-Marseille University, Marseille, France.
    (4)Neurochlore, Campus Scientifique de Luminy, 163 Route de Luminy, Marseille,
    France.
    (5)Mediterranean Institute of Neurobiology (INMED), U901, INSERM, Marseille, France.
    UMR 901, Aix-Marseille University, Marseille, France. Neurochlore, Campus
    Scientifique de Luminy, 163 Route de Luminy, Marseille, France.
    yehezkel.ben-ari@inserm.fr.
    
    Comment on
        Science. 2014 Oct 10;346(6206):176.
        Science. 2014 Feb 7;343(6171):675-9.
    
    Bambini-Junior et al. questioned whether our treatment in two rodent models of
    autism has a long-lasting effect into adulthood. In response, we show that
    bumetanide treatment around delivery attenuates autistic behavioral features in
    adult offspring. Therefore, the polarity of γ-aminobutyric acid (GABA) actions
    during delivery exerts long-lasting priming actions after birth.
    
    Copyright © 2014, American Association for the Advancement of Science.
    
    PMID: 25301611  [PubMed - in process]
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  • 14) Science. 2014 Oct 10;346(6206):176. doi: 10.1126/science.1255679.

    Comment on "Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring".

    Bambini-Junior V(1), Nunes GD(2), Schneider T(3), Gottfried C(2).
    
    Author information: 
    (1)Federal University of Rio Grande do Sul, Research Group in Neuroglial Plasticity 
    at the Department of Biochemistry, Institute of Health's Basic Science, Porto
    Alegre, Rio Grande do Sul, Brazil. Federal University of Rio Grande do Sul,
    Translational Research Group in Autism Spectrum Disorders (GETTEA), Porto Alegre,
    RS, Brazil. victoriobambini@gmail.com.
    (2)Federal University of Rio Grande do Sul, Research Group in Neuroglial Plasticity 
    at the Department of Biochemistry, Institute of Health's Basic Science, Porto
    Alegre, Rio Grande do Sul, Brazil. Federal University of Rio Grande do Sul,
    Translational Research Group in Autism Spectrum Disorders (GETTEA), Porto Alegre,
    RS, Brazil.
    (3)School of Medicine, Pharmacy and Health, TS17 6BH, Durham University, Durham, UK.
    
    Comment in
        Science. 2014 Oct 10;346(6206):176.
    
    Comment on
        Science. 2014 Feb 7;343(6171):675-9.
    
    Tyzio et al. (Reports, 7 February 2014, p. 675) reported that bumetanide restored
    the impaired oxytocin-mediated γ-aminobutyric acid (GABA) excitatory-inhibitory
    shift during delivery in animal models of autism, ameliorating some autistic-like
    characteristics in the offspring. However, standard practices in the study of
    these models, such as the use of sex-dimorphic or males-only analyses and
    implementation of tests measuring social behavior, are lacking to definitely
    associate their findings to autism.
    
    Copyright © 2014, American Association for the Advancement of Science.
    
    PMID: 25301610  [PubMed - in process]
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