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Papers of the Week

  • 1) Front Cell Neurosci. 2014 Sep 11;8:276. doi: 10.3389/fncel.2014.00276. eCollection 2014.

    Synaptic proteins and receptors defects in autism spectrum disorders.

    Chen J(1), Yu S(1), Fu Y(1), Li X(2).
    
    Author information: 
    (1)Shanghai Key Laboratory of Psychotic Disorders, Shanghai Mental Health Center,
    Shanghai Jiao Tong University School of Medicine Shanghai, China.
    (2)Department of Neurochemistry, New York State Institute for Basic Research in
    Developmental Disabilities Staten Island, NY USA.
    
    Recent studies have found that hundreds of genetic variants, including common and
    rare variants, rare and de novo mutations, and common polymorphisms contribute to
    the occurrence of autism spectrum disorders (ASDs). The mutations in a number of 
    genes such as neurexin, neuroligin, postsynaptic density protein 95, SH3, and
    multiple ankyrin repeat domains 3 (SHANK3), synapsin, gephyrin, cadherin, and
    protocadherin, thousand-and-one-amino acid 2 kinase, and contactin, have been
    shown to play important roles in the development and function of synapses. In
    addition, synaptic receptors, such as gamma-aminobutyric acid receptors and
    glutamate receptors, have also been associated with ASDs. This review will
    primarily focus on the defects of synaptic proteins and receptors associated with
    ASDs and their roles in the pathogenesis of ASDs via synaptic pathways.
    
    PMID: 25309321  [PubMed]
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  • 2) J Autism Dev Disord. 2014 Oct 12. [Epub ahead of print]

    Does WISC-IV Underestimate the Intelligence of Autistic Children?

    Nader AM(1), Courchesne V, Dawson M, Soulières I.
    
    Author information: 
    (1)Rivière-des-prairies Hospital, Centre d'Excellence en Troubles Envahissants du
    Développement de l'Université de Montréal (CETEDUM), 7070 Blvd Perras, Montreal, 
    QC, H1E 1A4, Canada.
    
    Wechsler Intelligence Scale for Children (WISC) is widely used to estimate
    autistic intelligence (Joseph in The neuropsychology of autism. Oxford University
    Press, Oxford, 2011; Goldstein et al. in Assessment of autism spectrum disorders.
    Guilford Press, New York, 2008; Mottron in J Autism Dev Disord 34(1):19-27,
    2004). However, previous studies suggest that while WISC-III and Raven's
    Progressive Matrices (RPM) provide similar estimates of non-autistic
    intelligence, autistic children perform significantly better on RPM (Dawson et
    al. in Psychol Sci 18(8):657-662, doi: 10.1111/j.1467-9280.2007.01954.x , 2007). 
    The latest WISC version introduces substantial changes in subtests and index
    scores; thus, we asked whether WISC-IV still underestimates autistic
    intelligence. Twenty-five autistic and 22 typical children completed WISC-IV and 
    RPM. Autistic children's RPM scores were significantly higher than their WISC-IV 
    FSIQ, but there was no significant difference in typical children. Further,
    autistic children showed a distinctively uneven WISC-IV index profile, with a
    "peak" in the new Perceptual Reasoning Index. In spite of major changes, WISC-IV 
    FSIQ continues to underestimate autistic intelligence.
    
    PMID: 25308198  [PubMed - as supplied by publisher]
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  • 3) Proc Natl Acad Sci U S A. 2014 Oct 13. pii: 201416940. [Epub ahead of print]

    Sulforaphane treatment of autism spectrum disorder (ASD).

    Singh K(1), Connors SL(2), Macklin EA(3), Smith KD(4), Fahey JW(5), Talalay P(6),
    Zimmerman AW(7).
    
    Author information: 
    (1)Lurie Center for Autism, Department of Pediatrics, Massachusetts General Hospital
    for Children, Harvard Medical School, Lexington, MA 02421; Department of
    Pediatrics (Neurology), University of Massachusetts Medical School, Worcester, MA
    01655;
    (2)Lurie Center for Autism, Department of Pediatrics, Massachusetts General Hospital
    for Children, Harvard Medical School, Lexington, MA 02421;
    (3)Department of Medicine, Massachusetts General Hospital Biostatistics Center and
    Harvard Medical School, Boston, MA 02114; and.
    (4)McKusick-Nathans Institute for Genetic Medicine and.
    (5)Department of Pharmacology and Molecular Sciences, Lewis B. and Dorothy Cullman
    Chemoprotection Center, The Johns Hopkins University School of Medicine,
    Baltimore, MD 21205.
    (6)Department of Pharmacology and Molecular Sciences, Lewis B. and Dorothy Cullman
    Chemoprotection Center, The Johns Hopkins University School of Medicine,
    Baltimore, MD 21205 ptalalay@jhmi.edu Andrew.Zimmerman@umassmemorial.org.
    (7)Lurie Center for Autism, Department of Pediatrics, Massachusetts General Hospital
    for Children, Harvard Medical School, Lexington, MA 02421; Department of
    Pediatrics (Neurology), University of Massachusetts Medical School, Worcester, MA
    01655; ptalalay@jhmi.edu Andrew.Zimmerman@umassmemorial.org.
    
    Autism spectrum disorder (ASD), characterized by both impaired communication and 
    social interaction, and by stereotypic behavior, affects about 1 in 68,
    predominantly males. The medico-economic burdens of ASD are enormous, and no
    recognized treatment targets the core features of ASD. In a placebo-controlled,
    double-blind, randomized trial, young men (aged 13-27) with moderate to severe
    ASD received the phytochemical sulforaphane (n = 29)-derived from broccoli sprout
    extracts-or indistinguishable placebo (n = 15). The effects on behavior of daily 
    oral doses of sulforaphane (50-150 µmol) for 18 wk, followed by 4 wk without
    treatment, were quantified by three widely accepted behavioral measures completed
    by parents/caregivers and physicians: the Aberrant Behavior Checklist (ABC),
    Social Responsiveness Scale (SRS), and Clinical Global Impression Improvement
    Scale (CGI-I). Initial scores for ABC and SRS were closely matched for
    participants assigned to placebo and sulforaphane. After 18 wk, participants
    receiving placebo experienced minimal change (<3.3%), whereas those receiving
    sulforaphane showed substantial declines (improvement of behavior): 34% for ABC
    (P < 0.001, comparing treatments) and 17% for SRS scores (P = 0.017). On CGI-I, a
    significantly greater number of participants receiving sulforaphane had
    improvement in social interaction, abnormal behavior, and verbal communication (P
    = 0.015-0.007). Upon discontinuation of sulforaphane, total scores on all scales 
    rose toward pretreatment levels. Dietary sulforaphane, of recognized low
    toxicity, was selected for its capacity to reverse abnormalities that have been
    associated with ASD, including oxidative stress and lower antioxidant capacity,
    depressed glutathione synthesis, reduced mitochondrial function and oxidative
    phosphorylation, increased lipid peroxidation, and neuroinflammmation.
    
    PMID: 25313065  [PubMed - as supplied by publisher]
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  • 4) Dev Med Child Neurol. 2014 Oct 14. doi: 10.1111/dmcn.12607. [Epub ahead of print]

    Congenital anomalies and etiological diversity in autism.

    Zwaigenbaum L.
    
    Author information: 
    University of Alberta - Pediatrics, Glenrose Rehabilitation Hospital, Edmonton,
    Alberta, Canada.
    
    PMID: 25312764  [PubMed - as supplied by publisher]
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  • 5) J Autism Dev Disord. 2014 Oct 14. [Epub ahead of print]

    Brief Report: Chimpanzee Social Responsiveness Scale (CSRS) Detects Individual Variation in Social Responsiveness for Captive Chimpanzees.

    Faughn C(1), Marrus N, Shuman J, Ross SR, Constantino JN, Pruett JR Jr, Povinelli
    DJ.
    
    Author information: 
    (1)Institute of Cognitive Science, University of Louisiana at Lafayette, Lafayette, 
    LA, USA, carley.faughn@gmail.com.
    
    Comparative studies of social responsiveness, a core impairment in autism
    spectrum disorder (ASD), will enhance our understanding of typical and atypical
    social behavior. We previously reported a quantitative, cross-species
    (human-chimpanzee) social responsiveness measure, which included the development 
    of the Chimpanzee Social Responsiveness Scale (CSRS). Here, we augment our prior 
    CSRS sample with 25 zoo chimpanzees at three sites: combined N = 54. The CSRS
    demonstrated strong interrater reliability, and low-ranked chimpanzees, on
    average, displayed higher CSRS scores. The CSRS continues to discriminate
    variation in chimpanzee social responsiveness, and the association of higher
    scores with lower chimpanzee social standing has implications for the
    relationship between autistic traits and human social status. Continued
    comparative investigations of social responsiveness will enhance our
    understanding of underlying impairments in ASD, improve early diagnosis, and
    inform future therapies.
    
    PMID: 25312279  [PubMed - as supplied by publisher]
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  • 6) Nat Rev Neurol. 2014 Oct 14. doi: 10.1038/nrneurol.2014.187. [Epub ahead of print]

    Maternal immune activation and abnormal brain development across CNS disorders.

    Knuesel I(1), Chicha L(2), Britschgi M(1), Schobel SA(1), Bodmer M(3), Hellings
    JA(4), Toovey S(5), Prinssen EP(1).
    
    Author information: 
    (1)Roche Pharma Research and Early Development, Roche Innovation Centre Basel,
    Grenzacherstrasse 124, 4070 Basel, Switzerland.
    (2)Brain Ischemia &Regeneration Group, Department of Biomedicine, University
    Hospital, Hebelstrasse 20, 4031 Basel, Switzerland.
    (3)Department of Internal Medicine, Emergency Unit, University Hospital,
    Petersgraben 2, 4031 Basel, Switzerland.
    (4)The Nisonger Centre, Ohio State University, 1581 Dodd Drive, Columbus, OH 43210, 
    USA.
    (5)Pegasus Research, Burggartenstrasse 32, 4103 Bottmingen, Switzerland.
    
    Epidemiological studies have shown a clear association between maternal infection
    and schizophrenia or autism in the progeny. Animal models have revealed maternal 
    immune activation (mIA) to be a profound risk factor for neurochemical and
    behavioural abnormalities in the offspring. Microglial priming has been proposed 
    as a major consequence of mIA, and represents a critical link in a causal chain
    that leads to the wide spectrum of neuronal dysfunctions and behavioural
    phenotypes observed in the juvenile, adult or aged offspring. Such diversity of
    phenotypic outcomes in the mIA model are mirrored by recent clinical evidence
    suggesting that infectious exposure during pregnancy is also associated with
    epilepsy and, to a lesser extent, cerebral palsy in children. Preclinical
    research also suggests that mIA might precipitate the development of Alzheimer
    and Parkinson diseases. Here, we summarize and critically review the emerging
    evidence that mIA is a shared environmental risk factor across CNS disorders that
    varies as a function of interactions between genetic and additional environmental
    factors. We also review ongoing clinical trials targeting immune pathways
    affected by mIA that may play a part in disease manifestation. In addition,
    future directions and outstanding questions are discussed, including potential
    symptomatic, disease-modifying and preventive treatment strategies.
    
    PMID: 25311587  [PubMed - as supplied by publisher]
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  • 7) Mol Psychiatry. 2014 Oct 14. doi: 10.1038/mp.2014.124. [Epub ahead of print]

    Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.

    Oguro-Ando A(1), Rosensweig C(2), Herman E(2), Nishimura Y(2), Werling D(2), Bill
    BR(2), Berg JM(2), Gao F(2), Coppola G(3), Abrahams BS(2), Geschwind DH(4).
    
    Author information: 
    (1)1] Neurogenetics Program, Department of Neurology, Center for Autism Research and
    Treatment, Semel Institute, David Geffen School of Medicine, University of
    California, Los Angeles, Los Angeles, CA, USA [2] Department of Translational
    Neuroscience, Brain Center Rudolf Magnus, University Medical Center Utrecht,
    Utrecht, The Netherlands.
    (2)Neurogenetics Program, Department of Neurology, Center for Autism Research and
    Treatment, Semel Institute, David Geffen School of Medicine, University of
    California, Los Angeles, Los Angeles, CA, USA.
    (3)1] Neurogenetics Program, Department of Neurology, Center for Autism Research and
    Treatment, Semel Institute, David Geffen School of Medicine, University of
    California, Los Angeles, Los Angeles, CA, USA [2] Semel Institute, David Geffen
    School of Medicine, University of California at Los Angeles, Los Angeles, CA,
    USA.
    (4)1] Neurogenetics Program, Department of Neurology, Center for Autism Research and
    Treatment, Semel Institute, David Geffen School of Medicine, University of
    California, Los Angeles, Los Angeles, CA, USA [2] Department of Human Genetics,
    David Geffen School of Medicine, University of California at Los Angeles, Los
    Angeles, CA, USA.
    
    Rare maternally inherited duplications at 15q11-13 are observed in ~1% of
    individuals with an autism spectrum disorder (ASD), making it among the most
    common causes of ASD. 15q11-13 comprises a complex region, and as this copy
    number variation encompasses many genes, it is important to explore individual
    genotype-phenotype relationships. Cytoplasmic FMR1-interacting protein 1 (CYFIP1)
    is of particular interest because of its interaction with Fragile X mental
    retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell
    lines from patients with duplications at 15q11-13 and ASD and the presence of
    smaller overlapping deletions of CYFIP1 in patients with schizophrenia and
    intellectual disability. Here, we confirm that CYFIP1 is upregulated in
    transformed lymphoblastoid cell lines and demonstrate its upregulation in the
    post-mortem brain from 15q11-13 duplication patients for the first time. To
    investigate how increased CYFIP1 dosage might predispose to neurodevelopmental
    disease, we studied the consequence of its overexpression in multiple systems. We
    show that overexpression of CYFIP1 results in morphological abnormalities
    including cellular hypertrophy in SY5Y cells and differentiated mouse neuronal
    progenitors. We validate these results in vivo by generating a BAC transgenic
    mouse, which overexpresses Cyfip1 under the endogenous promotor, observing an
    increase in the proportion of mature dendritic spines and dendritic spine
    density. Gene expression profiling on embryonic day 15 suggested the
    dysregulation of mammalian target of rapamycin (mTOR) signaling, which was
    confirmed at the protein level. Importantly, similar evidence of mTOR-related
    dysregulation was seen in brains from 15q11-13 duplication patients with ASD.
    Finally, treatment of differentiated mouse neuronal progenitors with an mTOR
    inhibitor (rapamycin) rescued the morphological abnormalities resulting from
    CYFIP1 overexpression. Together, these data show that CYFIP1 overexpression
    results in specific cellular phenotypes and implicate modulation by mTOR
    signaling, further emphasizing its role as a potential convergent pathway in some
    forms of ASD.Molecular Psychiatry advance online publication, 14 October 2014;
    doi:10.1038/mp.2014.124.
    
    PMID: 25311365  [PubMed - as supplied by publisher]
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  • 8) Cereb Cortex. 2014 Oct 14. pii: bhu242. [Epub ahead of print]

    Anatomical Abnormalities in Autism?

    Haar S(1), Berman S(2), Behrmann M(3), Dinstein I(4).
    
    Author information: 
    (1)Department of Brain and Cognitive Sciences.
    (2)Department of Industrial Engineering and Management, Ben Gurion University of the
    Negev, Beer Sheva 84105, Israel.
    (3)Department of Psychology, Carnegie Mellon University, Pittsburgh, PA 15213, USA.
    (4)Department of Brain and Cognitive Sciences Department of Psychology.
    
    Substantial controversy exists regarding the presence and significance of
    anatomical abnormalities in autism spectrum disorders (ASD). The release of the
    Autism Brain Imaging Data Exchange (∼1000 participants, age 6-65 years) offers an
    unprecedented opportunity to conduct large-scale comparisons of anatomical MRI
    scans across groups and to resolve many of the outstanding questions.
    Comprehensive univariate analyses using volumetric, thickness, and surface area
    measures of over 180 anatomically defined brain areas, revealed significantly
    larger ventricular volumes, smaller corpus callosum volume (central segment
    only), and several cortical areas with increased thickness in the ASD group.
    Previously reported anatomical abnormalities in ASD including larger intracranial
    volumes, smaller cerebellar volumes, and larger amygdala volumes were not
    substantiated by the current study. In addition, multivariate classification
    analyses yielded modest decoding accuracies of individuals' group identity
    (<60%), suggesting that the examined anatomical measures are of limited
    diagnostic utility for ASD. While anatomical abnormalities may be present in
    distinct subgroups of ASD individuals, the current findings show that many
    previously reported anatomical measures are likely to be of low clinical and
    scientific significance for understanding ASD neuropathology as a whole in
    individuals 6-35 years old.
    
    © The Author 2014. Published by Oxford University Press. All rights reserved. For
    Permissions, please e-mail: journals.permissions@oup.com.
    
    PMID: 25316335  [PubMed - as supplied by publisher]
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  • 9) J Child Psychol Psychiatry. 2014 Oct 15. doi: 10.1111/jcpp.12342. [Epub ahead of print]

    Early pragmatic language difficulties in siblings of children with autism: implications for DSM-5 social communication disorder?

    Miller M(1), Young GS, Hutman T, Johnson S, Schwichtenberg AJ, Ozonoff S.
    
    Author information: 
    (1)MIND Institute, University of California, Davis, Sacramento, CA, USA.
    
    BACKGROUND: We evaluated early pragmatic language skills in preschool-age
    siblings of children with autism spectrum disorder (ASD), and examined
    correspondence between pragmatic language impairments and general language
    difficulties, autism symptomatology, and clinical outcomes.
    METHODS: Participants were younger siblings of children with ASD (high-risk,
    n = 188) or typical development (low-risk, n = 119) who were part of a
    prospective study of infants at risk for ASD; siblings without ASD outcomes were 
    included in analyses. Pragmatic language skills were measured via the Language
    Use Inventory (LUI).
    RESULTS: At 36 months, the high-risk group had significantly lower parent-rated
    pragmatic language scores than the low-risk group. When defining pragmatic
    language impairment (PLI) as scores below the 10(th) percentile on the LUI, 35%
    of the high-risk group was identified with PLI versus 10% of the low-risk group. 
    Children with PLI had higher rates of general language impairment (16%), defined 
    as scores below the 10(th) percentile on the Receptive or Expressive Language
    subscales of the Mullen Scales of Early Learning, relative to those without PLI
    (3%), but most did not evidence general language impairments. Children with PLI
    had significantly higher ADOS scores than those without PLI and had higher rates 
    of clinician-rated atypical clinical best estimate outcomes (49%) relative to
    those without PLI (15%).
    CONCLUSIONS: Pragmatic language problems are present in some siblings of children
    with ASD as early as 36 months of age. As the new DSM-5 diagnosis of Social
    (Pragmatic) Communication Disorder (SCD) is thought to occur more frequently in
    family members of individuals with ASD, it is possible that some of these
    siblings will meet criteria for SCD as they get older. Close monitoring of early 
    pragmatic language development in young children at familial risk for ASD is
    warranted.
    
    © 2014 Association for Child and Adolescent Mental Health.
    
    PMID: 25315782  [PubMed - as supplied by publisher]
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  • 10) Psychiatr Genet. 2014 Oct 16. [Epub ahead of print]

    Association between autism spectrum disorder in individuals with velocardiofacial (22q11.2 deletion) syndrome and PRODH and COMT genotypes.

    Radoeva PD(1), Coman IL, Salazar CA, Gentile KL, Higgins AM, Middleton FA,
    Antshel KM, Fremont W, Shprintzen RJ, Morrow BE, Kates WR.
    
    Author information: 
    (1)Departments of aNeuroscience and Physiology bPsychiatry and Behavioral Sciences, 
    SUNY Upstate Medical University, Syracuse cThe Virtual Center for
    Velo-Cardio-Facial Syndrome, Manlius dDepartment of Genetics, Albert Einstein
    College of Medicine, Bronx, New York, USA.
    
    Velocardiofacial (VCFS; 22q11.2 deletion) syndrome is a genetic disorder that
    results from a hemizygous deletion of the q11.2 region on chromosome 22, and is
    associated with greatly increased risk for psychiatric disorders, including
    autism spectrum disorder (ASD) and schizophrenia. There is emerging evidence for 
    the involvement of catechol-O-methyltransferase (COMT) and proline dehydrogenase 
    (oxidase) 1 (PRODH) in the psychiatric phenotype of individuals with VCFS. Here, 
    we tested the hypothesis that PRODH and COMT are associated with ASD in youths
    with VCFS. We found that individuals with VCFS and the low-activity alleles of
    both PRODH and COMT (rs4819756A and rs4680A) were more likely to present with ASD
    as compared with individuals with VCFS and the high-activity alleles of these
    genes [P<0.05; odds ratio=6.0 (95% confidence interval=1.27-28.26; N=87)]. Our
    results suggest that PRODH and COMT may interact to contribute to the ASD
    phenotype in individuals with VCFS.
    
    PMID: 25325218  [PubMed - as supplied by publisher]
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  • 11) Med Image Comput Comput Assist Interv. 2014;17(Pt 3):113-20.

    Functionally driven brain networks using multi-layer graph clustering.

    Ghanbari Y, Bloy L, Shankar V, Edgar JC, Roberts TP, Schultz RT, Verma R.
    
    Connectivity analysis of resting state brain has provided a novel means of
    investigating brain networks in the study of neurodevelpmental disorders. The
    study of functional networks, often represented by high dimensional graphs,
    predicates on the ability of methods in succinctly extracting meaningful
    representative connectivity information at the subject and population level. This
    need motivates the development of techniques that can extract underlying network 
    modules that characterize the connectivity in a population, while capturing
    variations of these modules at the individual level. In this paper, we propose a 
    multi-layer raph clustering technique that fuses the information from a
    collection of connectivity networks of a population to extract the underlying
    common network modules that serve as network hubs for the population. These hubs 
    form a functional network atlas. In addition, our technique provides
    subject-specific factors designed to characterize and quantify the degree of
    intra- and inter- connectivity between hubs, thereby providing a representation
    that is amenable to group level statistical analyses. We demonstrate the utility 
    of the technique by creating a population network atlas of connectivity by
    examining MEG based functional connectivity in typically developing children, and
    using this to describe the individualized variation in those diagnosed with
    autism spectrum disorder.
    
    PMID: 25320789  [PubMed - in process]
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  • 12) J Autism Dev Disord. 2014 Oct 18. [Epub ahead of print]

    Editorial: The Importance of Early Intervention.

    Volkmar FR.
    
    Author information: 
    Yale Child Study Center, 230 South Frontage Road, P.O. Box 207900, New Haven, CT,
    06520-7900, USA, fred.volkmar@yale.edu.
    
    PMID: 25326254  [PubMed - as supplied by publisher]
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  • 13) J Autism Dev Disord. 2014 Oct 19. [Epub ahead of print]

    Cortical Variability in the Sensory-Evoked Response in Autism.

    Haigh SM(1), Heeger DJ, Dinstein I, Minshew N, Behrmann M.
    
    Author information: 
    (1)Department of Psychology, Carnegie Mellon University, 5000 Forbes Avenue,
    Pittsburgh, PA, 15213-3890, USA, haighsm@upmc.edu.
    
    Previous findings have shown that individuals with autism spectrum disorder (ASD)
    evince greater intra-individual variability (IIV) in their sensory-evoked fMRI
    responses compared to typical control participants. We explore the robustness of 
    this finding with a new sample of high-functioning adults with autism.
    Participants were presented with visual, somatosensory and auditory stimuli in
    the scanner whilst they completed a one-back task. While ASD and control
    participants were statistically indistinguishable with respect to behavioral
    responses, the new ASD group exhibited greater IIV relative to controls. We also 
    show that the IIV was equivalent across hemispheres and remained stable over the 
    duration of the experiment. This suggests that greater cortical IIV may be a
    replicable characteristic of sensory systems in autism.
    
    PMID: 25326820  [PubMed - as supplied by publisher]
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  • 14) Nat Genet. 2014 Oct 19. doi: 10.1038/ng.3120. [Epub ahead of print]

    Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability.

    Antonacci F(1), Dennis MY(2), Huddleston J(3), Sudmant PH(2), Steinberg KM(4),
    Rosenfeld JA(5), Miroballo M(1), Graves TA(4), Vives L(3), Malig M(2), Denman
    L(2), Raja A(3), Stuart A(6), Tang J(6), Munson B(2), Shaffer LG(7), Amemiya
    CT(6), Wilson RK(4), Eichler EE(3).
    
    Author information: 
    (1)Dipartimento di Biologia, Università degli Studi di Bari Aldo Moro, Bari, Italy.
    (2)Department of Genome Sciences, University of Washington, Seattle, Washington,
    USA.
    (3)1] Department of Genome Sciences, University of Washington, Seattle, Washington, 
    USA. [2] Howard Hughes Medical Institute, University of Washington, Seattle,
    Washington, USA.
    (4)Genome Institute at Washington University, Washington University School of
    Medicine, St. Louis, Missouri, USA.
    (5)Signature Genomic Laboratories, LLC, Spokane, Washington, USA.
    (6)Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
    (7)1] Signature Genomic Laboratories, LLC, Spokane, Washington, USA. [2] Genetic
    Veterinary Sciences, Inc., Paw Print Genetics, Spokane, Washington, USA.
    
    Recurrent deletions of chromosome 15q13.3 associate with intellectual disability,
    schizophrenia, autism and epilepsy. To gain insight into the instability of this 
    region, we sequenced it in affected individuals, normal individuals and nonhuman 
    primates. We discovered five structural configurations of the human chromosome
    15q13.3 region ranging in size from 2 to 3 Mb. These configurations arose
    recently (∼0.5-0.9 million years ago) as a result of human-specific expansions of
    segmental duplications and two independent inversion events. All inversion
    breakpoints map near GOLGA8 core duplicons-a ∼14-kb primate-specific chromosome
    15 repeat that became organized into larger palindromic structures.
    GOLGA8-flanked palindromes also demarcate the breakpoints of recurrent 15q13.3
    microdeletions, the expansion of chromosome 15 segmental duplications in the
    human lineage and independent structural changes in apes. The significant
    clustering (P = 0.002) of breakpoints provides mechanistic evidence for the role 
    of this core duplicon and its palindromic architecture in promoting the
    evolutionary and disease-related instability of chromosome 15.
    
    PMID: 25326701  [PubMed - as supplied by publisher]
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