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Papers of the Week

  • 1) RNA Biol. 2013 Apr 17;10(7). [Epub ahead of print]

    Dysregulation of the long non-coding RNA transcriptome in a Rett syndrome mouse model.

    Petazzi P, Sandoval J, Szczesna K, Jorge OC, Roa L, Sayols S, Gomez A, Huertas D,
Esteller M.

1 Cancer Epigenetics and Biology Program (PEBC); Bellvitge Biomedical Research
Institute (IDIBELL); Barcelona, Catalonia, Spain.

Mecp2 is a transcriptional repressor protein that is mutated in Rett syndrome, a 
neurodevelopmental disorder that is the second most common cause of mental
retardation in women. It has been shown that the loss of the Mecp2 protein in
Rett syndrome cells alters the transcriptional silencing of coding genes and
microRNAs. Herein, we have studied the impact of Mecp2 impairment in a Rett
syndrome mouse model on the global transcriptional patterns of long non-coding
RNAs (lncRNAs). Using a microarray platform that assesses 41,232 unique lncRNA
transcripts, we have identified the aberrant lncRNA transcriptome that is present
in the brain of Rett syndrome mice. The study of the most relevant lncRNAs
altered in the assay highlighted the upregulation of the AK081227 and AK087060
transcripts in Mecp2-null mice brains. Chromatin immunoprecipitation demonstrated
the Mecp2 occupancy in the 5'-end genomic loci of the described lncRNAs and its
absence in Rett syndrome mice. Most importantly, we were able to show that the
overexpression of AK081227 mediated by the Mecp2 loss was associated with the
downregulation of its host coding protein gene, the gamma-aminobutyric acid
receptor subunit Rho 2 (Gabrr2). Overall, our findings indicate that the
transcriptional dysregulation of lncRNAs upon Mecp2 loss contributes to the
neurological phenotype of Rett syndrome and highlights the complex interaction
between ncRNAs and coding-RNAs.

PMID: 23611944  [PubMed - as supplied by publisher]
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  • 2) J Autism Dev Disord. 2013 Apr 26. [Epub ahead of print]

    The Effects of a Multi-Component Higher-Functioning Autism Anti-Stigma Program on Adolescent Boys.

    Staniland JJ, Byrne MK.

School of Psychology, University of Wollongong, Northfields Avenue, Wollongong,
NSW, 2522, Australia.

A six-session higher-functioning autism anti-stigma program incorporating
descriptive, explanatory and directive information was delivered to adolescent
boys and the impact upon knowledge, attitudes and behavioural intentions towards 
peers with autism was evaluated. Participants were seventh-, eighth- and
ninth-grade students (N = 395) from regular classes in a mainstream school.
Two-eighth-grade classes were randomly allocated to the intervention condition
and all remaining students were either allocated to the no-intervention peer or
no-intervention non-peer condition. The anti-stigma program improved the
knowledge and attitudes, but not the behavioural intentions of participants
towards their peers with autism. Knowledge and attitudinal changes were
maintained at follow-up. There were no spill-over effects of the program to
non-targeted students. These results provide some preliminary evidence for the
effectiveness of multi-session anti-stigma programs incorporating combined
information for adolescent students in inclusive educational environments.

PMID: 23619951  [PubMed - as supplied by publisher]
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  • 3) J Autism Dev Disord. 2013 Apr 26. [Epub ahead of print]

    Grasping Motor Impairments in Autism: Not Action Planning but Movement Execution is Deficient.

    Stoit AM, van Schie HT, Slaats-Willemse DI, Buitelaar JK.

Karakter Child and Adolescent Psychiatry, P.O. Box 40244, 8004 DE, Zwolle, The
Netherlands.

Different views on the origin of deficits in action chaining in autism spectrum
disorders (ASD) have been posited, ranging from functional impairments in action 
planning to internal models supporting motor control. Thirty-one children and
adolescents with ASD and twenty-nine matched controls participated in a
two-choice reach-to-grasp paradigm wherein participants received cueing
information indicating either the object location or the required manner of
grasping. A similar advantage for location cueing over grip cueing was found in
both groups. Both accuracy and reaction times of the ASD group were
indistinguishable from the control group. In contrast, movement times of the ASD 
group were significantly delayed in comparison with controls. These findings
suggest that movement execution rather than action planning is deficient in ASD, 
and that deficits in action chaining derive from impairments in internal action
models supporting action execution.

PMID: 23619948  [PubMed - as supplied by publisher]
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  • 4) Behav Brain Res. 2013 Apr 22. pii: S0166-4328(13)00221-0. doi: 10.1016/j.bbr.2013.04.021. [Epub ahead of print]

    A two-year longitudinal pilot MRI study of the brainstem in autism.

    Jou RJ, Frazier TW, Keshavan MS, Minshew NJ, Hardan AY.

Child Neuroscience Laboratory, Child Study Center, Yale School of Medicine, 230
South Frontage Road, New Haven, CT 06519, USA. Electronic address:
roger.jou@yale.edu.

Research has demonstrated the potential role of the brainstem in the pathobiology
of autism. Previous studies have suggested reductions in brainstem volume and a
relationship between this structure and sensory abnormalities. However, little is
known regarding the developmental aspects of the brainstem across childhood and
adolescence. The goal of this pilot study was to examine brainstem development
via MRI volumetry using a longitudinal research design. Participants included 23 
boys with autism and 23 matched controls (age range=7-17 years), all without
intellectual disability. Participants underwent structural MRI scans once at
baseline and again at two-year follow-up. Brainstem volumetric measurements were 
performed using the BRAINS2 software package. There were no significant group
differences in age, gender, handedness, and total brain volume; however,
full-scale IQ was higher in controls. Autism and control groups showed different 
patterns of growth in brainstem volume. While whole brainstem volume remained
stable in controls over the two-year period, the autism group showed increases
with age reaching volumes comparable to controls by age 15 years. This increase
of whole brainstem volume was primarily driven by bilateral increases in gray
matter volume. Findings from this preliminary study are suggestive of
developmental brainstem abnormalities in autism primarily involving gray matter
structures. These findings are consistent with autism being conceptualized as a
neurodevelopmental disorder with alterations in brain-growth trajectories. More
longitudinal MRI studies are needed integrating longitudinal cognitive/behavioral
data to confirm and elucidate the clinical significance of these atypical growth 
patterns.

Copyright © 2013. Published by Elsevier B.V.

PMID: 23619132  [PubMed - as supplied by publisher]
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  • 5) Front Integr Neurosci. 2013 Apr 17;7:23. doi: 10.3389/fnint.2013.00023. Print 2013.

    Motor interactions with another person: do individuals with Autism Spectrum Disorder plan ahead?

    Gonzalez DA, Glazebrook CM, Studenka BE, Lyons J.

Department of Kinesiology, University of Waterloo Waterloo, ON, Canada ;
Department of Cognitive Neurology, Sunnybrook Health Sciences Centre Toronto, ON,
Canada.

Interpersonal motor interactions (joint-actions) occur on a daily basis. In
joint-action situations, typically developing (TD) individuals consider the
end-goal of their partner and adjust their own movements to accommodate the other
person. The movement planning processes required for joint-action may, however,
be difficult for individuals with an Autism Spectrum Disorder (ASD) given
documented difficulties in performance on theory of mind (ToM) and motor tasks.
The goal of this experiment was to determine if individuals with ASD exhibit
end-state comfort behaviors similar to their TD peers in joint-action situations.
Participants were asked to either pass, place, or use three common tools: a
wooden toy hammer, a stick, or a calculator. These tools were selected because
the degree of affordance they offer (i.e., the physical characteristics they
posses to prompt proper use) ranges from direct (hammer) to indirect
(calculator). Participants were asked to pass the tool to a confederate who
intended to place the tool down, or use the tool. Variables of interest included 
beginning and end-state grip orientations of the participant and confederate
(comfortable or uncomfortable) as a function of task goal, and the side to which 
the tool was placed or passed. Similar to Gonzalez et al. (2011), some
individuals with ASD maximized their partner's beginning-state comfort by
adopting personally uncomfortable postures. That said, their performance was more
variable than their TD peers who consistently passed tools in a manner that
facilitated comfortable use by the confederate. Therefore, the movement planning 
processes used to prepare to pass a tool are not stereotypical across all
individuals with ASD. We propose that the novel joint-action task described
herein provides the basis for testing an important link between motor performance
and more complex social and communication behaviors.

PMID: 23616751  [PubMed]
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  • 6) Exp Anim. 2013;62(2):71-8.

    Animal Models of Autism Spectrum Disorder (ASD): A Synaptic-Level Approach to Autistic-Like Behavior in Mice.

    Shinoda Y, Sadakata T, Furuichi T.

Department of Applied Biological Science, Faculty of Science and Technology,
Tokyo University of Science, 2641 Yamazaki, Noda, Chiba 278-8510, Japan.

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental
disorders and is thought to be closely associated with genetic factors. It is
noteworthy that many ASD-associated genes reported by genome-wide association
studies encode proteins related to synaptic formation, transmission, and
plasticity. Therefore, it is essential to elucidate the relationship between
deficiencies in these genes and the relevant ASD-related phenotypes using
synaptic and behavioral phenotypic analysis of mice that are genetically modified
for genes related to ASD (e.g., knockout or mutant mice). In this review, we
focus on the behavioral-, cellular-, and circuit-level phenotypes, including
synaptic formation and function, of several knockout mouse models with genetic
mutations related to ASD. Moreover, we introduce our recent findings on the
possible association of the dense-core vesicle secretion-related gene
CAPS2/CADPS2 with ASD by using knockout mice. Finally, we discuss the usefulness 
and limitations of various mouse models with single gene mutations for
understanding ASD.

PMID: 23615300  [PubMed - in process]
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  • 7) Hum Mol Genet. 2013 Apr 24. [Epub ahead of print]

    Loss of function of KIAA2022 causes mild to severe intellectual disability with an autism spectrum disorder and impairs neurite outgrowth.

    Van Maldergem L, Hou Q, Kalscheuer VM, Rio M, Doco-Fenzy M, Medeira A, de Brouwer
AP, Cabrol C, Haas SA, Cacciagli P, Moutton S, Landais E, Motte J, Colleaux L,
Bonnet C, Villard L, Dupont J, Man HY.

Centre de Génétique Humaine, Université de Franche-Comté, 25000 Besançon, France.

Existence of a discrete new X-linked intellectual disability (XLID) syndrome due 
to KIAA2022 deficiency was questioned by disruption of KIAA2022 by an
X-chromosome pericentric inversion in a XLID family we reported in 2004. Three
additional families with likely pathogenic KIAA2022 mutations were discovered
within the frame of systematic parallel sequencing of familial cases of XLID or
in the context of routine array-CGH evaluation of sporadic ID cases. The
c.186delC and c.3597dupA KIAA2022 truncating mutations were identified by
X-chromosome exome sequencing, while array-CGH discovered a 70kb microduplication
encompassing KIAA2022 exon 1 in the third family. This duplication decreased
KIAA2022 mRNA level in patients' lymphocytes by 60%. Detailed clinical
examination of all patients, including the two initially reported, indicated
moderate to severe ID with autistic features, strabismus in all patients, with no
specific dysmorphic features other than a round face in infancy, and no
structural brain abnormalities on MRI. Interestingly, the patient with decreased 
KIAA2022 expression had only mild ID with severe language delay and repetitives
behaviors falling in the range of an autism dpectrum disorder. Since little is
known on KIAA2022 function, we conducted morphometric studies in cultured rat
hippocampal neurons. We found that siRNA-mediated KIAA2022 knockdown resulted in 
marked impairment in neurite outgrowth including both the dendrites and the
axons, suggesting a major role for KIAA2022 in neuron development and brain
function.

PMID: 23615299  [PubMed - as supplied by publisher]
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  • 8) Neurogenetics. 2013 Apr 28. [Epub ahead of print]

    Peripheral blood gene expression signature differentiates children with autism from unaffected siblings.

    Kong SW, Shimizu-Motohashi Y, Campbell MG, Lee IH, Collins CD, Brewster SJ, Holm 
IA, Rappaport L, Kohane IS, Kunkel LM.

Informatics Program at the Harvard-Massachusetts Institute of Technology Division
of Health Sciences and Technology, Boston Children's Hospital, Boston, MA, 02115,
USA.

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental
disorders with high heritability, yet a majority of genetic contribution to
pathophysiology is not known. Siblings of individuals with ASD are at increased
risk for ASD and autistic traits, but the genetic contribution for simplex
families is estimated to be less when compared to multiplex families. To explore 
the genomic (dis-) similarity between proband and unaffected sibling in simplex
families, we used genome-wide gene expression profiles of blood from 20
proband-unaffected sibling pairs and 18 unrelated control individuals. The global
gene expression profiles of unaffected siblings were more similar to those from
probands as they shared genetic and environmental background. A total of 189
genes were significantly differentially expressed between proband-sib pairs
(nominal p < 0.01) after controlling for age, sex, and family effects. Probands
and siblings were distinguished into two groups by cluster analysis with these
genes. Overall, unaffected siblings were equally distant from the centroid of
probands and from that of unrelated controls with the differentially expressed
genes. Interestingly, five of 20 siblings had gene expression profiles that were 
more similar to unrelated controls than to their matched probands. In summary, we
found a set of genes that distinguished probands from the unaffected siblings,
and a subgroup of unaffected siblings who were more similar to probands. The
pathways that characterized probands compared to siblings using peripheral blood 
gene expression profiles were the up-regulation of ribosomal, spliceosomal, and
mitochondrial pathways, and the down-regulation of neuroreceptor-ligand, immune
response and calcium signaling pathways. Further integrative study with
structural genetic variations such as de novo mutations, rare variants, and copy 
number variations would clarify whether these transcriptomic changes are
structural or environmental in origin.

PMID: 23625158  [PubMed - as supplied by publisher]
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  • 9) J Autism Dev Disord. 2013 Apr 27. [Epub ahead of print]

    Multisensory Speech Perception in Children with Autism Spectrum Disorders.

    Woynaroski TG, Kwakye LD, Foss-Feig JH, Stevenson RA, Stone WL, Wallace MT.

Department of Hearing and Speech Sciences, Vanderbilt University, 1211 Medical
Center Drive, Nashville, TN, 37232, USA, tiffany.g.woynaroski@vanderbilt.edu.

This study examined unisensory and multisensory speech perception in 8-17 year
old children with autism spectrum disorders (ASD) and typically developing
controls matched on chronological age, sex, and IQ. Consonant-vowel syllables
were presented in visual only, auditory only, matched audiovisual, and mismatched
audiovisual ("McGurk") conditions. Participants with ASD displayed deficits in
visual only and matched audiovisual speech perception. Additionally, children
with ASD reported a visual influence on heard speech in response to mismatched
audiovisual syllables over a wider window of time relative to controls.
Correlational analyses revealed associations between multisensory speech
perception, communicative characteristics, and responses to sensory stimuli in
ASD. Results suggest atypical speech perception is linked to broader behavioral
characteristics of ASD.

PMID: 23624833  [PubMed - as supplied by publisher]
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  • 10) J Am Acad Child Adolesc Psychiatry. 2013 May;52(5):454-7. doi: 10.1016/j.jaac.2013.02.009.

    DSM-5 and Autism: Kicking the Tires and Making the Grade.

    King BH, Veenstra-Vanderweele J, Lord C.

University of Washington and Seattle Children's Autism Center. Electronic
address: bhking@u.washington.edu.

PMID: 23622845  [PubMed - in process]
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  • 11) Handb Clin Neurol. 2013;111:263-71. doi: 10.1016/B978-0-444-52891-9.00029-4.

    The autistic spectrum.

    Mottron L, Dawson M.

Department of Psychiatry, University of Montreal, Montréal, Quebec, Canada;
Centre d'Excellence en Troubles Envahissants du Developpement de l'Université de 
Montréal, Hôpital Rivière-des-Prairies, Montréal, Quebec, Canada. Electronic
address: mottronl@uniserve.com.

The autistic spectrum currently encompasses common precocious behaviourally
identified constellations of social and communication atypicalities associated
with restricted interests and repetitive behavior, together with uneven ability
profiles. It is associated with multiple but heterogeneous genetic, functional,
and structural variations whose established links with an autistic behavioral
phenotype are as yet minimal. Strong evidence of high heritability contrasts with
limited determination of genes and modes of transmission involved. Adaptation and
outcomes vary widely according to opportunities, accommodation, and co-occurring 
conditions. With current diagnostic practices, multiple genetic conditions
overlap with the autistic spectrum, with potential for confusion arising from
phenocopies. Recent advances question the often presumed association between
autism and intellectual disability and/or epilepsy. Autism is currently
understood as a final common phenotypical pathway resulting from an indefinite
number of genetic variations, possibly involving the same information processing 
pathways, and producing a variant in the way humans perceive, memorize,
manipulate, and attribute emotional value to available information. Findings
plausibly converge on more optional, rather than typically mandatory, hierarchies
of information processing as fundamental to autism. Adaptation of education and
employment according to individual strengths and needs, as well as attention to
co-occurring conditions as necessary, remains today the best way to assist
autistic individuals.

Copyright © 2013 Elsevier B.V. All rights reserved.

PMID: 23622174  [PubMed - in process]
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  • 12) Mol Autism. 2013 Apr 27;4(1):9. [Epub ahead of print]

    Insulin-like growth factor-1 rescues synaptic and motor deficits in a mouse model of autism and developmental delay.

    Bozdagi O, Tavassoli T, Buxbaum JD.

BACKGROUND: Haploinsufficiency of SHANK3, due to either hemizygous gene deletion 
(termed 22q13 deletion syndrome or Phelan-McDermid syndrome) or to gene mutation,
accounts for about 0.5% of the cases of autism spectrum disorder (ASD) and/or
developmental delay, and there is evidence for a wider role for SHANK3 and
glutamate signaling abnormalities in ASD and related conditions. Therapeutic
approaches that reverse deficits in SHANK3-haploinsufficiency may therefore be
broadly beneficial in ASD and in developmental delay. FINDINGS: We observed that 
daily intraperitoneal injections of human insulin-like growth factor 1 (IGF-1)
over a 2-week period reversed deficits in hippocampal
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) signaling,
long-term potentiation (LTP), and motor performance that we had previously
reported in Shank3-deficient mice. Positive effects were observed with an IGF-1
peptide derivative as well. CONCLUSIONS: We observed significant beneficial
effects of IGF-1 in a mouse model of ASD and of developmental delay. Studies in
mouse and human neuronal models of Rett syndrome also show benefits with IGF-1,
raising the possibility that this compound may have benefits broadly in ASD and
related conditions, even with differing molecular etiology. Given the extensive
safety data for IGF-1 in children with short stature due to primary IGF-1
deficiency, IGF-1 is an attractive candidate for controlled clinical trials in
SHANK3-deficiency and in ASD.

PMID: 23621888  [PubMed - as supplied by publisher]
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  • 13) PLoS Biol. 2013 Apr;11(4):e1001544. doi: 10.1371/journal.pbio.1001544. Epub 2013 Apr 23.

    Subgrouping the Autism "Spectrum": Reflections on DSM-5.

    Lai MC, Lombardo MV, Chakrabarti B, Baron-Cohen S.

Autism Research Centre, Department of Psychiatry, University of Cambridge,
Cambridge, United Kingdom ; Department of Psychiatry, National Taiwan University 
Hospital, Taipei, Taiwan.

DSM-5 has moved autism from the level of subgroups ("apples and oranges") to the 
prototypical level ("fruit"). But making progress in research, and ultimately
improving clinical practice, will require identifying subgroups within the autism
spectrum.

PMID: 23630456  [PubMed - in process]
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  • 14) Int J Psychophysiol. 2013 Apr 26. pii: S0167-8760(13)00116-5. doi: 10.1016/j.ijpsycho.2013.04.014. [Epub ahead of print]

    Autonomic arousal explains social cognitive abilities in high-functioning adults with autism spectrum disorder.

    Mathersul D, McDonald S, Rushby JA.

School of Psychology, University of New South Wales, Sydney, NSW 2052, Australia.
Electronic address: dmathersul@psy.unsw.edu.au.

Empirical research into behavioural profiles and autonomic responsivity in
individuals with autism spectrum disorders (ASDs) is highly variable and
inconsistent. Two preliminary studies of children with ASDs suggest that there
may be subgroups of ASDs depending on their resting arousal levels, and that
these subgroups show different profiles of autonomic responsivity. The aim of the
present study was to determine whether (i) adults with high-functioning ASDs may 
be separated into subgroups according to variation in resting arousal; and (ii)
these ASD arousal subgroups differ in their behavioural profiles for basic
emotion recognition, judgements of trustworthiness, and cognitive and affective
empathy. Thirty high-functioning adults with ASDs and 34 non-clinical controls
participated. Resting arousal was determined as the average skin conductance
(SCL) across a 2 min resting period. There was a subgroup of ASD adults with
significantly lower resting SCL. These individuals demonstrated poorer emotion
recognition, tended to judge faces more negatively, and had atypical
relationships between SCL and affective empathy. In contrast, low cognitive
empathy was a feature of all ASD adults. These findings have important
implications for clinical interventions and future studies investigating
autonomic functioning in ASDs.

Copyright © 2013. Published by Elsevier B.V.

PMID: 23628291  [PubMed - as supplied by publisher]
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  • 15) PLoS One. 2013 Apr 24;8(4):e62189. doi: 10.1371/journal.pone.0062189. Print 2013.

    The BTBR Mouse Model of Autism Spectrum Disorders Has Learning and Attentional Impairments and Alterations in Acetylcholine and Kynurenic Acid in Prefrontal Cortex.

    McTighe SM, Neal SJ, Lin Q, Hughes ZA, Smith DG.

Neuroscience Research Unit, Pfizer Global Research and Development, Cambridge,
Massachusetts, United States of America.

Autism is a complex spectrum of disorders characterized by core behavioral
deficits in social interaction, communication, repetitive stereotyped behaviors
and restricted interests. Autism frequently presents with additional cognitive
symptoms, including attentional deficits and intellectual disability. Preclinical
models are important tools for studying the behavioral domains and biological
underpinnings of autism, and potential treatment targets. The inbred BTBR T+tf/J 
(BTBR) mouse strain has been used as an animal model of core behavioral deficits 
in autism. BTBR mice exhibit repetitive behaviors and deficits in sociability and
communication, but other aspects of their cognitive phenotype, including
attentional performance, are not well characterized. We examined the attentional 
abilities of BTBR mice in the 5-choice serial reaction time task (5-CSRTT) using 
an automated touchscreen testing apparatus. The 5-CSRTT is an analogue of the
human continuous performance task of attention, and so both the task and
apparatus have translational relevance to human touchscreen cognitive testing. We
also measured basal extracellular levels of a panel of neurotransmitters within
the medial prefrontal cortex, a brain region critically important for performing 
the 5-CSRTT. We found that BTBR mice have increased impulsivity, defined as an
inability to withhold responding, and decreased motivation, as compared to
C57Bl/6J mice. Both of these features characterize attentional deficit disorders 
in humans. BTBR mice also display decreased accuracy in detecting short stimuli, 
lower basal levels of extracellular acetylcholine and higher levels of kynurenic 
acid within the prefrontal cortex. Intact cholinergic transmission in prefrontal 
cortex is required for accurate performance of the 5-CSRTT, consequently this
cholinergic deficit may underlie less accurate performance in BTBR mice. Based on
our findings that BTBR mice have attentional impairments and alterations in a key
neural substrate of attention, we propose that they may be valuable for studying 
mechanisms for treatment of cognitive dysfunction in individuals with attention
deficits and autism.

PMID: 23638000  [PubMed - in process]
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  • 16) PLoS One. 2013 Apr 18;8(4):e61365. doi: 10.1371/journal.pone.0061365. Print 2013.

    Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders.

    Tropeano M, Ahn JW, Dobson RJ, Breen G, Rucker J, Dixit A, Pal DK, McGuffin P,
Farmer A, White PS, Andrieux J, Vassos E, Ogilvie CM, Curran S, Collier DA.

MRC Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry,
King's College London, London, United Kingdom.

Copy number variants (CNVs) at chromosome 16p13.11 have been associated with a
range of neurodevelopmental disorders including autism, ADHD, intellectual
disability and schizophrenia. Significant sex differences in prevalence, course
and severity have been described for a number of these conditions but the
biological and environmental factors underlying such sex-specific features remain
unclear. We tested the burden and the possible sex-biased effect of CNVs at
16p13.11 in a sample of 10,397 individuals with a range of neurodevelopmental
conditions, clinically referred for array comparative genomic hybridisation
(aCGH); cases were compared with 11,277 controls. In order to identify candidate 
phenotype-associated genes, we performed an interval-based analysis and
investigated the presence of ohnologs at 16p13.11; finally, we searched the
DECIPHER database for previously identified 16p13.11 copy number variants. In the
clinical referral series, we identified 46 cases with CNVs of variable size at
16p13.11, including 28 duplications and 18 deletions. Patients were referred for 
various phenotypes, including developmental delay, autism, speech delay, learning
difficulties, behavioural problems, epilepsy, microcephaly and physical
dysmorphisms. CNVs at 16p13.11 were also present in 17 controls. Association
analysis revealed an excess of CNVs in cases compared with controls (OR = 2.59;
p = 0.0005), and a sex-biased effect, with a significant enrichment of CNVs only 
in the male subgroup of cases (OR = 5.62; p = 0.0002), but not in females
(OR = 1.19, p = 0.673). The same pattern of results was also observed in the
DECIPHER sample. Interval-based analysis showed a significant enrichment of case 
CNVs containing interval II (OR = 2.59; p = 0.0005), located in the 0.83 Mb
genomic region between 15.49-16.32 Mb, and encompassing the four ohnologs NDE1,
MYH11, ABCC1 and ABCC6. Our data confirm that duplications and deletions at
16p13.11 represent incompletely penetrant pathogenic mutations that predispose to
a range of neurodevelopmental disorders, and suggest a sex-limited effect on the 
penetrance of the pathological phenotypes at the 16p13.11 locus.

PMID: 23637818  [PubMed - in process]
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  • 17) Future Neurol. 2013 Jan 1;8(1):29-42.

    The expanding genomic landscape of autism: discovering the 'forest' beyond the 'trees'

    Hu VW.

Department of Biochemistry & Molecular Medicine, The George Washington
University, School of Medicine & Health Sciences, 2300 Eye St., N.W., Washington,
DC 20037, USA Tel.: +1 202 994 8431 valhu@gwu.edu.

Autism spectrum disorders are neurodevelopmental disorders characterized by
significant deficits in reciprocal social interactions, impaired communication
and restricted, repetitive behaviors. As autism spectrum disorders are among the 
most heritable of neuropsychiatric disorders, much of autism research has focused
on the search for genetic variants in protein-coding genes (i.e., the 'trees').
However, no single gene can account for more than 1% of the cases of autism
spectrum disorders. Yet, genome-wide association studies have often identified
statistically significant associations of genetic variations in regions of DNA
that do not code for proteins (i.e., intergenic regions). There is increasing
evidence that such noncoding regions are actively transcribed and may participate
in the regulation of genes, including genes on different chromosomes. This
article summarizes evidence that suggests that the research spotlight needs to be
expanded to encompass far-reaching gene-regulatory mechanisms that include a
variety of epigenetic modifications, as well as noncoding RNA (i.e., the
'forest'). Given that noncoding RNA represents over 90% of the transcripts in
most cells, we may be observing just the 'tip of the iceberg' or the 'edge of the
forest' in the genomic landscape of autism.

PMID: 23637569  [PubMed]
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  • 18) Eur J Hum Genet. 2013 May 1. doi: 10.1038/ejhg.2013.88. [Epub ahead of print]

    Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders.

    Nava C, Keren B, Mignot C, Rastetter A, Chantot-Bastaraud S, Faudet A, Fonteneau 
E, Amiet C, Laurent C, Jacquette A, Whalen S, Afenjar A, Périsse D, Doummar D,
Dorison N, Leboyer M, Siffroi JP, Cohen D, Brice A, Héron D, Depienne C.

1] INSERM, U975 (CRICM), Institut du cerveau et de la moelle épinière (ICM),
Hôpital Pitié-Salpêtrière, Paris, France [2] CNRS 7225 (CRICM), Hôpital
Pitié-Salpêtrière, Paris, France [3] Université Pierre et Marie Curie-Paris-6
(UPMC), UMR_S 975, Paris, France [4] AP-HP, Hôpital Pitié-Salpêtrière,
Département de Génétique et de Cytogénétique, Unité fonctionnelle de génétique
clinique, Paris, France.

Copy number variants (CNVs) have repeatedly been found to cause or predispose to 
autism spectrum disorders (ASDs). For diagnostic purposes, we screened 194
individuals with ASDs for CNVs using Illumina SNP arrays. In several probands, we
also analyzed candidate genes located in inherited deletions to unmask autosomal 
recessive variants. Three CNVs, a de novo triplication of chromosome 15q11-q12 of
paternal origin, a deletion on chromosome 9p24 and a de novo 3q29 deletion, were 
identified as the cause of the disorder in one individual each. An autosomal
recessive cause was considered possible in two patients: a homozygous 1p31.1
deletion encompassing PTGER3 and a deletion of the entire DOCK10 gene associated 
with a rare hemizygous missense variant. We also identified multiple private or
recurrent CNVs, the majority of which were inherited from asymptomatic parents.
Although highly penetrant CNVs or variants inherited in an autosomal recessive
manner were detected in rare cases, our results mainly support the hypothesis
that most CNVs contribute to ASDs in association with other CNVs or point
variants located elsewhere in the genome. Identification of these genetic
interactions in individuals with ASDs constitutes a formidable challenge.European
Journal of Human Genetics advance online publication, 1 May 2013; (2013) 0,
000-000. doi:10.1038/ejhg.2013.88.

PMID: 23632794  [PubMed - as supplied by publisher]
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  • 19) Eur J Hum Genet. 2013 May 1. doi: 10.1038/ejhg.2013.67. [Epub ahead of print]

    Reciprocal deletion and duplication at 2q23.1 indicates a role for MBD5 in autism spectrum disorder.

    Mullegama SV, Rosenfeld JA, Orellana C, van Bon BW, Halbach S, Repnikova EA,
Brick L, Li C, Dupuis L, Rosello M, Aradhya S, Stavropoulos DJ, Manickam K,
Mitchell E, Hodge JC, Talkowski ME, Gusella JF, Keller K, Zonana J, Schwartz S,
Pyatt RE, Waggoner DJ, Shaffer LG, Lin AE, de Vries BB, Mendoza-Londono R, Elsea 
SH.

Department of Human and Molecular Genetics, Virginia Commonwealth University
School of Medicine, Richmond, VA, USA.

Copy number variations associated with abnormal gene dosage have an important
role in the genetic etiology of many neurodevelopmental disorders, including
intellectual disability (ID) and autism. We hypothesize that the chromosome
2q23.1 region encompassing MBD5 is a dosage-dependent region, wherein deletion or
duplication results in altered gene dosage. We previously established the 2q23.1 
microdeletion syndrome and report herein 23 individuals with 2q23.1 duplications,
thus establishing a complementary duplication syndrome. The observed phenotype
includes ID, language impairments, infantile hypotonia and gross motor delay,
behavioral problems, autistic features, dysmorphic facial features (pinnae
anomalies, arched eyebrows, prominent nose, small chin, thin upper lip), and
minor digital anomalies (fifth finger clinodactyly and large broad first toe).
The microduplication size varies among all cases and ranges from 68 kb to
53.7 Mb, encompassing a region that includes MBD5, an important factor in
methylation patterning and epigenetic regulation. We previously reported that
haploinsufficiency of MBD5 is the primary causal factor in 2q23.1 microdeletion
syndrome and that mutations in MBD5 are associated with autism. In this study, we
demonstrate that MBD5 is the only gene in common among all duplication cases and 
that overexpression of MBD5 is likely responsible for the core clinical features 
present in 2q23.1 microduplication syndrome. Phenotypic analyses suggest that
2q23.1 duplication results in a slightly less severe phenotype than the
reciprocal deletion. The features associated with a deletion, mutation or
duplication of MBD5 and the gene expression changes observed support MBD5 as a
dosage-sensitive gene critical for normal development.European Journal of Human
Genetics advance online publication, 1 May 2013; doi:10.1038/ejhg.2013.67.

PMID: 23632792  [PubMed - as supplied by publisher]
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  • 20) Am J Psychiatry. 2013 May 3. doi: 10.1176/appi.ajp.2013.12101352. [Epub ahead of print]

    "Selfish Spermatogonial Selection": A Novel Mechanism for the Association Between Advanced Paternal Age and Neurodevelopmental Disorders.

    Goriely A, McGrath JJ, Hultman CM, Wilkie AO, Malaspina D.

There is robust evidence from epidemiological studies that the offspring of older
fathers have an increased risk of neurodevelopmental disorders, such as
schizophrenia and autism. The authors present a novel mechanism that may
contribute to this association. Because the male germ cell undergoes many more
cell divisions across the reproductive age range, copy errors taking place in the
paternal germline are associated with de novo mutations in the offspring of older
men. Recently it has been recognized that somatic mutations in male germ cells
that modify proliferation through dysregulation of the RAS protein pathway can
lead to within-testis expansion of mutant clonal lines. First identified in
association with rare disorders related to paternal age (e.g., Apert syndrome,
achondroplasia), this process is known as "selfish spermatogonial selection."
This mechanism favors propagation of germ cells carrying pathogenic mutations,
increasingly skews the mutational profile of sperm as men age, and enriches de
novo mutations in the offspring of older fathers that preferentially affect
specific cellular signaling pathways. This mechanism not only offers a
parsimonious explanation for the association between advanced paternal age and
various neurodevelopmental disorders but also provides insights into the genetic 
architecture (role of de novo mutations), neurobiological correlates (altered
cell cycle), and some epidemiological features of these disorders. The authors
outline hypotheses to test this model. Given the secular changes for delayed
parenthood in most societies, this hypothesis has important public health
implications.

PMID: 23639989  [PubMed - as supplied by publisher]
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  • 21) J Neurodev Disord. 2013 May 2;5(1):11. [Epub ahead of print]

    Autism and the broad autism phenotype: familial patterns and intergenerational transmission.

    Sasson NJ, Lam KS, Parlier M, Daniels JL, Piven J.

BACKGROUND: Features of the Broad Autism Phenotype (BAP) are disproportionately
prevalent in parents of a child with autism, highlighting familial patterns
indicative of heritability. It is unclear, however, whether the presence of BAP
features in both parents confers an increased liability for autism. The current
study explores whether the presence of BAP features in two biological parents
occurs more frequently in parents of a child with autism relative to comparison
parents, whether parental pairs of a child with autism more commonly consist of
one or two parents with BAP features, and whether these features are associated
with severity of autism behaviors in probands. METHOD: Seven hundred eleven
parents of a child with an autism spectrum disorder and 981 comparison parents
completed the Broad Autism Phenotype Questionnaire. Parents of a child with
autism also completed the Social Communication Questionnaire. RESULTS: Although
parental pairs of a child with autism were more likely than comparison parental
pairs to have both parents characterized by the presence of the BAP, they more
commonly consisted of a single parent with BAP features. The presence of the BAP 
in parents was associated with the severity of autism behaviors in probands, with
the lowest severity occurring for children of parental pairs in which neither
parent exhibited a BAP feature. Severity did not differ between children of two
affected parents and those of just one. CONCLUSIONS: Collectively, these findings
indicate that parental pairs of children with autism frequently consist of a
single parent with BAP characteristics and suggest that future studies searching 
for implicated genes may benefit from a more narrow focus that identifies the
transmitting parent. The evidence of intergenerational transmission reported here
also provides further confirmation of the high heritability of autism that is
unaccounted for by the contribution of de novo mutations currently emphasized in 
the field of autism genetics.

PMID: 23639131  [PubMed - as supplied by publisher]
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  • 22) J Child Psychol Psychiatry. 2013 May 3. doi: 10.1111/jcpp.12079. [Epub ahead of print]

    Social communication disorder outside autism? A diagnostic classification approach to delineating pragmatic language impairment, high functioning autism and specific language impairment.

    Gibson J, Adams C, Lockton E, Green J.

Department of Developmental Psychiatry, University of Cambridge, Cambridge, UK.

BACKGROUND: Developmental disorders of language and communication present
considerable diagnostic challenges due to overlapping of symptomatology and
uncertain aetiology. We aimed to further elucidate the behavioural and linguistic
profile associated with impairments of social communication occurring outside of 
an autism diagnosis. METHODS: Six to eleven year olds diagnosed with pragmatic
language impairment (PLI), high functioning autism (HFA) or specific language
impairment (SLI) were compared on measures of social interaction with peers (PI),
restricted and repetitive behaviours/interests (RRBIs) and language ability. Odds
ratios (OR) from a multinomial logistic regression were used to determine the
importance of each measure to diagnostic grouping. MANOVA was used to investigate
differences in subscale scores for the PI measure. RESULTS: Greater degrees of PI
difficulties (OR = 1.22, 95% CI = 1.05-1.41), RRBI (OR = 1.23, 95%
CI = 1.06-1.42) and expressive language ability (OR = 1.16, 95% CI = 1.03-1.30)
discriminated HFA from PLI. PLI was differentiated from SLI by elevated PI
difficulties (OR = 0.82, 95% CI = 0.70-0.96) and higher expressive language
ability (OR = 0.88, 95% CI = 0.77-0.98), but indistinguishable from SLI using
RRBI (OR = 1.01, 95% CI=0.94-1.09). A significant effect of group on PI subscales
was observed (θ = 1.38, F(4, 56) = 19.26, p < .01) and PLI and HFA groups shared 
a similar PI subscale profile. CONCLUSIONS: Results provide empirical support for
a conceptualisation of PLI as a developmental impairment distinguishable from HFA
by absence of RRBIs and by the presence of expressive language difficulties. PI
difficulties appear elevated in PLI compared with SLI, but may be less pervasive 
than in HFA. Findings are discussed with reference to the proposed new category
of 'social communication disorder' in DSM-5.

© 2013 The Authors Journal of Child Psychology and Psychiatry © 2013 Association 
for Child and Adolescent Mental Health.

PMID: 23639107  [PubMed - as supplied by publisher]
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  • 23) Genes Brain Behav. 2013 May 2. doi: 10.1111/gbb.12046. [Epub ahead of print]

    Human alpha- and beta-NRXN1 isoforms rescue behavioral impairments of C. elegans neurexin-deficient mutants.

    Calahorro F, Ruiz-Rubio M.

Department of Genetics, University of Córdoba.; Maimónides Institute of
Biomedical Research (IMIBIC), 14071, Córdoba, Spain.

Neurexins are cell adhesion proteins that interact with neuroligin and other
ligands at the synapse. In humans, mutations in neurexin or neuroligin genes have
been associated with autism and other mental disorders. The human neurexin and
neuroligin genes are orthologous to the C. elegans genes nrx-1 and nlg-1,
respectively. Here we show that nrx-1-deficient mutants are defective in
exploratory capacity, sinusoidal postural movements and gentle touch response.
Interestingly, the exploratory behavioral phenotype observed in nrx-1 mutants was
markedly different to nlg-1-deficient mutants; thus, while the former had a
"hyper-reversal" phenotype increasing the number of changes of direction with
respect to the wild type strain, the nlg-1 mutants presented a "hypo-reversal"
phenotype. On the other hand, the nrx-1- and nlg-1-defective mutants showed
similar abnormal sinusoidal postural movement phenotypes. The response of these
mutant strains to aldicarb (acetylcholinesterase inhibitor), levamisole (ACh
agonist) and pentylenetetrazole (GABA receptor antagonist), suggested that the
varying behavioral phenotypes were caused by defects in ACh and/or GABA inputs.
The defective behavioral phenotypes of nrx-1-deficient mutants were rescued in
transgenic strains expressing either human alpha- or beta-NRXN-1 isoforms under
the worm nrx-1 promoter. A previous report had shown that human and rat
neuroligins were functional in C. elegans. Together, these results suggest that
the functional mechanism underpinning both neuroligin and neurexin in the
nematode are comparable to human. In this sense the nematode might constitute a
simple in vivo model for understanding basic mechanisms involved in neurological 
diseases for which neuroligin and neurexin are implicated in having a role.

This article is protected by copyright. All rights reserved.

PMID: 23638761  [PubMed - as supplied by publisher]
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  • 24) Autism Res. 2013 May 7. doi: 10.1002/aur.1300. [Epub ahead of print]

    Association between MTHFR Gene Polymorphisms and the Risk of Autism Spectrum Disorders: A Meta-Analysis.

    Pu D, Shen Y, Wu J.

State Key Laboratory of Reproductive Medicine, Nanjing Medical University,
Nanjing, Jiangsu, China; Department of Obstetrics and Gynecology, The First
Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.

Methylenetetrahydrofolate reductase (MTHFR) is essential for DNA biosynthesis and
the epigenetic process of DNA methylation, and its gene polymorphisms have been
implicated as risk factors for birth defects, neurological disorders, and
cancers. However, reports on the association of MTHFR polymorphisms with autism
spectrum disorders (ASD) are inconclusive. Therefore, we investigated the
relationship of the MTHFR polymorphisms (C677T and A1298C) and the risk of ASD by
meta-analysis. Up to December 2012, eight case-control studies involving 1672
patients with ASD and 6760 controls were included for meta-analysis. The results 
showed that the C677T polymorphism was associated with significantly increased
ASD risk in all the comparison models [T vs. C allele (frequency of allele): odds
ratio (OR) = 1.42, 95% confidence interval (CI): 1.09-1.85; CT vs. CC
(heterozygote): OR = 1.48, 95% CI: 1.09-2.00; TT vs. CC (homozygote): OR = 1.86, 
95% CI: 1.08-3.20; CT+TT vs. CC (dominant model): OR = 1.56, 95% CI: 1.12-2.18;
and TT vs. CC+CT (recessive model): OR = 1.51, 95% CI: 1.02-2.22], whereas the
A1298C polymorphism was found to be significantly associated with reduced ASD
risk but only in a recessive model (CC vs. AA+AC: OR = 0.73, 95% CI: 0.56-0.97). 
In addition, we stratified the patient population based on whether they were from
a country with food fortification of folic acid or not. The meta-analysis showed 
that the C677T polymorphism was found to be associated with ASD only in children 
from countries without food fortification. Our study indicated that the MTHFR
C677T polymorphism contributes to increased ASD risk, and periconceptional folic 
acid may reduce ASD risk in those with MTHFR 677C>T polymorphism. Autism Res
2013, ●●: ●●-●●. © 2013 International Society for Autism Research, Wiley
Periodicals, Inc.

© 2013 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 23653228  [PubMed - as supplied by publisher]
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