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Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder.

January 13, 2016 - 8:19am
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Whole genome sequencing reveals a de novo SHANK3 mutation in familial autism spectrum disorder.

PLoS One. 2015;10(2):e0116358

Authors: Nemirovsky SI, Córdoba M, Zaiat JJ, Completa SP, Vega PA, González-Morón D, Medina NM, Fabbro M, Romero S, Brun B, Revale S, Ogara MF, Pecci A, Marti M, Vazquez M, Turjanski A, Kauffman MA

Abstract
INTRODUCTION: Clinical genomics promise to be especially suitable for the study of etiologically heterogeneous conditions such as Autism Spectrum Disorder (ASD). Here we present three siblings with ASD where we evaluated the usefulness of Whole Genome Sequencing (WGS) for the diagnostic approach to ASD.
METHODS: We identified a family segregating ASD in three siblings with an unidentified cause. We performed WGS in the three probands and used a state-of-the-art comprehensive bioinformatic analysis pipeline and prioritized the identified variants located in genes likely to be related to ASD. We validated the finding by Sanger sequencing in the probands and their parents.
RESULTS: Three male siblings presented a syndrome characterized by severe intellectual disability, absence of language, autism spectrum symptoms and epilepsy with negative family history for mental retardation, language disorders, ASD or other psychiatric disorders. We found germline mosaicism for a heterozygous deletion of a cytosine in the exon 21 of the SHANK3 gene, resulting in a missense sequence of 5 codons followed by a premature stop codon (NM_033517:c.3259_3259delC, p.Ser1088Profs*6).
CONCLUSIONS: We reported an infrequent form of familial ASD where WGS proved useful in the clinic. We identified a mutation in SHANK3 that underscores its relevance in Autism Spectrum Disorder.

PMID: 25646853 [PubMed - indexed for MEDLINE]

Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with emotional and cognitive empathy.

January 13, 2016 - 8:19am
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Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with emotional and cognitive empathy.

Horm Behav. 2015 Jan;67:60-5

Authors: Uzefovsky F, Shalev I, Israel S, Edelman S, Raz Y, Mankuta D, Knafo-Noam A, Ebstein RP

Abstract
Empathy is the ability to recognize and share in the emotions of others. It can be considered a multifaceted concept with cognitive and emotional aspects. Little is known regarding the underlying neurochemistry of empathy and in the current study we used a neurogenetic approach to explore possible brain neurotransmitter pathways contributing to cognitive and emotional empathy. Both the oxytocin receptor (OXTR) and the arginine vasopressin receptor 1a (AVPR1a) genes contribute to social cognition in both animals and humans and hence are prominent candidates for contributing to empathy. The following research examined the associations between polymorphisms in these two genes and individual differences in emotional and cognitive empathy in a sample of 367 young adults. Intriguingly, we found that emotional empathy was associated solely with OXTR, whereas cognitive empathy was associated solely with AVPR1a. Moreover, no interaction was observed between the two genes and measures of empathy. The current findings contribute to our understanding of the distinct neurogenetic pathways involved in cognitive and emotional empathy and underscore the pervasive role of both oxytocin and vasopressin in modulating human emotions.

PMID: 25476609 [PubMed - indexed for MEDLINE]

Cerebellar oxidative DNA damage and altered DNA methylation in the BTBR T+tf/J mouse model of autism and similarities with human post mortem cerebellum.

January 13, 2016 - 8:19am
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Cerebellar oxidative DNA damage and altered DNA methylation in the BTBR T+tf/J mouse model of autism and similarities with human post mortem cerebellum.

PLoS One. 2014;9(11):e113712

Authors: Shpyleva S, Ivanovsky S, de Conti A, Melnyk S, Tryndyak V, Beland FA, James SJ, Pogribny IP

Abstract
The molecular pathogenesis of autism is complex and involves numerous genomic, epigenomic, proteomic, metabolic, and physiological alterations. Elucidating and understanding the molecular processes underlying the pathogenesis of autism is critical for effective clinical management and prevention of this disorder. The goal of this study is to investigate key molecular alterations postulated to play a role in autism and their role in the pathophysiology of autism. In this study we demonstrate that DNA isolated from the cerebellum of BTBR T+tf/J mice, a relevant mouse model of autism, and from human post-mortem cerebellum of individuals with autism, are both characterized by an increased levels of 8-oxo-7-hydrodeoxyguanosine (8-oxodG), 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC). The increase in 8-oxodG and 5mC content was associated with a markedly reduced expression of the 8-oxoguanine DNA-glycosylase 1 (Ogg1) and increased expression of de novo DNA methyltransferases 3a and 3b (Dnmt3a and Dnmt3b). Interestingly, a rise in the level of 5hmC occurred without changes in the expression of ten-eleven translocation expression 1 (Tet1) and Tet2 genes, but significantly correlated with the presence of 8-oxodG in DNA. This finding and similar elevation in 8-oxodG in cerebellum of individuals with autism and in the BTBR T+tf/J mouse model warrant future large-scale studies to specifically address the role of OGG1 alterations in pathogenesis of autism.

PMID: 25423485 [PubMed - indexed for MEDLINE]

LEGO: a novel method for gene set over-representation analysis by incorporating network-based gene weights.

January 12, 2016 - 8:17am

LEGO: a novel method for gene set over-representation analysis by incorporating network-based gene weights.

Sci Rep. 2016;6:18871

Authors: Dong X, Hao Y, Wang X, Tian W

Abstract
Pathway or gene set over-representation analysis (ORA) has become a routine task in functional genomics studies. However, currently widely used ORA tools employ statistical methods such as Fisher's exact test that reduce a pathway into a list of genes, ignoring the constitutive functional non-equivalent roles of genes and the complex gene-gene interactions. Here, we develop a novel method named LEGO (functional Link Enrichment of Gene Ontology or gene sets) that takes into consideration these two types of information by incorporating network-based gene weights in ORA analysis. In three benchmarks, LEGO achieves better performance than Fisher and three other network-based methods. To further evaluate LEGO's usefulness, we compare LEGO with five gene expression-based and three pathway topology-based methods using a benchmark of 34 disease gene expression datasets compiled by a recent publication, and show that LEGO is among the top-ranked methods in terms of both sensitivity and prioritization for detecting target KEGG pathways. In addition, we develop a cluster-and-filter approach to reduce the redundancy among the enriched gene sets, making the results more interpretable to biologists. Finally, we apply LEGO to two lists of autism genes, and identify relevant gene sets to autism that could not be found by Fisher.

PMID: 26750448 [PubMed - in process]

Novel systems modeling methodology in comparative microbial metabolomics: identifying key enzymes and metabolites implicated in autism spectrum disorders.

January 12, 2016 - 8:17am
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Novel systems modeling methodology in comparative microbial metabolomics: identifying key enzymes and metabolites implicated in autism spectrum disorders.

Int J Mol Sci. 2015;16(4):8949-67

Authors: Heberling C, Dhurjati P

Abstract
Autism spectrum disorders are a group of mental illnesses highly correlated with gastrointestinal dysfunction. Recent studies have shown that there may be one or more microbial "fingerprints" in terms of the composition characterizing individuals with autism, which could be used for diagnostic purposes. This paper proposes a computational approach whereby metagenomes characteristic of "healthy" and autistic individuals are artificially constructed via genomic information, analyzed for the enzymes coded within, and then these enzymes are compared in detail. This is a text mining application. A custom-designed online application was built and used for the comparative metabolomics study and made publically available. Several of the enzyme-catalyzing reactions involved with the amino acid glutamate were curiously missing from the "autism" microbiome and were coded within almost every organism included in the "control" microbiome. Interestingly, there exists a leading hypothesis regarding autism and glutamate involving a neurological excitation/inhibition imbalance; but the association with this study is unclear. The results included data on the transsulfuration and transmethylation pathways, involved with oxidative stress, also of importance to autism. The results from this study are in alignment with leading hypotheses in the field, which is impressive, considering the purely in silico nature of this study. The present study provides new insight into the complex metabolic interactions underlying autism, and this novel methodology has potential to be useful for developing new hypotheses. However, limitations include sparse genome data availability and conflicting literature experimental data. We believe our software tool and methodology has potential for having great utility as data become more available, comprehensive and reliable.

PMID: 25913376 [PubMed - indexed for MEDLINE]

Modulation of the genome and epigenome of individuals susceptible to autism by environmental risk factors.

January 12, 2016 - 8:17am
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Modulation of the genome and epigenome of individuals susceptible to autism by environmental risk factors.

Int J Mol Sci. 2015;16(4):8699-718

Authors: Koufaris C, Sismani C

Abstract
Diverse environmental factors have been implicated with the development of autism spectrum disorders (ASD). Genetic factors also underlie the differential vulnerability to environmental risk factors of susceptible individuals. Currently the way in which environmental risk factors interact with genetic factors to increase the incidence of ASD is not well understood. A greater understanding of the metabolic, cellular, and biochemical events involved in gene x environment interactions in ASD would have important implications for the prevention and possible treatment of the disorder. In this review we discuss various established and more alternative processes through which environmental factors implicated in ASD can modulate the genome and epigenome of genetically-susceptible individuals.

PMID: 25903146 [PubMed - indexed for MEDLINE]

Autism spectrum disorder and epilepsy: Disorders with a shared biology.

January 12, 2016 - 8:17am
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Autism spectrum disorder and epilepsy: Disorders with a shared biology.

Epilepsy Behav. 2015 Jun;47:191-201

Authors: Lee BH, Smith T, Paciorkowski AR

Abstract
There is an increasing recognition of clinical overlap in patients presenting with epilepsy and autism spectrum disorder (ASD), and a great deal of new information regarding the genetic causes of both disorders is available. Several biological pathways appear to be involved in both disease processes, including gene transcription regulation, cellular growth, synaptic channel function, and maintenance of synaptic structure. We review several genetic disorders where ASD and epilepsy frequently co-occur, and we discuss the screening tools available for practicing neurologists and epileptologists to help determine which patients should be referred for formal ASD diagnostic evaluation. Finally, we make recommendations regarding the workflow of genetic diagnostic testing available for children with both ASD and epilepsy. This article is part of a Special Issue entitled "Autism and Epilepsy".

PMID: 25900226 [PubMed - indexed for MEDLINE]

Reversal of social deficits by subchronic oxytocin in two autism mouse models.

January 10, 2016 - 8:12am

Reversal of social deficits by subchronic oxytocin in two autism mouse models.

Neuropharmacology. 2015 Dec 31;

Authors: Teng BL, Nikolova VD, Riddick NV, Agster KL, Crowley JJ, Baker LK, Koller BH, Pedersen CA, Jarstfer MB, Moy SS

Abstract
Social deficits are a hallmark feature of autism spectrum disorder (ASD) and related developmental syndromes. Although there is no standard treatment for social dysfunction, clinical studies have identified oxytocin as a potential therapeutic with prosocial efficacy. We have previously reported that peripheral oxytocin treatment can increase sociability and ameliorate repetitive stereotypy in adolescent mice from the C58/J model of ASD-like behavior. In the present study, we determined that prosocial oxytocin effects were not limited to the adolescent period, since C58/J mice, tested in adulthood, demonstrated significant social preference up to 2 weeks following subchronic oxytocin treatment. Oxytocin was also evaluated in adult mice with underexpression of the N-methyl-D-aspartate receptor NR1 subunit (encoded by Grin1), a genetic model of autism- and schizophrenia-like behavior. Subchronic oxytocin had striking prosocial efficacy in male Grin1 knockdown mice; in contrast, chronic regimens with clozapine (66 mg/kg/day) or risperidone (2 mg/kg/day) failed to reverse deficits in sociability. Neither the subchronic oxytocin regimen, nor chronic treatment with clozapine or risperidone, reversed impaired prepulse inhibition in the Grin1 knockdown mice. Overall, these studies demonstrate oxytocin can enhance sociability in mouse models with divergent genotypes and behavioral profiles, adding to the evidence that this neurohormone could have therapeutic prosocial efficacy across a spectrum of developmental disorders.

PMID: 26748053 [PubMed - as supplied by publisher]

RYR2, PTDSS1 and AREG genes are implicated in a Lebanese population-based study of copy number variation in autism.

January 9, 2016 - 8:06am

RYR2, PTDSS1 and AREG genes are implicated in a Lebanese population-based study of copy number variation in autism.

Sci Rep. 2016;6:19088

Authors: Soueid J, Kourtian S, Makhoul NJ, Makoukji J, Haddad S, Ghanem SS, Kobeissy F, Boustany RM

Abstract
Autism Spectrum Disorders (ASDs) are a group of neurodevelopmental disorders characterized by ritualistic-repetitive behaviors and impaired verbal and non-verbal communication. Objectives were to determine the contribution of genetic variation to ASDs in the Lebanese. Affymetrix Cytogenetics Whole-Genome 2.7 M and CytoScan(™) HD Arrays were used to detect CNVs in 41 Lebanese autistic children and 35 non-autistic, developmentally delayed and intellectually disabled patients. 33 normal participants were used as controls. 16 de novo CNVs and 57 inherited CNVs, including recognized pathogenic 16p11.2 duplications and 2p16.3 deletions were identified. A duplication at 1q43 classified as likely pathogenic encompasses RYR2 as a potential ASD candidate gene. This previously identified CNV has been classified as both pathogenic, and, of uncertain significance. A duplication of unknown significance at 10q11.22, proposed as a modulator for phenotypic disease expression in Rett syndrome, was also identified. The novel potential autism susceptibility genes PTDSS1 and AREG were uncovered and warrant further genetic and functional analyses. Previously described and novel genetic targets in ASD were identified in Lebanese families with autism. These findings may lead to improved diagnosis of ASDs and informed genetic counseling, and may also lead to untapped therapeutic targets applicable to Lebanese and non-Lebanese patients.

PMID: 26742492 [PubMed - in process]

Autism in siblings often caused by different faulty genes, study says.

January 9, 2016 - 8:06am
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Autism in siblings often caused by different faulty genes, study says.

Am J Med Genet A. 2015 May;167A(5):ix

Authors: Levenson D

PMID: 25885072 [PubMed - indexed for MEDLINE]

MEIS2 involvement in cardiac development, cleft palate, and intellectual disability.

January 9, 2016 - 8:06am
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MEIS2 involvement in cardiac development, cleft palate, and intellectual disability.

Am J Med Genet A. 2015 May;167A(5):1142-6

Authors: Louw JJ, Corveleyn A, Jia Y, Hens G, Gewillig M, Devriendt K

Abstract
MEIS2 has been associated with cleft palate and cardiac septal defects as well as varying degrees of intellectual disability. We present a female patient with a more severe phenotype compared to previous reported patients. She has multiple congenital malformations; cleft palate and congenital heart defect characterized by septal defects and aortic coarctation. She has severe feeding problems, facial dysmorphism, severely delayed gross motor and verbal development, and autism spectrum disorder. Facial dysmorphism consisting of bitemporal narrowing, arched and laterally extended eyebrows, mild upslanting palpebral fissures, deep-set eyes, a tented upper lip, thin upper vermilion, full lower vermilion, broad first ray of hands and feet, a gap between the first and second toes, and syndactyly of toe II-III. Exome sequencing revealed a non-frameshift deletion (c.998_1000del:p.Arg333del) of three base pairs in the MEIS2 homeodomain. The more severe phenotype is most probably due to dominant-negative mechanisms. This is the first report showing a de novo small intragenic mutation in MEIS2 and further confirms the important role of this gene in normal development.

PMID: 25712757 [PubMed - indexed for MEDLINE]

Novel features of 3q29 deletion syndrome: Results from the 3q29 registry.

January 8, 2016 - 8:03am

Novel features of 3q29 deletion syndrome: Results from the 3q29 registry.

Am J Med Genet A. 2016 Jan 6;

Authors: Glassford MR, Rosenfeld JA, Freedman AA, Zwick ME, Unique Rare Chromosome Disorder Support Group, Mulle JG

Abstract
3q29 deletion syndrome is caused by a recurrent, typically de novo heterozygous 1.6 Mb deletion, but because incidence of the deletion is rare (1 in 30,000 births) the phenotype is not well described. To characterize the range of phenotypic manifestations associated with 3q29 deletion syndrome, we have developed an online registry (3q29deletion.org) for ascertainment of study subjects and phenotypic data collection via Internet-based survey instruments. We report here on data collected during the first 18 months of registry operation, from 44 patients. This is the largest cohort of 3q29 deletion carriers ever assembled and surveyed in a systematic way. Our data reveal that 28% of registry participants report neuropsychiatric phenotypes, including anxiety disorder, panic attacks, depression, bipolar disorder, and schizophrenia. Other novel findings include a high prevalence (64%) of feeding problems in infancy and reduced weight at birth for 3q29 deletion carriers (average reduction 13.9 oz (394 g), adjusted for gestational age and sex, P = 6.5e-07). We further report on the frequency of heart defects, autism, recurrent ear infections, gastrointestinal phenotypes, and dental phenotypes, among others. We also report on the expected timing of delayed developmental milestones. This is the most comprehensive description of the 3q29 deletion phenotype to date. These results are clinically actionable toward improving patient care for 3q29 deletion carriers, and can guide the expectations of physicians and parents. These data also demonstrate the value of patient-reported outcomes to reveal the full phenotypic spectrum of rare genomic disorders. © 2016 Wiley Periodicals, Inc.

PMID: 26738761 [PubMed - as supplied by publisher]

The autism-associated gene chromodomain helicase DNA-binding protein 8 (CHD8) regulates noncoding RNAs and autism-related genes.

January 8, 2016 - 8:03am
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The autism-associated gene chromodomain helicase DNA-binding protein 8 (CHD8) regulates noncoding RNAs and autism-related genes.

Transl Psychiatry. 2015;5:e568

Authors: Wilkinson B, Grepo N, Thompson BL, Kim J, Wang K, Evgrafov OV, Lu W, Knowles JA, Campbell DB

Abstract
Chromodomain helicase DNA-binding protein 8 (CHD8) was identified as a leading autism spectrum disorder (ASD) candidate gene by whole-exome sequencing and subsequent targeted-sequencing studies. De novo loss-of-function mutations were identified in 12 individuals with ASD and zero controls, accounting for a highly significant association. Small interfering RNA-mediated knockdown of CHD8 in human neural progenitor cells followed by RNA sequencing revealed that CHD8 insufficiency results in altered expression of 1715  genes, including both protein-coding and noncoding RNAs. Among the 10 most changed transcripts, 4 (40%) were noncoding RNAs. The transcriptional changes among protein-coding genes involved a highly interconnected network of genes that are enriched in neuronal development and in previously identified ASD candidate genes. These results suggest that CHD8 insufficiency may be a central hub in neuronal development and ASD risk.

PMID: 25989142 [PubMed - indexed for MEDLINE]

The promise of multi-omics and clinical data integration to identify and target personalized healthcare approaches in autism spectrum disorders.

January 8, 2016 - 8:03am
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The promise of multi-omics and clinical data integration to identify and target personalized healthcare approaches in autism spectrum disorders.

OMICS. 2015 Apr;19(4):197-208

Authors: Higdon R, Earl RK, Stanberry L, Hudac CM, Montague E, Stewart E, Janko I, Choiniere J, Broomall W, Kolker N, Bernier RA, Kolker E

Abstract
Complex diseases are caused by a combination of genetic and environmental factors, creating a difficult challenge for diagnosis and defining subtypes. This review article describes how distinct disease subtypes can be identified through integration and analysis of clinical and multi-omics data. A broad shift toward molecular subtyping of disease using genetic and omics data has yielded successful results in cancer and other complex diseases. To determine molecular subtypes, patients are first classified by applying clustering methods to different types of omics data, then these results are integrated with clinical data to characterize distinct disease subtypes. An example of this molecular-data-first approach is in research on Autism Spectrum Disorder (ASD), a spectrum of social communication disorders marked by tremendous etiological and phenotypic heterogeneity. In the case of ASD, omics data such as exome sequences and gene and protein expression data are combined with clinical data such as psychometric testing and imaging to enable subtype identification. Novel ASD subtypes have been proposed, such as CHD8, using this molecular subtyping approach. Broader use of molecular subtyping in complex disease research is impeded by data heterogeneity, diversity of standards, and ineffective analysis tools. The future of molecular subtyping for ASD and other complex diseases calls for an integrated resource to identify disease mechanisms, classify new patients, and inform effective treatment options. This in turn will empower and accelerate precision medicine and personalized healthcare.

PMID: 25831060 [PubMed - indexed for MEDLINE]

Mutations and Modeling of the Chromatin Remodeler CHD8 Define an Emerging Autism Etiology.

January 7, 2016 - 8:00am

Mutations and Modeling of the Chromatin Remodeler CHD8 Define an Emerging Autism Etiology.

Front Neurosci. 2015;9:477

Authors: Barnard RA, Pomaville MB, O'Roak BJ

Abstract
Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder with a strong but complex genetic component. Recent family based exome-sequencing strategies have identified recurrent de novo mutations at specific genes, providing strong evidence for ASD risk, but also highlighting the extreme genetic heterogeneity of the disorder. However, disruptions in these genes converge on key molecular pathways early in development. In particular, functional enrichment analyses have found that there is a bias toward genes involved in transcriptional regulation, such as chromatin modifiers. Here we review recent genetic, animal model, co-expression network, and functional genomics studies relating to the high confidence ASD risk gene, CHD8. CHD8, a chromatin remodeling factor, may serve as a "master regulator" of a common ASD etiology. Individuals with a CHD8 mutation show an ASD subtype that includes similar physical characteristics, such as macrocephaly and prolonged GI problems including recurrent constipation. Similarly, animal models of CHD8 disruption exhibit enlarged head circumference and reduced gut motility phenotypes. Systems biology approaches suggest CHD8 and other candidate ASD risk genes are enriched during mid-fetal development, which may represent a critical time window in ASD etiology. Transcription and CHD8 binding site profiles from cell and primary tissue models of early development indicate that CHD8 may also positively regulate other candidate ASD risk genes through both direct and indirect means. However, continued study is needed to elucidate the mechanism of regulation as well as identify which CHD8 targets are most relevant to ASD risk. Overall, these initial studies suggest the potential for common ASD etiologies and the development of personalized treatments in the future.

PMID: 26733790 [PubMed]

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome.

January 7, 2016 - 8:00am

KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome.

Proc Natl Acad Sci U S A. 2016 Jan 5;

Authors: Tang X, Kim J, Zhou L, Wengert E, Zhang L, Wu Z, Carromeu C, Muotri AR, Marchetto MC, Gage FH, Chen G

Abstract
Rett syndrome is a severe form of autism spectrum disorder, mainly caused by mutations of a single gene methyl CpG binding protein 2 (MeCP2) on the X chromosome. Patients with Rett syndrome exhibit a period of normal development followed by regression of brain function and the emergence of autistic behaviors. However, the mechanism behind the delayed onset of symptoms is largely unknown. Here we demonstrate that neuron-specific K(+)-Cl(-) cotransporter2 (KCC2) is a critical downstream gene target of MeCP2. We found that human neurons differentiated from induced pluripotent stem cells from patients with Rett syndrome showed a significant deficit in KCC2 expression and consequently a delayed GABA functional switch from excitation to inhibition. Interestingly, overexpression of KCC2 in MeCP2-deficient neurons rescued GABA functional deficits, suggesting an important role of KCC2 in Rett syndrome. We further identified that RE1-silencing transcriptional factor, REST, a neuronal gene repressor, mediates the MeCP2 regulation of KCC2. Because KCC2 is a slow onset molecule with expression level reaching maximum later in development, the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. Our studies suggest that restoring KCC2 function in Rett neurons may lead to a potential treatment for Rett syndrome.

PMID: 26733678 [PubMed - as supplied by publisher]

Monogenic Mouse Models of Autism Spectrum Disorders: Common Mechanisms and Missing Links.

January 7, 2016 - 8:00am

Monogenic Mouse Models of Autism Spectrum Disorders: Common Mechanisms and Missing Links.

Neuroscience. 2015 Dec 27;

Authors: Hulbert SW, Jiang YH

Abstract
Autism Spectrum Disorders (ASDs) present unique challenges in the fields of genetics and neurobiology because of the clinical and molecular heterogeneity underlying these disorders. Genetic mutations found in ASD patients provide opportunities to dissect the molecular and circuit mechanisms underlying autistic behaviors using animal models. Ongoing studies of genetically modified models have offered critical insight into possible common mechanisms arising from different mutations, but links between molecular abnormalities and behavioral phenotypes remain elusive. The challenges encountered in modeling autism in mice demand a new analytic paradigm that integrates behavioral analysis with circuit-level analysis in genetically modified models with strong construct validity.

PMID: 26733386 [PubMed - as supplied by publisher]

Annual Research Review: Discovery science strategies in studies of the pathophysiology of child and adolescent psychiatric disorders: promises and limitations.

January 7, 2016 - 8:00am

Annual Research Review: Discovery science strategies in studies of the pathophysiology of child and adolescent psychiatric disorders: promises and limitations.

J Child Psychol Psychiatry. 2016 Jan 6;

Authors: Zhao Y, Castellanos FX

Abstract
BACKGROUND AND SCOPE: Psychiatric science remains descriptive, with a categorical nosology intended to enhance interobserver reliability. Increased awareness of the mismatch between categorical classifications and the complexity of biological systems drives the search for novel frameworks including discovery science in Big Data. In this review, we provide an overview of incipient approaches, primarily focused on classically categorical diagnoses such as schizophrenia (SZ), autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD), but also reference convincing, if focal, advances in cancer biology, to describe the challenges of Big Data and discovery science, and outline approaches being formulated to overcome existing obstacles.
FINDINGS: A paradigm shift from categorical diagnoses to a domain/structure-based nosology and from linear causal chains to complex causal network models of brain-behavior relationship is ongoing. This (r)evolution involves appreciating the complexity, dimensionality, and heterogeneity of neuropsychiatric data collected from multiple sources ('broad' data) along with data obtained at multiple levels of analysis, ranging from genes to molecules, cells, circuits, and behaviors ('deep' data). Both of these types of Big Data landscapes require the use and development of robust and powerful informatics and statistical approaches. Thus, we describe Big Data analysis pipelines and the promise and potential limitations in using Big Data approaches to study psychiatric disorders.
CONCLUSION: We highlight key resources available for psychopathological studies and call for the application and development of Big Data approaches to dissect the causes and mechanisms of neuropsychiatric disorders and identify corresponding biomarkers for early diagnosis.

PMID: 26732133 [PubMed - as supplied by publisher]

Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability.

January 7, 2016 - 8:00am
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Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability.

Eur J Hum Genet. 2015 May;23(5):628-32

Authors: Vergult S, Dheedene A, Meurs A, Faes F, Isidor B, Janssens S, Gautier A, Le Caignec C, Menten B

Abstract
Voltage-gated calcium channels have an important role in neurotransmission. Aberrations affecting genes encoding the alpha subunit of these channels have been associated with epilepsy and neuropsychiatric disorders such as autism or schizophrenia. Here we report three patients with a genomic aberration affecting the CACNA2D1 gene encoding the α2δ subunit of these voltage-gated calcium channels. All three patients present with epilepsy and intellectual disability pinpointing the CACNA2D1 gene as an interesting candidate gene for these clinical features. Besides these characteristics, patient 2 also presents with obesity with hyperinsulinism, which is very likely to be caused by deletion of the CD36 gene.

PMID: 25074461 [PubMed - indexed for MEDLINE]

Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study.

January 6, 2016 - 7:58am

Absence of evidence for increase in risk for autism or attention-deficit hyperactivity disorder following antidepressant exposure during pregnancy: a replication study.

Transl Psychiatry. 2016;6:e708

Authors: Castro VM, Kong SW, Clements CC, Brady R, Kaimal AJ, Doyle AE, Robinson EB, Churchill SE, Kohane IS, Perlis RH

Abstract
Multiple studies have examined the risk of prenatal antidepressant exposure and risk for autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD), with inconsistent results. Precisely estimating such risk, if any, is of great importance in light of the need to balance such risk with the benefit of depression and anxiety treatment. We developed a method to integrate data from multiple New England health systems, matching offspring and maternal health data in electronic health records to characterize diagnoses and medication exposure. Children with ASD or ADHD were matched 1:3 with children without neurodevelopmental disorders. Association between maternal antidepressant exposure and ASD or ADHD liability was examined using logistic regression, adjusting for potential sociodemographic and psychiatric confounding variables. In new cohorts of 1245 ASD cases and 1701 ADHD cases, along with age-, sex- and socioeconomic status matched controls, neither disorder was significantly associated with prenatal antidepressant exposure in crude or adjusted models (adjusted odds ratio 0.90, 95% confidence interval 0.50-1.54 for ASD; 0.97, 95% confidence interval 0.53-1.69 for ADHD). Pre-pregnancy antidepressant exposure significantly increased risk for both disorders. These results suggest that prior reports of association between prenatal antidepressant exposure and neurodevelopmental disease are likely to represent a false-positive finding, which may arise in part through confounding by indication. They further demonstrate the potential to integrate data across electronic health records studies spanning multiple health systems to enable efficient pharmacovigilance investigation.

PMID: 26731445 [PubMed - as supplied by publisher]

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