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Papers of the Week

  • 1) J Am Acad Child Adolesc Psychiatry. 2014 May;53(5):500-8. doi: 10.1016/j.jaac.2013.12.021. Epub 2014 Jan 21.

    A Comparison of DSM-IV Pervasive Developmental Disorder and DSM-5 Autism Spectrum Disorder Prevalence in an Epidemiologic Sample.

    Kim YS(1), Fombonne E(2), Koh YJ(3), Kim SJ(4), Cheon KA(5), Leventhal BL(6).
    
    Author information: 
    (1)Child Study Center, Yale University, New Haven, CT, the Nathan S. Kline Institute
    for Psychiatric Research, Orangeburg, NY, and Yonsei University, Seoul, South
    Korea.
    (2)Oregon Health and Science University, Portland, OR.
    (3)Korea Institute for Children's Social Development ("Rudolph"), Seoul, South
    Korea.
    (4)University of Washington, Seattle, WA.
    (5)Yonsei University, Seoul, South Korea.
    (6)Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, Yonsei
    University, Seoul, South Korea, and the University of Illinois, Chicago, IL.
    Electronic address: bennett.leventhal@nki.rfmh.org.
    
    OBJECTIVE: Changes in autism diagnostic criteria found in DSM-5 may affect autism
    spectrum disorder (ASD) prevalence, research findings, diagnostic processes, and 
    eligibility for clinical and other services. Using our published,
    total-population Korean prevalence data, we compute DSM-5 ASD and social
    communication disorder (SCD) prevalence and compare them with DSM-IV pervasive
    developmental disorder (PDD) prevalence estimates. We also describe individuals
    previously diagnosed with DSM-IV PDD when diagnoses change with DSM-5 criteria.
    METHOD: The target population was all children from 7 to 12 years of age in a
    South Korean community (N = 55,266), those in regular and special education
    schools, and a disability registry. We used the Autism Spectrum Screening
    Questionnaire for systematic, multi-informant screening. Parents of
    screen-positive children were offered comprehensive assessments using
    standardized diagnostic procedures, including the Autism Diagnostic
    Interview-Revised and Autism Diagnostic Observation Schedule. Best-estimate
    clinical diagnoses were made using DSM-IV PDD and DSM-5 ASD and SCD criteria.
    RESULTS: DSM-5 ASD estimated prevalence was 2.20% (95% confidence interval =
    1.77-3.64). Combined DSM-5 ASD and SCD prevalence was virtually the same as
    DSM-IV PDD prevalence (2.64%). Most children with autistic disorder (99%),
    Asperger disorder (92%), and PDD-NOS (63%) met DSM-5 ASD criteria, whereas 1%,
    8%, and 32%, respectively, met SCD criteria. All remaining children (2%) had
    other psychopathology, principally attention-deficit/hyperactivity disorder and
    anxiety disorder.
    CONCLUSION: Our findings suggest that most individuals with a prior DSM-IV PDD
    meet DSM-5 diagnostic criteria for ASD and SCD. PDD, ASD or SCD; extant
    diagnostic criteria identify a large, clinically meaningful group of individuals 
    and families who require evidence-based services.
    
    Copyright © 2014 American Academy of Child and Adolescent Psychiatry. Published
    by Elsevier Inc. All rights reserved.
    
    PMID: 24745950  [PubMed - in process]
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  • 2) PLoS One. 2014 Apr 16;9(4):e93533. doi: 10.1371/journal.pone.0093533. eCollection 2014.

    The Potential of Accelerating Early Detection of Autism through Content Analysis of YouTube Videos.

    Fusaro VA(1), Daniels J(2), Duda M(2), Deluca TF(1), D'Angelo O(1), Tamburello
    J(1), Maniscalco J(1), Wall DP(3).
    
    Author information: 
    (1)Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts,
    United States of America.
    (2)Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts,
    United States of America; Department of Pediatrics, Division of Systems Medicine,
    Stanford University, Stanford, California, United States of America.
    (3)Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts,
    United States of America; Department of Pathology, Beth Israel Deaconess Medical 
    Center, Boston, Massachusetts, United States of America; Department of
    Pediatrics, Division of Systems Medicine, Stanford University, Stanford,
    California, United States of America.
    
    Autism is on the rise, with 1 in 88 children receiving a diagnosis in the United 
    States, yet the process for diagnosis remains cumbersome and time consuming.
    Research has shown that home videos of children can help increase the accuracy of
    diagnosis. However the use of videos in the diagnostic process is uncommon. In
    the present study, we assessed the feasibility of applying a gold-standard
    diagnostic instrument to brief and unstructured home videos and tested whether
    video analysis can enable more rapid detection of the core features of autism
    outside of clinical environments. We collected 100 public videos from YouTube of 
    children ages 1-15 with either a self-reported diagnosis of an ASD (N = 45) or
    not (N = 55). Four non-clinical raters independently scored all videos using one 
    of the most widely adopted tools for behavioral diagnosis of autism, the Autism
    Diagnostic Observation Schedule-Generic (ADOS). The classification accuracy was
    96.8%, with 94.1% sensitivity and 100% specificity, the inter-rater correlation
    for the behavioral domains on the ADOS was 0.88, and the diagnoses matched a
    trained clinician in all but 3 of 22 randomly selected video cases. Despite the
    diversity of videos and non-clinical raters, our results indicate that it is
    possible to achieve high classification accuracy, sensitivity, and specificity as
    well as clinically acceptable inter-rater reliability with nonclinical personnel.
    Our results also demonstrate the potential for video-based detection of autism in
    short, unstructured home videos and further suggests that at least a percentage
    of the effort associated with detection and monitoring of autism may be mobilized
    and moved outside of traditional clinical environments.
    
    PMID: 24740236  [PubMed - in process]
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  • 3) J Psychiatr Res. 2014 Mar 29. pii: S0022-3956(14)00092-2. doi: 10.1016/j.jpsychires.2014.03.019. [Epub ahead of print]

    Prenatal and perinatal risk factors in a twin study of autism spectrum disorders.

    Froehlich-Santino W(1), Londono Tobon A(2), Cleveland S(2), Torres A(2), Phillips
    J(2), Cohen B(3), Torigoe T(3), Miller J(3), Fedele A(3), Collins J(4), Smith
    K(5), Lotspeich L(2), Croen LA(4), Ozonoff S(6), Lajonchere C(3), Grether JK(7), 
    O'Hara R(2), Hallmayer J(2).
    
    Author information: 
    (1)Department of Psychiatry, Stanford University School of Medicine, Stanford, CA,
    USA. Electronic address: wendyf@stanford.edu.
    (2)Department of Psychiatry, Stanford University School of Medicine, Stanford, CA,
    USA.
    (3)Autism Genetic Resource Exchange, Autism Speaks, Los Angeles, CA, USA.
    (4)Division of Research, Kaiser Permanente Northern California, Oakland, CA, USA.
    (5)Impact Assessment, Inc, La Jolla, CA, USA.
    (6)University of California, Davis, MIND Institute, Sacramento, CA, USA.
    (7)Environmental Health Investigations Branch, California Department of Public
    Health, Richmond, CA, USA.
    
    INTRODUCTION: Multiple studies associate prenatal and perinatal complications
    with increased risks for autism spectrum disorders (ASDs). The objectives of this
    study were to utilize a twin study design to 1) Investigate whether shared
    gestational and perinatal factors increase concordance for ASDs in twins, 2)
    Determine whether individual neonatal factors are associated with the presence of
    ASDs in twins, and 3) Explore whether associated factors may influence males and 
    females differently.
    METHODS: Data from medical records and parent response questionnaires from 194
    twin pairs, in which at least one twin had an ASD, were analyzed.
    RESULTS: Shared factors including parental age, prenatal use of medications,
    uterine bleeding, and prematurity did not increase concordance risks for ASDs in 
    twins. Among the individual factors, respiratory distress demonstrated the
    strongest association with increased risk for ASDs in the group as a whole (OR
    2.11, 95% CI 1.27-3.51). Furthermore, respiratory distress (OR 2.29, 95% CI
    1.12-4.67) and other markers of hypoxia (OR 1.99, 95% CI 1.04-3.80) were
    associated with increased risks for ASDs in males, while jaundice was associated 
    with an increased risk for ASDs in females (OR 2.94, 95% CI 1.28-6.74).
    CONCLUSIONS: Perinatal factors associated with respiratory distress and other
    markers of hypoxia appear to increase risk for autism in a subgroup of twins.
    Future studies examining potential gender differences and additional prenatal,
    perinatal and postnatal environmental factors are required for elucidating the
    etiology of ASDs and suggesting new methods for treatment and prevention.
    
    Copyright © 2014 Elsevier Ltd. All rights reserved.
    
    PMID: 24726638  [PubMed - as supplied by publisher]
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  • 4) J Autism Dev Disord. 2014 Mar 25. [Epub ahead of print]

    Abnormal Corpus Callosum Connectivity, Socio-communicative Deficits, and Motor Deficits in Children with Autism Spectrum Disorder: A Diffusion Tensor Imaging Study.

    Hanaie R(1), Mohri I, Kagitani-Shimono K, Tachibana M, Matsuzaki J, Watanabe Y,
    Fujita N, Taniike M.
    
    Author information: 
    (1)Division of Developmental Neuroscience, United Graduate School of Child
    Development, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
    
    In addition to social and communicative deficits, many studies have reported
    motor deficits in autism spectrum disorder (ASD). This study investigated the
    macro and microstructural properties of the corpus callosum (CC) of 18 children
    with ASD and 12 typically developing controls using diffusion tensor imaging
    tractography. We aimed to explore whether abnormalities of the CC were related to
    motor deficits, as well as social and communication deficits in children with
    ASD. The ASD group displayed abnormal macro and microstructure of the total CC
    and its subdivisions and its structural properties were related to
    socio-communicative deficits, but not to motor deficits in ASD. These findings
    advance our understanding of the contributions of the CC to ASD symptoms.
    
    PMID: 24710811  [PubMed - as supplied by publisher]
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  • 5) Pediatrics. 2014 Apr 14. [Epub ahead of print]

    Prenatal SSRI Use and Offspring With Autism Spectrum Disorder or Developmental Delay.

    Harrington RA(1), Lee LC, Crum RM, Zimmerman AW, Hertz-Picciotto I.
    
    Author information: 
    (1)Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, and.
    
    OBJECTIVE: To examine associations between prenatal use of selective serotonin
    reuptake inhibitors (SSRIs) and the odds of autism spectrum disorders (ASDs) and 
    other developmental delays (DDs).
    METHODS: A total of 966 mother-child pairs were evaluated (492 ASD, 154 DD, 320
    typical development [TD]) from the Childhood Autism Risks from Genetics and the
    Environment (CHARGE) Study, a population-based case-control study. Standardized
    measures confirmed developmental status. Interviews with biological mothers
    ascertained prenatal SSRI use, maternal mental health history, and
    sociodemographic information.
    RESULTS: Overall, prevalence of prenatal SSRI exposure was lowest in TD children 
    (3.4%) but did not differ significantly from ASD (5.9%) or DD (5.2%) children.
    Among boys, prenatal SSRI exposure was nearly 3 times as likely in children with 
    ASD relative to TD (adjusted odds ratio [OR]: 2.91; 95% confidence interval [CI]:
    1.07-7.93); the strongest association occurred with first-trimester exposure (OR:
    3.22; 95% CI: 1.17-8.84). Exposure was also elevated among boys with DD (OR:
    3.39; 95% CI: 0.98-11.75) and was strongest in the third trimester (OR: 4.98; 95%
    CI: 1.20-20.62). Findings were similar among mothers with an anxiety or mood
    disorder history.
    CONCLUSIONS: In boys, prenatal exposure to SSRIs may increase susceptibility to
    ASD or DD. Findings from published studies on SSRIs and ASD continues to be
    inconsistent. Potential recall bias and residual confounding by indication are
    concerns. Larger samples are needed to replicate DD results. Because maternal
    depression itself carries risks for the fetus, the benefits of prenatal SSRI use 
    should be carefully weighed against potential harms.
    
    PMID: 24733881  [PubMed - as supplied by publisher]
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  • 6) Pediatrics. 2014 Apr 7. [Epub ahead of print]

    Parental Obesity and Risk of Autism Spectrum Disorder.

    Surén P(1), Gunnes N, Roth C, Bresnahan M, Hornig M, Hirtz D, Lie KK, Lipkin WI, 
    Magnus P, Reichborn-Kjennerud T, Schjølberg S, Susser E, Oyen AS, Smith GD,
    Stoltenberg C.
    
    Author information: 
    (1)Norwegian Institute of Public Health, Oslo, Norway;
    
    OBJECTIVES: The objective of the study was to investigate the associations among 
    maternal prepregnancy BMI, paternal BMI, and the risk of autism spectrum
    disorders (ASDs) in children.
    METHODS: The study sample of 92 909 children was derived from the
    population-based, prospective Norwegian Mother and Child Cohort Study. The age
    range was 4.0 through 13.1 (mean 7.4) years. Relative risks of ASDs were
    estimated by odds ratios (ORs) and 95% confidence intervals (CIs) from logistic
    regression models.
    RESULTS: At the end of follow-up on December 31, 2012, 419 children in the study 
    sample had been diagnosed with ASDs: 162 with autistic disorder, 103 with
    Asperger disorder, and 154 with pervasive developmental disorder not otherwise
    specified. Maternal obesity (BMI ≥30) was only weakly associated with ASD risk,
    whereas paternal obesity was associated with an increased risk of autistic
    disorder and Asperger disorder. The risk of autistic disorder was 0.27% (25 of
    9267) in children of obese fathers and 0.14% (59 of 41 603) in children of
    fathers with normal weight (BMI <25), generating an adjusted OR of 1.73 (95% CI: 
    1.07-2.82). For Asperger disorder, analyses were limited to children aged ≥7
    years (n = 50 116). The risk was 0.38% (18 of 4761) in children of obese fathers 
    and 0.18% (42 of 22 736) in children of normal-weight fathers, and the adjusted
    OR was 2.01 (95% CI: 1.13-3.57). No associations were found for pervasive
    developmental disorder not otherwise specified.
    CONCLUSIONS: Paternal obesity is an independent risk factor for ASDs in children.
    The associations should be investigated further in genetic and epigenetic
    studies.
    
    PMID: 24709932  [PubMed - as supplied by publisher]
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  • 7) Mol Syndromol. 2014 Feb;5(2):65-75. doi: 10.1159/000357962. Epub 2014 Jan 29.

    Microdeletions including FMR1 in three female patients with intellectual disability - further delineation of the phenotype and expression studies.

    Zink AM(1), Wohlleber E(1), Engels H(1), Rødningen OK(2), Ravn K(3), Heilmann
    S(4), Rehnitz J(5), Katzorke N(5), Kraus C(6), Blichfeldt S(7), Hoffmann P(8),
    Reutter H(9), Brockschmidt FF(4), Kreiß-Nachtsheim M(1), Vogt PH(5), Prescott
    TE(2), Tümer Z(10), Lee JA(11).
    
    Author information: 
    (1)Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn,
    Germany.
    (2)Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
    (3)Applied Human Molecular Genetics, Kennedy Center, Glostrup, Denmark.
    (4)Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn,
    Germany ; Department of Genomics, Life & Brain Center, Rheinische
    Friedrich-Wilhelms-University, Bonn, Germany.
    (5)Molecular Genetics and Infertility Unit, Department of Gynecology, Endocrinology 
    and Reproductive Medicine, University Women Hospital, Heidelberg, Germany.
    (6)Institute of Human Genetics, Friedrich-Alexander-University, Erlangen-Nuremberg, 
    Germany.
    (7)Pediatric Department L55, Glostrup University Hospital, Glostrup, Denmark.
    (8)Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn,
    Germany ; Department of Genomics, Life & Brain Center, Rheinische
    Friedrich-Wilhelms-University, Bonn, Germany ; Medical Genetics, Department of
    Biomedicine, University Hospital, Basel, Switzerland.
    (9)Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn,
    Germany ; Department of Neonatology, Children's Hospital, Rheinische
    Friedrich-Wilhelms-University, Bonn, Germany.
    (10)Applied Human Molecular Genetics, Kennedy Center, Glostrup, Denmark ; Department 
    of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen,
    Denmark.
    (11)Institute of Human Genetics, Rheinische Friedrich-Wilhelms-University, Bonn,
    Germany ; Department of Genomics, Life & Brain Center, Rheinische
    Friedrich-Wilhelms-University, Bonn, Germany ; Greenwood Genetic Center,
    Greenwood, S.C., USA.
    
    Fragile X syndrome (FXS) is one of the most common causes of intellectual
    disability/developmental delay (ID/DD), especially in males. It is caused most
    often by CGG trinucleotide repeat expansions, and less frequently by point
    mutations and partial or full deletions of the FMR1 gene. The wide clinical
    spectrum of affected females partly depends on their X-inactivation status. Only 
    few female ID/DD patients with microdeletions including FMR1 have been reported. 
    We describe 3 female patients with 3.5-, 4.2- and 9.2-Mb de novo microdeletions
    in Xq27.3-q28 containing FMR1. X-inactivation was random in all patients, yet
    they presented with ID/DD as well as speech delay, macrocephaly and other
    features attributable to FXS. No signs of autism were present. Here, we further
    delineate the clinical spectrum of female patients with microdeletions. FMR1
    expression studies gave no evidence for an absolute threshold below which signs
    of FXS present. Since FMR1 expression is known to be highly variable between
    unrelated females, and since FMR1 mRNA levels have been suggested to be more
    similar among family members, we further explored the possibility of an
    intrafamilial effect. Interestingly, FMR1 mRNA levels in all 3 patients were
    significantly lower than in their respective mothers, which was shown to be
    specific for patients with microdeletions containing FMR1.
    
    PMID: 24715853  [PubMed]
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  • 8) Am J Med Genet A. 2014 Apr 8. doi: 10.1002/ajmg.a.36554. [Epub ahead of print]

    Phenotypic features in patients with 15q11.2(BP1-BP2) deletion: Further delineation of an emerging syndrome.

    Cafferkey M(1), Ahn JW, Flinter F, Ogilvie C.
    
    Author information: 
    (1)Department of Medical and Molecular Genetics, King's College, London, UK.
    
    15q11.2 deletions flanked by BP1 and BP2 of the Prader-Willi/Angelman syndrome
    region have recently been linked to a range of neurodevelopment disorders
    including intellectual disability, speech and language delay, motor delay, autism
    spectrum disorders, epilepsy, and schizophrenia. Array CGH analysis of 14,605
    patients referred for diagnostic cytogenetic testing found that 83 patients
    (0.57%) carried the 15q11.2(BP1-BP2) deletion. Phenotypic frequencies in the
    deleted cohort (n = 83) were compared with frequencies in the non-deleted cohort 
    (n = 14,522); developmental delay, motor delay, and speech and language delay
    were all more prevalent in the deleted cohort. Notably, motor delay was
    significantly more common (OR = 6.37). These data indicate that developmental
    delay, motor delay, and speech and language delay are common clinical features
    associated with this deletion, providing substantial evidence to support this CNV
    as a susceptibility locus for a spectrum of neurodevelopmental disorders. © 2014 
    Wiley Periodicals, Inc.
    
    © 2014 Wiley Periodicals, Inc.
    
    PMID: 24715682  [PubMed - as supplied by publisher]
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  • 9) Am J Med Genet A. 2014 Apr 9. doi: 10.1002/ajmg.a.36573. [Epub ahead of print]

    Autism traits in children and adolescents with Cornelia de Lange syndrome.

    Srivastava S(1), Landy-Schmitt C, Clark B, Kline AD, Specht M, Grados MA.
    
    Author information: 
    (1)Department of Neurology and Developmental Medicine, Kennedy Krieger Institute,
    Baltimore, Maryland.
    
    Cornelia de Lange syndrome (CdLS) is a cohesinopathy causing delayed growth and
    limb deficits. Individuals with CdLS have mild to profound intellectual
    disability and autistic features. This study characterizes the behavioral
    phenotype of children with CdLS, focusing on autistic features, maladaptive
    behaviors, and impact of age. Children with CdLS (5-18 years) were administered
    normed instruments to characterize autism features (Childhood Autism Rating
    Scale, CARS), maladaptive behaviors (Aberrant Behavior Checklist), and adaptive
    skills (Vineland Adaptive Behaviors Scales). CdLS features and severity were
    rated with Diagnostic Criteria for CdLS. Forty-one children with CdLS (23
    females, 18 males) were classified as having "no autism" (n = 7; 17.1%), "mild
    autism" (n = 17; 41.4%), and "severe autism" (n = 17; 41.4%), using CARS scores. 
    Characteristic items were abnormal emotional response, stereotypies, odd object
    use, rigidity, lack of verbal communication, and low intellectual functioning.
    Verbal communication deficits and repetitive behaviors were higher compared to
    sensory, social cognition, and behavior abnormalities (P ≤ 0.0001). Maladaptive
    behaviors associated with autism traits were stereotypies (P = 0.003),
    hyperactivity (P = 0.01), and lethargy (P = 0.03). Activities of daily living
    were significantly affected; socialization adaptive skills were a relative
    strength. However, with advancing age, both socialization (P < 0.0001) and
    communication (P = 0.001) domains declined significantly. CdLS is characterized
    by autistic features, notably excessive repetitive behaviors and expressive
    language deficits. While other adaptive skills are impacted, socialization
    adaptive skills are less affected. Advancing age can worsen communication and
    socialization deficits relative to neurotypical peers. © 2014 Wiley Periodicals, 
    Inc.
    
    © 2014 Wiley Periodicals, Inc.
    
    PMID: 24718998  [PubMed - as supplied by publisher]
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  • 10) Nat Commun. 2014 Apr 11;5:3650. doi: 10.1038/ncomms4650.

    Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism.

    Corominas R(1), Yang X(2), Lin GN(1), Kang S(1), Shen Y(3), Ghamsari L(2), Broly 
    M(3), Rodriguez M(3), Tam S(3), Trigg SA(2), Fan C(3), Yi S(3), Tasan M(4),
    Lemmens I(5), Kuang X(6), Zhao N(6), Malhotra D(7), Michaelson JJ(8), Vacic V(9),
    Calderwood MA(3), Roth FP(10), Tavernier J(5), Horvath S(11), Salehi-Ashtiani
    K(2), Korkin D(6), Sebat J(7), Hill DE(3), Hao T(3), Vidal M(3), Iakoucheva
    LM(12).
    
    Author information: 
    (1)1] Department of Psychiatry, University of California San Diego, La Jolla,
    California 92093, USA [2].
    (2)1] Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology,
    Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of 
    Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [3].
    (3)1] Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology,
    Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of 
    Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
    (4)Donnelly Centre and Departments of Molecular Genetics & Computer Science,
    University of Toronto, and Samuel Lunenfeld Research Institute, Mt. Sinai
    Hospital, Toronto, Ontario, Canada M5S 3E1.
    (5)Department of Medical Protein Research, VIB, and Department of Biochemistry,
    Faculty of Medicine and Health Sciences, Ghent University, Ghent B-9000, Belgium.
    (6)Department of Computer Science and Informatics Institute, University of Missouri,
    Columbia, Missouri 65203, USA.
    (7)Beyster Center for Genomics of Psychiatric Diseases and Department of Psychiatry,
    University of California San Diego, La Jolla, California 92093, USA.
    (8)1] Beyster Center for Genomics of Psychiatric Diseases and Department of
    Psychiatry, University of California San Diego, La Jolla, California 92093, USA
    [2].
    (9)New York Genome Center, New York, New York 10013, USA.
    (10)1] Center for Cancer Systems Biology (CCSB) and Department of Cancer Biology,
    Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA [2] Department of 
    Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA [3] Donnelly
    Centre and Departments of Molecular Genetics & Computer Science, University of
    Toronto, and Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto,
    Ontario, Canada M5S 3E1.
    (11)Department of Human Genetics and Biostatistics, University of California, Los
    Angeles, California 90095, USA.
    (12)Department of Psychiatry, University of California San Diego, La Jolla,
    California 92093, USA.
    
    Increased risk for autism spectrum disorders (ASD) is attributed to hundreds of
    genetic loci. The convergence of ASD variants have been investigated using
    various approaches, including protein interactions extracted from the published
    literature. However, these datasets are frequently incomplete, carry biases and
    are limited to interactions of a single splicing isoform, which may not be
    expressed in the disease-relevant tissue. Here we introduce a new interactome
    mapping approach by experimentally identifying interactions between
    brain-expressed alternatively spliced variants of ASD risk factors. The Autism
    Spliceform Interaction Network reveals that almost half of the detected
    interactions and about 30% of the newly identified interacting partners represent
    contribution from splicing variants, emphasizing the importance of isoform
    networks. Isoform interactions greatly contribute to establishing direct physical
    connections between proteins from the de novo autism CNVs. Our findings
    demonstrate the critical role of spliceform networks for translating genetic
    knowledge into a better understanding of human diseases.
    
    PMID: 24722188  [PubMed - in process]
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  • 11) Twin Res Hum Genet. 2014 Apr 15:1-13. [Epub ahead of print]

    The Roots of Autism and ADHD Twin Study in Sweden (RATSS).

    Bölte S(1), Willfors C(1), Berggren S(1), Norberg J(1), Poltrago L(1), Mevel
    K(1), Coco C(1), Fransson P(2), Borg J(1), Sitnikov R(3), Toro R(4), Tammimies
    K(1), Anderlid BM(5), Nordgren A(5), Falk A(6), Meyer U(7), Kere J(8), Landén
    M(9), Dalman C(10), Ronald A(11), Anckarsäter H(12), Lichtenstein P(13).
    
    Author information: 
    (1)Center of Neurodevelopmental Disorders at Karolinska Institutet, Pediatric
    Neuropsychiatry Unit, Department of Women's and Children's Health, Karolinska
    Institutet, Stockholm, Sweden.
    (2)Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    (3)MRI Research Center, Neuroradiology Clinic, Karolinska University Hospital,
    Stockholm, Sweden.
    (4)Human Genetics and Cognitive Functions, Institut Pasteur, Paris, France.
    (5)Department of Clinical Genetics, Karolinska University Hospital, Stockholm,
    Sweden.
    (6)Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden.
    (7)Physiology and Behavior Laboratory, Swiss Federal Institute of Technology (ETH)
    Zurich, Switzerland.
    (8)Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
    (9)Section of Psychiatry and Neurochemistry, Sahlgrenska Academy, Gothenburg,
    Sweden.
    (10)Public Health Epidemiology, Department of Public Health Sciences, Karolinska
    Institutet, Stockholm, Sweden.
    (11)Centre for Brain and Cognitive Development, Department of Psychological Sciences,
    Birkbeck, University of London, London, UK.
    (12)Neuroscience and Physiology, Forensic Psychiatry, University of Gothenburg,
    Gothenburg, Sweden.
    (13)Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,
    Stockholm, Sweden.
    
    Neurodevelopmental disorders affect a substantial minority of the general
    population. Their origins are still largely unknown, but a complex interplay of
    genetic and environmental factors causing disturbances of the central nervous
    system's maturation and a variety of higher cognitive skills is presumed. Only
    limited research of rather small sample size and narrow scope has been conducted 
    in neurodevelopmental disorders using a twin-differences design. The Roots of
    Autism and ADHD Twin Study in Sweden (RATSS) is an ongoing project targeting
    monozygotic twins discordant for categorical or dimensional autistic and
    inattentive/hyperactive-impulsive phenotypes as well as other neurodevelopmental 
    disorders, and typically developing twin controls. Included pairs are 9 years of 
    age or older, and comprehensively assessed for psychopathology, medical history, 
    neuropsychology, and dysmorphology, as well as structural, functional, and
    molecular brain imaging. Specimens are collected for induced pluripotent (iPS)
    and neuroepithelial stem cells, genetic, gut bacteria, protein-/monoamine, and
    electron microscopy analyses. RATSS's objective is to generate a launch pad for
    novel surveys to understand the complexity of genotype-environment-phenotype
    interactions in autism spectrum disorder and attention-deficit hyperactivity
    disorder (ADHD). By October 2013, RATSS had collected data from 55 twin pairs,
    among them 10 monozygotic pairs discordant for autism spectrum disorder, seven
    for ADHD, and four for other neurodevelopmental disorders. This article describes
    the design, recruitment, data collection, measures, collected pairs'
    characteristics, as well as ongoing and planned analyses in RATSS. Potential
    gains of the study comprise the identification of environmentally mediated
    biomarkers, the emergence of candidates for drug development, translational
    modeling, and new leads for prevention of incapacitating outcomes.
    
    PMID: 24735654  [PubMed - as supplied by publisher]
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  • 12) Mol Autism. 2014 Apr 10;5(1):28. [Epub ahead of print]

    Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders.

    Correia CT, Conceição IC, Oliveira B, Coelho J, Sousa I, Sequeira AF, Almeida J, 
    Café C, Duque F, Mouga S, Roberts W, Gao K, Lowe JK, Thiruvahindrapuram B, Walker
    S, Marshall CR, Pinto D, Nurnberger JI, Scherer SW, Geschwind DH, Oliveira G,
    Vicente AM.
    
    BACKGROUND: Validating the potential pathogenicity of copy number variants (CNVs)
    identified in genome-wide studies of autism spectrum disorders (ASD) requires
    detailed assessment of case/control frequencies, inheritance patterns, clinical
    correlations, and functional impact. Here, we characterize a small recurrent
    duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome
    Project (AGP) study.
    METHODS: From the AGP CNV genomic screen in 2,147 ASD individuals, we selected
    for characterization an ANXA1 gene duplication that was absent in 4,964
    population-based controls. We further screened the duplication in a follow-up
    sample including 1,496 patients and 410 controls, and evaluated clinical
    correlations and family segregation. Sequencing of exonic/downstream ANXA1
    regions was performed in 490 ASD patients for identification of additional
    variants.
    RESULTS: The ANXA1 duplication, overlapping the last four exons and 3'UTR region,
    had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was
    not identified in 5,374 controls. Duplication carriers presented no distinctive
    clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD
    traits in multiple relatives carrying the duplication, suggestive of a complex
    genetic inheritance. Sequencing of exonic regions and the 3'UTR identified 11
    novel changes, but no obvious variants with clinical significance.
    CONCLUSIONS: We provide multilevel evidence for a role of ANXA1 in ASD etiology. 
    Given its important role as mediator of glucocorticoid function in a wide variety
    of brain processes, including neuroprotection, apoptosis, and control of the
    neuroendocrine system, the results add ANXA1 to the growing list of rare
    candidate genetic etiological factors for ASD.
    
    PMID: 24720851  [PubMed - as supplied by publisher]
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  • 13) Neurosci Biobehav Rev. 2014 Apr 9. pii: S0149-7634(14)00078-5. doi: 10.1016/j.neubiorev.2014.03.021. [Epub ahead of print]

    Ultrasonic Vocalizations in Shank Mouse Models for Autism Spectrum Disorders: Detailed Spectrographic Analyses and Developmental Profiles.

    Wöhr M.
    
    Author information: 
    Behavioral Neuroscience, Experimental and Biological Psychology,
    Philipps-University of Marburg, Gutenbergstr. 18, D-35032 Germany. Electronic
    address: markus.woehr@staff.uni-marburg.de.
    
    Autism spectrum disorders (ASD) are a class of neurodevelopmental disorders
    characterized by persistent deficits in social behavior and communication across 
    multiple contexts, together with repetitive patterns of behavior, interests, or
    activities. The high concordance rate between monozygotic twins supports a strong
    genetic component. Among the most promising candidate genes for ASD is the SHANK 
    gene family, including SHANK1, SHANK2 (ProSAP1), and SHANK3 (ProSAP2). SHANK
    genes are therefore important candidates for modeling ASD in mice and various
    genetic models were generated within the last few years. As the diagnostic
    criteria for ASD are purely behaviorally defined, the validity of mouse models
    for ASD strongly depends on their behavioral phenotype. Behavioral phenotyping is
    therefore a key component of the current translational approach and requires
    sensitive behavioral test paradigms with high relevance to each diagnostic
    symptom category. While behavioral phenotyping assays for social deficits and
    repetitive patterns of behavior, interests, or activities are well-established,
    the development of sensitive behavioral test paradigms to assess communication
    deficits in mice is a daunting challenge. Measuring ultrasonic vocalizations
    (USV) appears to be a promising strategy. In the first part of the review, an
    overview on the different types of mouse USV and their communicative function
    will be provided. The second part is devoted to studies on the emission of USV in
    Shank mouse models for ASD. Evidence for communication deficits was obtained in
    Shank1, Shank2, and Shank3 genetic mouse models for ASD, often paralleled by
    behavioral phenotypes relevant to social deficits seen in ASD.
    
    Copyright © 2014. Published by Elsevier Ltd.
    
    PMID: 24726578  [PubMed - as supplied by publisher]
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  • 14) J Abnorm Psychol. 2014 Apr 14. [Epub ahead of print]

    Symptoms of autism and adhd: A swedish twin study examining their overlap.

    Ronald A, Larsson H, Anckarsäter H, Lichtenstein P.
    
    Autism spectrum disorders (ASD) and attention deficit hyperactivity disorder
    (ADHD) show high comorbidity. The following questions were addressed regarding
    their specific symptoms: What is the factor structure of ASD and ADHD symptoms,
    to what degree do different symptom domains cluster together, to what extent are 
    these domains caused by the same genetic and environmental influences, and what
    is the best model of their co-occurrence? A population-based twin cohort of over 
    17,000 9- and 12-year-olds were assessed using the Autism-Tics, AD/HD, and other 
    Comorbidities parental interview inventory. Principal component analyses were
    conducted, and symptom domain clustering was assessed. Four multivariate twin
    models were compared. Factors split into three ASD (social impairments,
    communication impairments, and restricted repetitive behaviors and interests),
    and three ADHD (inattention, hyperactivity, and impulsivity) symptom domains.
    Some ASD-ADHD symptom domain combinations clustered together often, although
    others not at all. A two-factor common pathway model fit the data, suggesting
    that ASD and ADHD symptom domains tap into separate "ASD" and "ADHD" latent
    factors that showed high genetic overlap. All subdomains also showed significant 
    specific genetic and environmental influences, reflecting the etiological
    heterogeneity both within and between ASD and ADHD. These findings support the
    conceptual distinction of ASD and ADHD, and demonstrate the considerable natural 
    co-occurrence of particular ASD/ADHD symptom domains. The results imply that more
    children with 1 condition show features of the other condition than show complete
    comorbidity. Emphasis on symptom co-occurrence, rather than complete comorbidity 
    between disorders, may help focus clinical approaches and advance molecular
    genetic research. (PsycINFO Database Record (c) 2014 APA, all rights reserved).
    
    PMID: 24731073  [PubMed - as supplied by publisher]
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  • 15) AJOB Prim Res. 2014 Jan 1;5(1):44-55.

    Focusing on Cause or Cure?: Priorities and Stakeholder Presence in Childhood Psychiatry Research.

    Milner LC(1), Cho MK(2).
    
    Author information: 
    (1)Center for the Integration of Research on Genetics and Ethics (CIRGE), Stanford
    Center for Biomedical Ethics, Stanford University, 1215 Welch Road, Modular A,
    Stanford, CA 94305.
    (2)Center for the Integration of Research on Genetics and Ethics (CIRGE), Stanford
    Center for Biomedical Ethics, Stanford University, 1215 Welch Road, Modular A,
    Stanford, CA 94305, Tel: (650) 725-7993, micho@stanford.edu.
    
    BACKGROUND: Biomedical research is influenced by many factors, including the
    involvement of stakeholder groups invested in research outcomes. Stakeholder
    involvement in research efforts raise questions of justice as their specific
    interests and motivations play a role in directing research resources that
    ultimately produce knowledge shaping how different conditions (and affected
    individuals) are understood and treated by society. This issue is highly relevant
    to child psychiatry research where diagnostic criteria and treatment strategies
    are often controversial. Biological similarities and stakeholder differences
    between attention deficit hyperactivity disorder (ADHD) and autism spectrum
    disorder (ASD) provide an opportunity to explore this issue by comparing research
    foci and stakeholder involvement in these conditions.
    METHODS: A subset of ADHD and ASD research articles published between 1970-2010
    were randomly selected from the PubMed database and coded for research focus,
    funding source(s), and author-reported conflicts of interest (COIs). Chi-square
    analyses were performed to identify differences between and within ADHD and ASD
    research across time.
    RESULTS: The proportion of ADHD research dedicated to basic, description, and
    treatment research was roughly similar and remained stable over time, while ASD
    research showed a significant increase in basic research over the past decade.
    Government was the primary research funder for both conditions, but for-profit
    funders were a notable presence in ADHD research, while joint-funding efforts
    between non-profit and government funders were a notable presence in ASD
    research. Lastly, COIs were noted more frequently in ADHD than in ASD research.
    CONCLUSIONS: Our study shows significant differences in research foci and funding
    sources between the conditions, and identifies the specific involvement of
    for-profit and non-profit groups in ADHD and ASD, respectively. Our findings
    highlight the relationship between stakeholders outside the research community
    and research trajectories and suggest that examinations of these relationships
    must be included in broader considerations of biomedical research ethics.
    
    PMID: 24729931  [PubMed]
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  • 16) EMBO Mol Med. 2014 Apr 14. pii: emmm.201303235v1. doi: 10.1002/emmm.201303235. [Epub ahead of print]

    Maternally inherited genetic variants of CADPS2 are present in Autism Spectrum Disorders and Intellectual Disability patients.

    Bonora E(1), Graziano C, Minopoli F, Bacchelli E, Magini P, Diquigiovanni C,
    Lomartire S, Bianco F, Vargiolu M, Parchi P, Marasco E, Mantovani V, Rampoldi L, 
    Trudu M, Parmeggiani A, Battaglia A, Mazzone L, Tortora G; IMGSAC, Maestrini E,
    Seri M, Romeo G.
    
    Author information: 
    (1)Unit of Medical Genetics, Department of Medical and Surgical Sciences, S.
    Orsola-Malpighi Hospital University of Bologna, Bologna, Italy.
    
    Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex
    neuropsychiatric conditions, with overlapping clinical boundaries in many
    patients. We identified a novel intragenic deletion of maternal origin in two
    siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic
    protein involved in neurotrophin release and interaction with dopamine receptor
    type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36
    with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR
    interaction. CADPS2 allelic expression was tested in blood and different adult
    human brain regions, revealing that the gene was monoallelically expressed in
    blood and amygdala, and the expressed allele was the one of maternal origin.
    Cadps2 gene expression performed in mice at different developmental stages was
    biallelic in the postnatal and adult stages; however, a monoallelic (maternal)
    expression was detected in the embryonal stage, suggesting that CADPS2 is
    subjected to tissue- and temporal-specific regulation in human and mice. We
    suggest that CADPS2 variants may contribute to ID/ASD development, possibly
    through a parent-of-origin effect.
    
    PMID: 24737869  [PubMed - as supplied by publisher]
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  • 17) Autism Res. 2014 Apr;7(2):216-28. doi: 10.1002/aur.1361. Epub 2014 Mar 12.

    The association between social cognition and executive functioning and symptoms of anxiety and depression in adolescents with autism spectrum disorders.

    Hollocks MJ(1), Jones CR, Pickles A, Baird G, Happé F, Charman T, Simonoff E.
    
    Author information: 
    (1)Department of Child & Adolescent Psychiatry, Institute of Psychiatry, King's
    College London, London, United Kingdom.
    
    While high levels of anxiety and depression are now recognized as major
    co-occurring problems in children and young people with an autism spectrum
    disorder (ASD), research examining possible associations with individual
    differences in neurocognitive functioning has been limited. This study included
    90 adolescents with an ASD aged 14-16 years with a full-scale IQ > 50. Using
    structural equation modeling, we examined the independent relationships between
    multiple measures of executive functioning and social cognition on severity of
    anxiety or depressive symptoms. Results indicated a significant association
    between poorer executive functioning and higher levels of anxiety, but not
    depression. In contrast, social cognition ability was not associated with either 
    anxiety or depression. This study is the first to report significant associations
    between executive functions and anxiety in ASD. This may suggest that poor
    executive functioning is one factor associated with the high prevalence of
    anxiety disorder in children and adolescents with ASD. Autism Res 2014, 7:
    216-228. © 2014 International Society for Autism Research, Wiley Periodicals,
    Inc.
    
    © 2014 International Society for Autism Research, Wiley Periodicals, Inc.
    
    PMID: 24737743  [PubMed - in process]
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  • 18) Hum Brain Mapp. 2014 Apr 15. doi: 10.1002/hbm.22521. [Epub ahead of print]

    Topological methods reveal high and low functioning neuro-phenotypes within fragile X syndrome.

    Romano D(1), Nicolau M, Quintin EM, Mazaika PK, Lightbody AA, Cody Hazlett H,
    Piven J, Carlsson G, Reiss AL.
    
    Author information: 
    (1)Center for Interdisciplinary Brain Sciences Research, Stanford University Medical
    School, Stanford, California.
    
    Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common
    known inherited cause of developmental disability as well as the most common
    single-gene risk factor for autism. Our goal was to examine variation in brain
    structure in FXS with topological data analysis (TDA), and to assess how such
    variation is associated with measures of IQ and autism-related behaviors. To this
    end, we analyzed imaging and behavioral data from young boys (n = 52; aged
    1.57-4.15 years) diagnosed with FXS. Application of topological methods to
    structural MRI data revealed two large subgroups within the study population.
    Comparison of these subgroups showed significant between-subgroup neuroanatomical
    differences similar to those previously reported to distinguish children with FXS
    from typically developing controls (e.g., enlarged caudate). In addition to
    neuroanatomy, the groups showed significant differences in IQ and autism severity
    scores. These results suggest that despite arising from a single gene mutation,
    FXS may encompass two biologically, and clinically separable phenotypes. In
    addition, these findings underscore the potential of TDA as a powerful tool in
    the search for biological phenotypes of neuropsychiatric disorders. Hum Brain
    Mapp, 2014. © 2014 Wiley Periodicals, Inc.
    
    Copyright © 2014 Wiley Periodicals, Inc.
    
    PMID: 24737721  [PubMed - as supplied by publisher]
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  • 19) Dev Neurorehabil. 2014 Apr 16. [Epub ahead of print]

    Effects associated with on- and off-label stimulant treatment of core autism and ADHD symptoms exhibited by children with autism spectrum disorder.

    Barnard-Brak L(1), Davis TN, Schmidt M, Richman DM.
    
    Author information: 
    (1)College of Education, Texas Tech University, Lubbock , Texas , USA .
    
    Abstract Objective: Families of children with autism spectrum disorder are
    barraged by different treatment options. Some of these options have the support
    of empirical evidence while others do not. Stimulant treatments are typically
    utilized to treat symptoms of ADHD indicating an on-label use of such treatment. 
    Methods: This study examines the association of stimulant treatment with the on- 
    (symptoms of ADHD) and off- (symptoms of ASD) label symptoms among children with 
    ASD via a non-clinical, population-based sample. Results: Results indicate no
    significant association of stimulant treatment with a reduction of on- or
    off-label symptoms among children with ASD. Conclusion: Stimulant medications
    utilized in the treatment of DSM core symptoms of autism spectrum disorder would 
    be considered an off-label use because there is limited evidence to support that 
    stimulants are effective in treating core symptoms of ASD, which is supported by 
    the results of the current study.
    
    PMID: 24739141  [PubMed - as supplied by publisher]
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