pubmed: autism and genetics

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Human-directed social behaviour in dogs shows significant heritability.

February 24, 2015 - 7:46am

Human-directed social behaviour in dogs shows significant heritability.

Genes Brain Behav. 2015 Feb 19;

Authors: Persson ME, Roth LS, Johnsson M, Wright D, Jensen P

Abstract
Through domestication and co-evolution with humans, dogs have developed abilities to attract human attention, e.g. in a manner of seeking assistance when faced with a problem solving task. The aims of this study were to investigate within breed variation in human-directed contact seeking in dogs and to estimate its genetic basis. To do this, 498 research beagles, bred and kept under standardised conditions, were tested in an unsolvable problem task. Contact seeking behaviours recorded included both eye contact and physical interactions. Behavioural data was summarised through a principal component analysis, resulting in four components: test interactions, social interactions, eye contact and physical contact. Females scored significantly higher on social interactions and physical contact and age had an effect on eye contact scores. Narrow sense heritabilities (h(2) ) of the two largest components were estimated at 0.32 and 0.23 but were not significant for the last two components. These results show that within the studied dog population, behavioural variation in human-directed social behaviours was sex dependent and that the utilisation of eye contact seeking increased with age and experience. Hence, heritability estimates indicate a significant genetic contribution to the variation found in human-directed social interactions, suggesting that social skills in dogs have a genetic basis, but can also be shaped and enhanced through individual experiences. This research gives the opportunity to further investigate the genetics behind dogs' social skills, which could also play a significant part into research on human social disorders such as autism.

PMID: 25703740 [PubMed - as supplied by publisher]

Diagnostic Yield of Chromosomal Microarray Analysis in a Cohort of Patients with Autism Spectrum Disorders from a Highly Consanguineous Population.

February 24, 2015 - 7:46am

Diagnostic Yield of Chromosomal Microarray Analysis in a Cohort of Patients with Autism Spectrum Disorders from a Highly Consanguineous Population.

J Autism Dev Disord. 2015 Feb 24;

Authors: Al-Mamari W, Al-Saegh A, Al-Kindy A, Bruwer Z, Al-Murshedi F, Al-Thihli K

Abstract
Autism Spectrum Disorders are a complicated group of disorders characterized with heterogeneous genetic etiologies. The genetic investigations for this group of disorders have expanded considerably over the past decade. In our study we designed a tired approach and studied the diagnostic yield of chromosomal microarray analysis on patients referred to the Genetic and Developmental Medicine clinic in Sultan Qaboos University in Oman for autism spectrum disorders in a highly consanguineous population. Copy number variants were seen in 27 % of our studied cohort of patients and it was strongly associated with dysmorphic features and congenital anomalies.

PMID: 25703031 [PubMed - as supplied by publisher]

Mouse IDGenes: a reference database for genetic interactions in the developing mouse brain.

February 24, 2015 - 7:46am
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Mouse IDGenes: a reference database for genetic interactions in the developing mouse brain.

Database (Oxford). 2014;2014

Authors: Matthes M, Preusse M, Zhang J, Schechter J, Mayer D, Lentes B, Theis F, Prakash N, Wurst W, Trümbach D

Abstract
UNLABELLED: The study of developmental processes in the mouse and other vertebrates includes the understanding of patterning along the anterior-posterior, dorsal-ventral and medial- lateral axis. Specifically, neural development is also of great clinical relevance because several human neuropsychiatric disorders such as schizophrenia, autism disorders or drug addiction and also brain malformations are thought to have neurodevelopmental origins, i.e. pathogenesis initiates during childhood and adolescence. Impacts during early neurodevelopment might also predispose to late-onset neurodegenerative disorders, such as Parkinson's disease. The neural tube develops from its precursor tissue, the neural plate, in a patterning process that is determined by compartmentalization into morphogenetic units, the action of local signaling centers and a well-defined and locally restricted expression of genes and their interactions. While public databases provide gene expression data with spatio-temporal resolution, they usually neglect the genetic interactions that govern neural development. Here, we introduce Mouse IDGenes, a reference database for genetic interactions in the developing mouse brain. The database is highly curated and offers detailed information about gene expressions and the genetic interactions at the developing mid-/hindbrain boundary. To showcase the predictive power of interaction data, we infer new Wnt/β-catenin target genes by machine learning and validate one of them experimentally. The database is updated regularly. Moreover, it can easily be extended by the research community. Mouse IDGenes will contribute as an important resource to the research on mouse brain development, not exclusively by offering data retrieval, but also by allowing data input.
DATABASE URL: http://mouseidgenes.helmholtz-muenchen.de.

PMID: 25145340 [PubMed - indexed for MEDLINE]

Neuropathology of 22q11 deletion syndrome in an infant.

February 24, 2015 - 7:46am
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Neuropathology of 22q11 deletion syndrome in an infant.

Pediatr Dev Pathol. 2014 Sep-Oct;17(5):386-92

Authors: Wu P, Teot L, Murdoch G, Monaghan-Nichols AP, McFadden K

Abstract
The 22q11 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans and one of the chromosomal conditions most associated with psychosis and autism spectrum disorder. To date, only 2 neuropathologic studies of 22q11DS have been reported. Findings included polymicrogyria, neuronal heterotopias, excess subcortical white-matter (interstitial) neurons, significant white-matter gliosis/hypomyelination, and microvasculopathy. Here, we report on a 3-month-old infant with documented 22q11DS, tetralogy of Fallot, and pulmonary atresia. The brain exhibited tortuous cerebral vessels and proportionately smaller occipital lobes. Histologic examination revealed cerebral white-matter pathology and subtle differences in cortical lamination, including an excess of interstitial white-matter neurons compared with a sample of age-matched controls. There was a 15% increase in DARPP-32+ medium spiny neurons in the anterior-superior caudate. In this first neuropathologic report of an infant with 22q11DS, the findings were similar to previously reported manifestations and are likely secondary to perfusion issues, developmental microvasculopathy, and abnormal frontal cortical development.

PMID: 25019421 [PubMed - indexed for MEDLINE]

The involvement of serotonin polymorphisms in autistic spectrum symptomatology.

February 24, 2015 - 7:46am
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The involvement of serotonin polymorphisms in autistic spectrum symptomatology.

Psychiatr Genet. 2014 Aug;24(4):158-63

Authors: Hervás A, Toma C, Romarís P, Ribasés M, Salgado M, Bayes M, Balmaña N, Cormand B, Maristany M, Guijarro S, Arranz MJ

Abstract
BACKGROUND: Autism spectrum disorders (ASD) are highly inherited developmental syndromes, resulting from a complex interaction between environmental and genetic factors. To date, only a limited number of genetic variants have been discovered with respect to autism, and their contribution to the development of the disorder has not been clearly determined. Investigation of specific autistic symptomatology may improve the chances of identifying related genes and may help to better understand these disorders.
MATERIALS AND METHODS: We investigated the contribution of 80 genetic variants in 15 serotonin genes to ASD phenotypes [intelligence quotation (IQ), intellectual disability (ID) and language onset delay (LD)] in a cohort of 141 children and young adults (121 male patients and 20 female patients, average age 14.5±5.1 years).
RESULTS: Two polymorphisms in the HTR2B gene, rs10194776 and rs16827801, were associated with IQ (P=0.0004 and 0.003, respectively), ID (P=0.02 and 0.03) and LD (P=0.04 and 0.004). Nominal associations were also detected between the ASD phenotypes investigated and 5-HT2A, 5-HT4 and 5-HT6 genetic variants.
CONCLUSION: Our study provides evidence of the contribution of serotonergic variants to IQ, ID and LD in ASD patients.

PMID: 24887447 [PubMed - indexed for MEDLINE]

A pilot proteomic study of protein markers in autism spectrum disorder.

February 24, 2015 - 7:46am
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A pilot proteomic study of protein markers in autism spectrum disorder.

Electrophoresis. 2014 Jul;35(14):2046-54

Authors: Ngounou Wetie AG, Wormwood K, Thome J, Dudley E, Taurines R, Gerlach M, Woods AG, Darie CC

Abstract
Autism spectrum disorder (ASD) diagnosis is increasing, with 1/88 children believed to be affected by the disorder, with a most recent survey suggesting numbers as high as 1/50. Treatment and understanding of ASD causes is a pressing health concern. ASD protein biomarkers may provide clues about ASD cause. Protein biomarkers for ASDs could be used for ASD diagnosis, subtyping, treatment monitoring, and identifying therapeutic targets. Here, we analyzed the sera from seven children with ASD and seven matched controls using Tricine gel electrophoresis (Tricine-PAGE) and LC-MS/MS. Overall, we found increased levels of apolipoproteins ApoA1 and ApoA4, involved in cholesterol metabolism and of serum paraoxanase/arylesterase 1, involved in preventing oxidative damage, in the sera of children with ASD, compared with their matched controls. All three proteins are predicted to interact with each other and are parts of high-density lipoproteins. Further studies are needed to validate these findings in larger subject numbers.

PMID: 24687421 [PubMed - indexed for MEDLINE]

Allelic expression analysis in the brain suggests a role for heterogeneous insults affecting epigenetic processes in autism spectrum disorders.

February 24, 2015 - 7:46am
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Allelic expression analysis in the brain suggests a role for heterogeneous insults affecting epigenetic processes in autism spectrum disorders.

Hum Mol Genet. 2014 Aug 1;23(15):4111-24

Authors: Ben-David E, Shohat S, Shifman S

Abstract
Monoallelic expression, including genomic imprinting, X-chromosome inactivation and random monoallelic expression of autosomal genes are epigenetic phenomena. Genes that are expressed in a monoallelic way may be more vulnerable to genetic or epigenetic mutations. Thus, comprehensive exploration of monoallelic expression in human brains may shed light on complex brain disorders. Autism-related disorders are known to be associated with imprinted genes on chromosome 15. However, it is not clear whether other imprinted regions or other types of monoallelic expression are associated with autism spectrum disorder (ASD). Here, we performed a genome-wide survey of allele expression imbalance (AEI) in the human brain using single-nucleotide polymorphisms (SNPs), in 18 individuals with ASD and 15 controls. Individuals with ASD had the most extreme number of monoallelic expressed SNPs in both the autosomes and the X chromosome. In two cases that were studied in detail, the monoallelic expression was confined to specific brain region or cell type. Using these data, we were also able to define the allelic expression status of known imprinted genes in the human brain and to identify abnormal imprinting in an individual with ASD. Lastly, we developed an analysis of individual-level expression, focusing on the difference of each individual from the mean. We found that individuals with ASD had more genes that were up- or down-regulated in an individual-specific manner. We also identified pathways perturbed in specific individuals. These results underline the heterogeneity in gene regulation in ASD, at the level of both allelic and total expression.

PMID: 24659497 [PubMed - indexed for MEDLINE]

Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome.

February 24, 2015 - 7:46am
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Decreased cerebral spinal fluid neurotransmitter levels in Smith-Lemli-Opitz syndrome.

J Inherit Metab Dis. 2014 May;37(3):415-20

Authors: Sparks SE, Wassif CA, Goodwin H, Conley SK, Lanham DC, Kratz LE, Hyland K, Gropman A, Tierney E, Porter FD

Abstract
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital anomaly syndrome with cognitive impairment and a distinct behavioral phenotype that includes autistic features. SLOS is caused by a defect in 3β-hydroxysterol Δ(7)-reductase which leads to decreased cholesterol levels and elevated cholesterol precursors, specifically 7- and 8-dehydrocholesterol. However, the pathological processes contributing to the neurological abnormalities in SLOS have not been defined. In view of prior data suggesting defects in SLOS in vesicular release and given the association of altered serotonin metabolism with autism, we were interested in measuring neurotransmitter metabolite levels in SLOS to assess their potential to be used as biomarkers in therapeutic trials. We measured cerebral spinal fluid levels of serotonin and dopamine metabolites, 5-hydroxyindoleacetic acid (5HIAA) and homovanillic acid (HVA) respectively, in 21 SLOS subjects. Results were correlated with the SLOS anatomical severity score, Aberrant Behavior Checklist scores and concurrent sterol biochemistry. Cerebral spinal fluid (CSF) levels of both 5HIAA and HVA were significantly reduced in SLOS subjects. In individual patients, the levels of both 5HIAA and HVA were reduced to a similar degree. CSF neurotransmitter metabolite levels did not correlate with either CSF sterols or behavioral measures. This is the first study demonstrating decreased levels of CSF neurotransmitter metabolites in SLOS. We propose that decreased levels of neurotransmitters in SLOS are caused by a sterol-related defect in synaptic vesicle formation and that CSF 5HIAA and HVA will be useful biomarkers in development of future therapeutic trials.

PMID: 24500076 [PubMed - indexed for MEDLINE]

Shared familial transmission of autism spectrum and attention-deficit/hyperactivity disorders.

February 24, 2015 - 7:46am
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Shared familial transmission of autism spectrum and attention-deficit/hyperactivity disorders.

J Child Psychol Psychiatry. 2014 Jul;55(7):819-27

Authors: Musser ED, Hawkey E, Kachan-Liu SS, Lees P, Roullet JB, Goddard K, Steiner RD, Nigg JT

Abstract
BACKGROUND: To determine whether familial transmission is shared between autism spectrum disorders and attention-deficit/hyperactivity disorder, we assessed the prevalence, rates of comorbidity, and familial transmission of both disorders in a large population-based sample of children during a recent 7 year period.
METHODS: Study participants included all children born to parents with the Kaiser Permanente Northwest (KPNW) Health Plan between 1 January 1998 and 31 December 2004 (n = 35,073). Children and mothers with physician-identified autism spectrum disorders (ASD) and/or attention-deficit/hyperactivity disorder (ADHD) were identified via electronic medical records maintained for all KPNW members.
RESULTS: Among children aged 6-12 years, prevalence was 2.0% for ADHD and 0.8% for ASD; within those groups, 0.2% of the full sample (19% of the ASD sample and 9.6% of the ADHD sample) had co-occurring ASD and ADHD, when all children were included. When mothers had a diagnosis of ADHD, first born offspring were at 6-fold risk of ADHD alone (OR = 5.02, p < .0001) and at 2.5-fold risk of ASD alone (OR = 2.52, p < .01). Results were not accounted for by maternal age, child gestational age, child gender, and child race.
CONCLUSIONS: Autism spectrum disorders shares familial transmission with ADHD. ADHD and ASD have a partially overlapping diathesis.

PMID: 24444366 [PubMed - indexed for MEDLINE]

Cortical overgrowth in fetuses with isolated ventriculomegaly.

February 24, 2015 - 7:46am
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Cortical overgrowth in fetuses with isolated ventriculomegaly.

Cereb Cortex. 2014 Aug;24(8):2141-50

Authors: Kyriakopoulou V, Vatansever D, Elkommos S, Dawson S, McGuinness A, Allsop J, Molnár Z, Hajnal J, Rutherford M

Abstract
Mild cerebral ventricular enlargement is associated with schizophrenia, autism, epilepsy, and attention-deficit/hyperactivity disorder. Fetal ventriculomegaly is the most common central nervous system (CNS) abnormality affecting 1% of fetuses and is associated with cognitive, language, and behavioral impairments in childhood. Neurodevelopmental outcome is partially predictable by the 2-dimensional size of the ventricles in the absence of other abnormalities. We hypothesized that isolated fetal ventriculomegaly is a marker of altered brain development characterized by relative overgrowth and aimed to quantify brain growth using volumetric magnetic resonance imaging (MRI) in fetuses with isolated ventriculomegaly. Fetal brain MRI (1.5 T) was performed in 60 normal fetuses and 65 with isolated ventriculomegaly, across a gestational age range of 22-38 weeks. Volumetric analysis of the ventricles and supratentorial brain structures was performed on 3-dimensional reconstructed datasets. Fetuses with isolated ventriculomegaly had increased brain parenchyma volumes when compared with the control cohort (9.6%, P < 0.0001) with enlargement restricted to the cortical gray matter (17.2%, P = 0.002). The extracerebral cerebrospinal fluid and third and fourth ventricles were also enlarged. White matter, basal ganglia, and thalamic volumes were not significantly different between cohorts. The presence of relative cortical overgrowth in fetuses with ventriculomegaly may represent the neurobiological substrate for cognitive, language, and behavioral deficits in these children.

PMID: 23508710 [PubMed - indexed for MEDLINE]

Spatiotemporal 16p11.2 Protein Network Implicates Cortical Late Mid-Fetal Brain Development and KCTD13-Cul3-RhoA Pathway in Psychiatric Diseases.

February 20, 2015 - 7:26am

Spatiotemporal 16p11.2 Protein Network Implicates Cortical Late Mid-Fetal Brain Development and KCTD13-Cul3-RhoA Pathway in Psychiatric Diseases.

Neuron. 2015 Feb 18;85(4):742-754

Authors: Lin GN, Corominas R, Lemmens I, Yang X, Tavernier J, Hill DE, Vidal M, Sebat J, Iakoucheva LM

Abstract
The psychiatric disorders autism and schizophrenia have a strong genetic component, and copy number variants (CNVs) are firmly implicated. Recurrent deletions and duplications of chromosome 16p11.2 confer a high risk for both diseases, but the pathways disrupted by this CNV are poorly defined. Here we investigate the dynamics of the 16p11.2 network by integrating physical interactions of 16p11.2 proteins with spatiotemporal gene expression from the developing human brain. We observe profound changes in protein interaction networks throughout different stages of brain development and/or in different brain regions. We identify the late mid-fetal period of cortical development as most critical for establishing the connectivity of 16p11.2 proteins with their co-expressed partners. Furthermore, our results suggest that the regulation of the KCTD13-Cul3-RhoA pathway in layer 4 of the inner cortical plate is crucial for controlling brain size and connectivity and that its dysregulation by de novo mutations may be a potential determinant of 16p11.2 CNV deletion and duplication phenotypes.

PMID: 25695269 [PubMed - as supplied by publisher]

Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1.

February 20, 2015 - 7:26am

Gene expression analysis of human induced pluripotent stem cell-derived neurons carrying copy number variants of chromosome 15q11-q13.1.

Mol Autism. 2014;5:44

Authors: Germain ND, Chen PF, Plocik AM, Glatt-Deeley H, Brown J, Fink JJ, Bolduc KA, Robinson TM, Levine ES, Reiter LT, Graveley BR, Lalande M, Chamberlain SJ

Abstract
BACKGROUND: Duplications of the chromosome 15q11-q13.1 region are associated with an estimated 1 to 3% of all autism cases, making this copy number variation (CNV) one of the most frequent chromosome abnormalities associated with autism spectrum disorder (ASD). Several genes located within the 15q11-q13.1 duplication region including ubiquitin protein ligase E3A (UBE3A), the gene disrupted in Angelman syndrome (AS), are involved in neural function and may play important roles in the neurobehavioral phenotypes associated with chromosome 15q11-q13.1 duplication (Dup15q) syndrome.
METHODS: We have generated induced pluripotent stem cell (iPSC) lines from five different individuals containing CNVs of 15q11-q13.1. The iPSC lines were differentiated into mature, functional neurons. Gene expression across the 15q11-q13.1 locus was compared among the five iPSC lines and corresponding iPSC-derived neurons using quantitative reverse transcription PCR (qRT-PCR). Genome-wide gene expression was compared between neurons derived from three iPSC lines using mRNA-Seq.
RESULTS: Analysis of 15q11-q13.1 gene expression in neurons derived from Dup15q iPSCs reveals that gene copy number does not consistently predict expression levels in cells with interstitial duplications of 15q11-q13.1. mRNA-Seq experiments show that there is substantial overlap in the genes differentially expressed between 15q11-q13.1 deletion and duplication neurons, Finally, we demonstrate that UBE3A transcripts can be pharmacologically rescued to normal levels in iPSC-derived neurons with a 15q11-q13.1 duplication.
CONCLUSIONS: Chromatin structure may influence gene expression across the 15q11-q13.1 region in neurons. Genome-wide analyses suggest that common neuronal pathways may be disrupted in both the Angelman and Dup15q syndromes. These data demonstrate that our disease-specific stem cell models provide a new tool to decipher the underlying cellular and genetic disease mechanisms of ASD and may also offer a pathway to novel therapeutic intervention in Dup15q syndrome.

PMID: 25694803 [PubMed]

A case of autism spectrum disorder arising from a de novo missense mutation in POGZ.

February 20, 2015 - 7:26am

A case of autism spectrum disorder arising from a de novo missense mutation in POGZ.

J Hum Genet. 2015 Feb 19;

Authors: Fukai R, Hiraki Y, Yofune H, Tsurusaki Y, Nakashima M, Saitsu H, Tanaka F, Miyake N, Matsumoto N

Abstract
Autism spectrum disorder (ASD) is a clinically heterogeneous psychiatric disorder with various genetic backgrounds. Here, we report a novel mutation in the pogo transposable element-derived protein with zinc finger domain gene (POGZ) identified by trio-based whole exome sequencing. To date, a total of seven de novo POGZ mutations in ASD have been reported. POGZ contains a total of five functional domains, and this study reports the first de novo missense mutation in the centromere protein B-like DNA-binding domain. POGZ is highly expressed in the human fetal brain and is involved in mitosis and the regulation of neuronal proliferation. Therefore its loss-of-function or pathogenic missense mutations are likely to be causative of ASD.Journal of Human Genetics advance online publication, 19 February 2015; doi:10.1038/jhg.2015.13.

PMID: 25694107 [PubMed - as supplied by publisher]

MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus.

February 20, 2015 - 7:26am
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MET receptor tyrosine kinase controls dendritic complexity, spine morphogenesis, and glutamatergic synapse maturation in the hippocampus.

J Neurosci. 2014 Dec 3;34(49):16166-79

Authors: Qiu S, Lu Z, Levitt P

Abstract
The MET receptor tyrosine kinase (RTK), implicated in risk for autism spectrum disorder (ASD) and in functional and structural circuit integrity in humans, is a temporally and spatially regulated receptor enriched in dorsal pallial-derived structures during mouse forebrain development. Here we report that loss or gain of function of MET in vitro or in vivo leads to changes, opposite in nature, in dendritic complexity, spine morphogenesis, and the timing of glutamatergic synapse maturation onto hippocampus CA1 neurons. Consistent with the morphological and biochemical changes, deletion of Met in mutant mice results in precocious maturation of excitatory synapse, as indicated by a reduction of the proportion of silent synapses, a faster GluN2A subunit switch, and an enhanced acquisition of AMPA receptors at synaptic sites. Thus, MET-mediated signaling appears to serve as a mechanism for controlling the timing of neuronal growth and functional maturation. These studies suggest that mistimed maturation of glutamatergic synapses leads to the aberrant neural circuits that may be associated with ASD risk.

PMID: 25471559 [PubMed - indexed for MEDLINE]

Role of an adaptor protein Lin-7B in brain development: possible involvement in autism spectrum disorders.

February 20, 2015 - 7:26am
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Role of an adaptor protein Lin-7B in brain development: possible involvement in autism spectrum disorders.

J Neurochem. 2015 Jan;132(1):61-9

Authors: Mizuno M, Matsumoto A, Hamada N, Ito H, Miyauchi A, Jimbo EF, Momoi MY, Tabata H, Yamagata T, Nagata K

Abstract
Using comparative genomic hybridization analysis for an autism spectrum disorder (ASD) patient, a 73-Kb duplication at 19q13.33 (nt. 49 562 755-49 635 956) including LIN7B and 5 other genes was detected. We then identified a novel frameshift mutation in LIN7B in another ASD patient. Since LIN7B encodes a scaffold protein essential for neuronal function, we analyzed the role of Lin-7B in the development of cerebral cortex. Acute knockdown of Lin-7B with in utero electroporation caused a delay in neuronal migration during corticogenesis. When Lin-7B was knocked down in cortical neurons in one hemisphere, their axons failed to extend efficiently into the contralateral hemisphere after leaving the corpus callosum. Meanwhile, enhanced expression of Lin-7B had no effects on both cortical neuron migration and axon growth. Notably, silencing of Lin-7B did not affect the proliferation of neuronal progenitors and stem cells. Taken together, Lin-7B was found to play a pivotal role in corticogenesis through the regulation of excitatory neuron migration and interhemispheric axon growth, while further analyses are required to directly link functional defects of Lin-7B to ASD pathophysiology. Lin-7 plays a pivotal role as a scaffold protein in synaptic development and plasticity. Based on genetic analyses we identified mutations in LIN-7B gene in some ASD (autism-spectrum disorder) patients. Functional defects in Lin-7B caused abnormal neuronal migration and interhemispheric axon growth during mouse brain development. Thus, functional deficiency in Lin-7B could be implicated in clinical phenotypes in some ASD patients through bringing about abnormal cortical architecture.

PMID: 25196215 [PubMed - indexed for MEDLINE]

Cognitive styles in depressed children with and without comorbid conduct disorder.

February 20, 2015 - 7:26am
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Cognitive styles in depressed children with and without comorbid conduct disorder.

J Adolesc. 2014 Jul;37(5):622-31

Authors: Schepman K, Fombonne E, Collishaw S, Taylor E

Abstract
Little is known about patterns of cognitive impairment in depression comorbid with conduct disorder. The study included clinically depressed children with (N = 23) or without conduct disorder (N = 29), and controls without psychiatric disorder (N = 37). Cognitive biases typical of depression and patterns of social information processing were assessed. Both depressed groups had substantially higher rates of negative cognitive distortions, attributional biases and ruminative responses than non-depressed children. Children in the comorbid group made more hostile attributions and suggested more aggressive responses for dealing with threatening social situations, whilst children with depression only were more likely to be unassertive. Depression has a number of similar depressotypic cognitive biases whether or not complicated by conduct disorder, and may be potentially susceptible to similar interventions. The results also highlight the importance of recognising social information processing deficits when they occur and targeting those too, especially in comorbid presentations.

PMID: 24931565 [PubMed - indexed for MEDLINE]

Duplication Xp11.22-p14 in females: Does X-inactivation help in assessing their significance?

February 19, 2015 - 7:06am

Duplication Xp11.22-p14 in females: Does X-inactivation help in assessing their significance?

Am J Med Genet A. 2015 Mar;167(3):553-62

Authors: Evers C, Mitter D, Strobl-Wildemann G, Haug U, Hackmann K, Maas B, Janssen JW, Jauch A, Hinderhofer K, Moog U

Abstract
In females, large duplications in Xp often lead to preferential inactivation of the aberrant X chromosome and a normal phenotype. Recently, a recurrent ∼4.5 Mb microduplication of Xp11.22-p11.23 was found in females with developmental delay/intellectual disability and other neurodevelopmental disorders (speech development disorder, epilepsy or EEG anomalies, autism spectrum disorder, or behavioral disorder). Unexpectedly, most of them showed preferential inactivation of the normal X chromosome. We describe five female patients carrying de novo Xp duplications encompassing p11.23. Patient 1 carried the recurrent microduplication Xp11.22-p11.23, her phenotype and X-chromosome inactivation (XI) pattern was consistent with previous reports. The other four patients had novel Xp duplications. Two were monozygotic twins with a similar phenotype to Patient 1 and unfavorable XI skewing carrying an overlapping ∼5 Mb duplication of Xp11.23-p11.3. Patient 4 showed a duplication of ∼5.5 Mb comparable to the twins but had a more severe phenotype and unskewed XI. Patient 5 had a ∼8.5 Mb duplication Xp11.23-p11.4 and presented with mild ID, epilepsy, behavioral problems, and inconsistent results of XI analysis. A comparison of phenotype, size and location of the duplications and XI patterns in Patients 1-5 and previously reported females with overlapping duplications provides further evidence that microduplications encompassing Xp11.23 are associated with ID and other neurodevelopmental disorders in females. To further assess the implication of XI for female carriers, we recommend systematic analysis of XI pattern in any female with X imbalances that are known or suspected to be pathogenic. © 2015 Wiley Periodicals, Inc.

PMID: 25691408 [PubMed - in process]

Fetal DNA Methylation of Autism Spectrum Disorders (ASD) Candidate Genes: Association with Spontaneous Preterm Birth.

February 18, 2015 - 6:14am

Fetal DNA Methylation of Autism Spectrum Disorders (ASD) Candidate Genes: Association with Spontaneous Preterm Birth.

Am J Obstet Gynecol. 2015 Feb 13;

Authors: Behnia F, Parets SE, Kechichian T, Yin H, Dutta EH, Saade GR, Smith AK, Menon R

Abstract
OBJECTIVE: Autism Spectrum Disorder (ASD) is associated with preterm birth (PTB); though the reason underlying this relationship is still unclear. Our objective was to examine DNA methylation patterns of four ASD candidate genes in human fetal membranes from spontaneous PTB and uncomplicated term birth (TB).
STUDY DESIGN: A literature search for genes implicated in ASD yielded 14 candidate genes (OXTR, SHANK3, BCL2, RORA, EN2, RELN, MECP2, AUTS2, NLGN3, NRXN1, SLC6A4, UBE3A, GABA, AFF2) that were epigenetically modified in relation to ASD. DNA methylation in fetal leukocyte DNA in four of these genes (OXTR, SHANK3, BCL2 and RORA) associated with PTB in a previous study. This study evaluated DNA methylation, transcription (qPCR) and translation patterns (immunostaining and western blot) in fetal membrane from term labor (TL; n=14), term not in labor (TNIL; n=29) and spontaneous preterm birth (PTB; n=27). Statistical analysis was performed using ANOVA and a p-value of < 0.05 was significant.
RESULTS: Higher methylation of the OXTR promoter was seen in fetal membranes from PTB compared to TL or TNIL. No other gene showed any methylation differences between groups. Expression of OXTR was not different between groups but the 70 kDa OXTR protein was seen only in PTB, and immunostaining was more intense in PTB amniocytes than TL or TNIL.
CONCLUSION: Among the four genes studied, fetal membranes from PTB demonstrate differences in OXTR methylation and regulation and expression, suggesting that epigenetic alteration of this gene in fetal membrane may likely be indicating an in utero programing of this gene and serve as a surrogate in a subset of PTB. The usefulness of OXTR hypermethylation as a surrogate for link to ASD should be further evaluated in longitudinal and in vitro studies.

PMID: 25687563 [PubMed - as supplied by publisher]

How might epigenetic dysregulation in early embryonic life contribute to autism spectrum disorder?

February 18, 2015 - 6:14am

How might epigenetic dysregulation in early embryonic life contribute to autism spectrum disorder?

Epigenomics. 2015 Feb;7(1):1-4

Authors: Berko ER, Greally JM

PMID: 25687459 [PubMed - in process]

Genetic and Developmental Perspective of Language Abnormality in Autism and Schizophrenia: One Disease Occurring at Different Ages in Humans?

February 18, 2015 - 6:14am

Genetic and Developmental Perspective of Language Abnormality in Autism and Schizophrenia: One Disease Occurring at Different Ages in Humans?

Neuroscientist. 2015 Feb 16;

Authors: Wang HG, Jeffries JJ, Wang TF

Abstract
Language and communication through it are two of the defining features of normally developed human beings. However, both these functions are often impaired in autism and schizophrenia. In the former disorder, the problem usually emerges in early childhood (~2 years old) and typically includes a lack of communication. In the latter condition, the language problems usually occur in adolescence and adulthood and presents as disorganized speech. What are the fundamental mechanisms underlying these two disorders? Is there a shared genetic basis? Are the traditional beliefs about them true? Are there any common strategies for their prevention and management? To answer these questions, we searched PubMed by using autism, schizophrenia, gene, and language abnormality as keywords, and we reconsidered the basic concepts about these two diseases or syndromes. We found many functional genes, for example, FOXP2, COMT, GABRB3, and DISC1, are actually implicated in both of them. After observing the symptoms, genetic correlates, and temporal progression of these two disorders as well as their relationships more carefully, we now infer that the occurrence of these two diseases is likely developmentally regulated via interaction between the genome and the environment. Furthermore, we propose a unified view of autism and schizophrenia: a single age-dependently occurred disease that is newly named as Systemic Integral Disorder: if occurring in children before age 2, it is called autism; if in adolescence or a later age, it is called schizophrenia.

PMID: 25686622 [PubMed - as supplied by publisher]

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