pubmed: autism and genetics

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Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops.

March 18, 2016 - 8:14am

Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops.

Neuron. 2016 Mar 16;89(6):1131-1156

Authors: Mullins C, Fishell G, Tsien RW

Abstract
Understanding the mechanisms underlying autism spectrum disorders (ASDs) is a challenging goal. Here we review recent progress on several fronts, including genetics, proteomics, biochemistry, and electrophysiology, that raise motivation for forming a viable pathophysiological hypothesis. In place of a traditionally unidirectional progression, we put forward a framework that extends homeostatic hypotheses by explicitly emphasizing autoregulatory feedback loops and known synaptic biology. The regulated biological feature can be neuronal electrical activity, the collective strength of synapses onto a dendritic branch, the local concentration of a signaling molecule, or the relative strengths of synaptic excitation and inhibition. The sensor of the biological variable (which we have termed the homeostat) engages mechanisms that operate as negative feedback elements to keep the biological variable tightly confined. We categorize known ASD-associated gene products according to their roles in such feedback loops and provide detailed commentary for exemplar genes within each module.

PMID: 26985722 [PubMed - as supplied by publisher]

Characterization of molecular and cellular phenotypes associated with a heterozygous CNTNAP2 deletion using patient-derived hiPSC neural cells.

March 18, 2016 - 8:14am

Characterization of molecular and cellular phenotypes associated with a heterozygous CNTNAP2 deletion using patient-derived hiPSC neural cells.

NPJ Schizophr. 2015 Jun 24;1

Authors: Lee IS, Carvalho CM, Douvaras P, Ho SM, Hartley BJ, Zuccherato LW, Ladran IG, Siegel AJ, McCarthy S, Malhotra D, Sebat J, Rapoport J, Fossati V, Lupski JR, Levy DL, Brennand KJ

Abstract
Neurodevelopmental disorders, such as autism spectrum disorders (ASD) and schizophrenia (SZ), are complex disorders with a high degree of heritability. Genetic studies have identified several candidate genes associated with these disorders, including contactin-associated protein-like 2 (CNTNAP2). Traditionally, in animal models or in vitro, the function of CNTNAP2 has been studied by genetic deletion or transcriptional knockdown, which reduce the expression of the entire gene; however, it remains unclear whether the mutations identified in clinical settings are sufficient to alter CNTNAP2 expression in human neurons. Here, using human induced pluripotent stem cells (hiPSCs) derived from two individuals with a large (289kb) and heterozygous deletion in CNTNAP2 (affecting exons 14-15) and discordant clinical outcomes, we have characterized CNTNAP2 expression patterns in hiPSC neural progenitor cells (NPCs), two independent populations of hiPSC-derived neurons and hiPSC-derived oligodendrocyte precursor cells (OPCs). First, we observed exon-specific changes in CNTNAP2 expression in both carriers; although the expression of exons 14-15 is significantly decreased, the expression of other exons is upregulated. Second, we observed significant differences in patterns of allele-specific expression in CNTNAP2 carriers that were consistent with clinical outcome. Third, we observed a robust neural migration phenotype that correlated with diagnosis and exon- and allele-specific CNTNAP2 expression patterns, but not with genotype. In all, our data highlight the importance of considering the nature, location and regulation of mutated alleles when attempting to connect GWAS studies to gene function.

PMID: 26985448 [PubMed - as supplied by publisher]

Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression.

March 18, 2016 - 8:14am

Genes with high penetrance for syndromic and non-syndromic autism typically function within the nucleus and regulate gene expression.

Mol Autism. 2016;7:18

Authors: Casanova EL, Sharp JL, Chakraborty H, Sumi NS, Casanova MF

Abstract
BACKGROUND: Intellectual disability (ID), autism, and epilepsy share frequent yet variable comorbidities with one another. In order to better understand potential genetic divergence underlying this variable risk, we studied genes responsible for monogenic IDs, grouped according to their autism and epilepsy comorbidities.
METHODS: Utilizing 465 different forms of ID with known molecular origins, we accessed available genetic databases in conjunction with gene ontology (GO) to determine whether the genetics underlying ID diverge according to its comorbidities with autism and epilepsy and if genes highly penetrant for autism or epilepsy share distinctive features that set them apart from genes that confer comparatively variable or no apparent risk.
RESULTS: The genetics of ID with autism are relatively enriched in terms associated with nervous system-specific processes and structural morphogenesis. In contrast, we find that ID with highly comorbid epilepsy (HCE) is modestly associated with lipid metabolic processes while ID without autism or epilepsy comorbidity (ID only) is enriched at the Golgi membrane. Highly comorbid autism (HCA) genes, on the other hand, are strongly enriched within the nucleus, are typically involved in regulation of gene expression, and, along with IDs with more variable autism, share strong ties with a core protein-protein interaction (PPI) network integral to basic patterning of the CNS.
CONCLUSIONS: According to GO terminology, autism-related gene products are integral to neural development. While it is difficult to draw firm conclusions regarding IDs unassociated with autism, it is clear that the majority of HCA genes are tightly linked with general dysregulation of gene expression, suggesting that disturbances to the chronology of neural maturation and patterning may be key in conferring susceptibility to autism spectrum conditions.

PMID: 26985359 [PubMed]

MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high-resolution melting analysis for mutation scanning.

March 18, 2016 - 8:14am

MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high-resolution melting analysis for mutation scanning.

J Hum Genet. 2016 Mar 17;

Authors: Zahorakova D, Lelkova P, Gregor V, Magner M, Zeman J, Martasek P

Abstract
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder characterized by developmental regression with loss of motor, communication and social skills, onset of stereotypic hand movements and often seizures. RTT is primarily caused by de novo mutations in the methyl-CpG-binding protein 2 gene (MECP2). We established a high-resolution melting (HRM) technique for mutation scanning of the MECP2 gene and performed analyses in Czech patients with RTT, autism spectrum conditions and intellectual disability with Rett-like features. In the cases with confirmed MECP2 mutations, we determined X-chromosome inactivation (XCI), examined the relationships between genotype and clinical severity and evaluated the modifying influence of XCI. Our results demonstrate that HRM analysis is a reliable method for the detection of point mutations, small deletions and duplications in the MECP2 gene. We identified 29 pathogenic mutations in 75 girls, including four novel mutations: c.155_1189del1035;909_932inv;insC, c.573delC, c.857_858dupAA and c.1163_1200del38. Skewed XCI (ratio >75%) was found in 19.3% of the girls, but no gross divergence in clinical severity was observed. Our findings confirm a high mutation frequency in classic RTT (92%) and a correlation between the MECP2 mutation type and clinical severity. We also demonstrate limitations of XCI in explaining all of the phenotypic differences in RTT.Journal of Human Genetics advance online publication, 17 March 2016; doi:10.1038/jhg.2016.19.

PMID: 26984561 [PubMed - as supplied by publisher]

Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) - study protocol for a randomised controlled trial.

March 18, 2016 - 8:14am

Glutamatergic medication in the treatment of obsessive compulsive disorder (OCD) and autism spectrum disorder (ASD) - study protocol for a randomised controlled trial.

Trials. 2016;17(1):141

Authors: Häge A, Banaschewski T, Buitelaar JK, Dijkhuizen RM, Franke B, Lythgoe DJ, Mechler K, Williams SC, Dittmann RW, TACTICS Consortium

Abstract
BACKGROUND: Compulsivity is a cross-disorder trait underlying phenotypically distinct psychiatric disorders that emerge in childhood or adolescence. Despite the effectiveness of serotonergic compounds in the treatment of obsessive-compulsive disorder, treatment-resistant symptoms remaining in 40 to 60 % of patients present a pressing clinical problem. There are currently no medications that effectively treat the core impairments of autism spectrum disorder. There is an urgent need for the development of conceptually novel pharmacological strategies. Agents targeting glutamate neurotransmission, such as memantine, represent promising candidates. This proof-of-concept clinical study will allow pilot-testing of memantine for both clinical effectiveness and tolerability/safety. Memantine is an N-methyl-D-aspartate receptor antagonist, approved for the treatment of Alzheimer's dementia in a number of countries.
METHODS/DESIGN: This 12-week study has an add-on, randomised, double-blind, placebo-controlled design of treatment with memantine, including an up-titration phase (forced flexible dose design, 5-15 mg/day), in patients aged 6-17 years and 9 months with obsessive-compulsive disorder or autism spectrum disorder. It is planned to include patients with obsessive-compulsive disorder (N = 50) or autism spectrum disorder (N = 50) across four centres in three European countries. Patients will be randomly assigned to memantine or placebo in a 1:1 ratio. Primary objectives are the investigation of the effectiveness of memantine in paediatric patients for improving symptoms of compulsivity (primary outcome measure: total score on the Children's Yale-Brown Obsessive-Compulsive Scale) and to explore its tolerability and safety. Secondary objectives are to explore the effects of memantine at the level of structure, function and biochemistry of the fronto-striatal circuits, and to collect blood for genetic analyses and biomarkers. Tertiary objectives are to explore the role of new candidate genes and pathways for compulsivity by linking genes to clinical phenotypes, response to treatment, neurocognitive test performance, and key structural and functional neuroimaging measures of the fronto-striatal circuits and to explore biomarkers/proteomics for compulsivity traits.
DISCUSSION: This study is part of the large, translational project TACTICS ( http://www.tactics-project.eu/ ) that is funded by the European Union and investigates the neural, genetic and molecular factors involved in the pathogenesis of compulsivity. Its results will provide clinically relevant solid information on potential new mechanisms and medication treatment in obsessive-compulsive and autism spectrum disorders.
TRIAL REGISTRATION: EudraCT Number: 2014-003080-38 , date of registration: 14 July 2014.

PMID: 26983548 [PubMed - in process]

De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.

March 18, 2016 - 8:14am
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De novo SHANK3 mutation causes Rett syndrome-like phenotype in a female patient.

Am J Med Genet A. 2015 Jul;167(7):1593-6

Authors: Hara M, Ohba C, Yamashita Y, Saitsu H, Matsumoto N, Matsuishi T

Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder predominantly affecting females. Females with the MECP2 mutations exhibit a broad spectrum of clinical manifestations ranging from classical Rett syndrome to asymptomatic carriers. Mutations of genes encoding cyclin-dependent kinase-like 5 (CDKL5) and forkhead box G1 (FOXG1) are also found in early onset RTT variants. Here, we present the first report of a female patient with RTT-like phenotype caused by SHANK3 (SH3 and multiple ankylin repeat domain 3) mutation, indicating that the clinical spectrum of SHANK3 mutations may extend to RTT-like phenotype in addition to (severe) developmental delay, absence of expressive speech, autistic behaviors and intellectual disability.

PMID: 25931020 [PubMed - indexed for MEDLINE]

Children with 7q11.23 duplication syndrome: psychological characteristics.

March 18, 2016 - 8:14am
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Children with 7q11.23 duplication syndrome: psychological characteristics.

Am J Med Genet A. 2015 Jul;167(7):1436-50

Authors: Mervis CB, Klein-Tasman BP, Huffman MJ, Velleman SL, Pitts CH, Henderson DR, Woodruff-Borden J, Morris CA, Osborne LR

Abstract
To begin to delineate the psychological characteristics associated with classic 7q11.23 duplication syndrome (duplication of the classic Williams syndrome region; hereafter classic Dup7), we tested 63 children with classic Dup7 aged 4-17 years. Sixteen toddlers aged 18-45 months with classic Dup7 and 12 adults identified by cascade testing also were assessed. For the child group, median General Conceptual Ability (similar to IQ) on the Differential Ability Scales-II was 85.0 (low average), with a range from severe disability to high average ability. Median reading and mathematics achievement standard scores were at the low average to average level, with a range from severe impairment to high average or superior ability. Adaptive behavior was considerably more limited; median Scales of Independent Behavior-Revised Broad Independence standard score was 62.0 (mild impairment), with a range from severe adaptive impairment to average adaptive ability. Anxiety disorders were common, with 50.0% of children diagnosed with Social Phobia, 29.0% with Selective Mutism, 12.9% with Separation Anxiety Disorder, and 53.2% with Specific Phobia. In addition, 35.5% were diagnosed with Attention Deficit/Hyperactivity Disorder and 24.2% with Oppositional Defiant Disorder or Disruptive Behavior Disorder-Not Otherwise Specified. 33.3% of the children screened positive for a possible Autism Spectrum Disorder and 82.3% were diagnosed with Speech Sound Disorder. We compare these findings to previously reported results for children with Williams syndrome and argue that genotype/phenotype studies involving the Williams syndrome region offer important opportunities to understand the contribution of genes in this region to common disorders affecting the general population.

PMID: 25900101 [PubMed - indexed for MEDLINE]

Erratum to: Neural selectivity for communicative auditory signals in Phelan-McDermid syndrome.

March 17, 2016 - 11:00am
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Erratum to: Neural selectivity for communicative auditory signals in Phelan-McDermid syndrome.

J Neurodev Disord. 2016;8:8

Authors: Wang AT, Lim T, Jamison J, Bush L, Soorya LV, Tavassoli T, Siper PM, Buxbaum JD, Kolevzon A

Abstract
[This corrects the article DOI: 10.1186/s11689-016-9138-9.].

PMID: 26981159 [PubMed - as supplied by publisher]

A Pilot Proteomic Analysis of Salivary Biomarkers in Autism Spectrum Disorder.

March 17, 2016 - 11:00am
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A Pilot Proteomic Analysis of Salivary Biomarkers in Autism Spectrum Disorder.

Autism Res. 2015 Jun;8(3):338-50

Authors: Ngounou Wetie AG, Wormwood KL, Russell S, Ryan JP, Darie CC, Woods AG

Abstract
Autism spectrum disorder (ASD) prevalence is increasing, with current estimates at 1/68-1/50 individuals diagnosed with an ASD. Diagnosis is based on behavioral assessments. Early diagnosis and intervention is known to greatly improve functional outcomes in people with ASD. Diagnosis, treatment monitoring and prognosis of ASD symptoms could be facilitated with biomarkers to complement behavioral assessments. Mass spectrometry (MS) based proteomics may help reveal biomarkers for ASD. In this pilot study, we have analyzed the salivary proteome in individuals with ASD compared to neurotypical control subjects, using MS-based proteomics. Our goal is to optimize methods for salivary proteomic biomarker discovery and to identify initial putative biomarkers in people with ASDs. The salivary proteome is virtually unstudied in ASD, and saliva could provide an easily accessible biomaterial for analysis. Using nano liquid chromatography-tandem mass spectrometry, we found statistically significant differences in several salivary proteins, including elevated prolactin-inducible protein, lactotransferrin, Ig kappa chain C region, Ig gamma-1 chain C region, Ig lambda-2 chain C regions, neutrophil elastase, polymeric immunoglobulin receptor and deleted in malignant brain tumors 1. Our results indicate that this is an effective method for identification of salivary protein biomarkers, support the concept that immune system and gastrointestinal disturbances may be present in individuals with ASDs and point toward the need for larger studies in behaviorally-characterized individuals.

PMID: 25626423 [PubMed - indexed for MEDLINE]

Discovery of a Novel Seminal Fluid Microbiome and Influence of Estrogen Receptor Alpha Genetic Status.

March 15, 2016 - 7:06am

Discovery of a Novel Seminal Fluid Microbiome and Influence of Estrogen Receptor Alpha Genetic Status.

Sci Rep. 2016;6:23027

Authors: Javurek AB, Spollen WG, Ali AM, Johnson SA, Lubahn DB, Bivens NJ, Bromert KH, Ellersieck MR, Givan SA, Rosenfeld CS

Abstract
Bacteria harbored in the male reproductive system may influence reproductive function and health of the male and result in developmental origins of adult health and disease (DOHaD) effects in his offspring. Such effects could be due to the seminal fluid, which is slightly basic and enriched with carbohydrates; thereby, creating an ideal habitat for microbes or a potential seminal fluid microbiome (SFM). Using wild-type (WT) and estrogen receptor-alpha (ESR1) knockout (KO) male mice, we describe a unique SFM whose inhabitants differ from gut microbes. The bacterial composition of the SFM is influenced according to whether mice have functional Esr1 genes. Propionibacterium acnes, causative agent of chronic prostatitis possibly culminating in prostate cancer, is reduced in SFM of ESR1 KO compared to WT mice (P ≤ 0.0007). In certain genetic backgrounds, WT mice show a greater incidence of prostate cancer than ESR1 KO, which may be due to increased abundance of P. acnes. Additionally, select gut microbiome residents in ESR1 KO males, such as Lachnospiraceae and Christensenellaceae, might contribute to previously identified phenotypes, especially obesity, in these mutant mice. Understanding how genetics and environmental factors influence the SFM may provide the next frontier in male reproductive disorders and possibly paternal-based DOHaD diseases.

PMID: 26971397 [PubMed - in process]

Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1.

March 15, 2016 - 7:06am
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Mitochondrial free radical overproduction due to respiratory chain impairment in the brain of a mouse model of Rett syndrome: protective effect of CNF1.

Free Radic Biol Med. 2015 Jun;83:167-77

Authors: De Filippis B, Valenti D, de Bari L, De Rasmo D, Musto M, Fabbri A, Ricceri L, Fiorentini C, Laviola G, Vacca RA

Abstract
Rett syndrome (RTT) is a pervasive neurodevelopmental disorder mainly caused by mutations in the X-linked MECP2 gene associated with severe intellectual disability, movement disorders, and autistic-like behaviors. Its pathogenesis remains mostly not understood and no effective therapy is available. High circulating levels of oxidative stress markers in patients and the occurrence of oxidative brain damage in MeCP2-deficient mouse models suggest the involvement of oxidative stress in RTT pathogenesis. However, the molecular mechanism and the origin of the oxidative stress have not been elucidated. Here we demonstrate that a redox imbalance arises from aberrant mitochondrial functionality in the brain of MeCP2-308 heterozygous female mice, a condition that more closely recapitulates that of RTT patients. The marked increase in the rate of hydrogen peroxide generation in the brain of RTT mice seems mainly produced by the dysfunctional complex II of the mitochondrial respiratory chain. In addition, both membrane potential generation and mitochondrial ATP synthesis are decreased in RTT mouse brains when succinate, the complex II respiratory substrate, is used as an energy source. Respiratory chain impairment is brain area specific, owing to a decrease in either cAMP-dependent phosphorylation or protein levels of specific complex subunits. Further, we investigated whether the treatment of RTT mice with the bacterial protein CNF1, previously reported to ameliorate the neurobehavioral phenotype and brain bioenergetic markers in an RTT mouse model, exerts specific effects on brain mitochondrial function and consequently on hydrogen peroxide production. In RTT brains treated with CNF1, we observed the reactivation of respiratory chain complexes, the rescue of mitochondrial functionality, and the prevention of brain hydrogen peroxide overproduction. These results provide definitive evidence of mitochondrial reactive oxygen species overproduction in RTT mouse brain and highlight CNF1 efficacy in counteracting RTT-related mitochondrial defects.

PMID: 25708779 [PubMed - indexed for MEDLINE]

Epigenetics of autism-related impairment: copy number variation and maternal infection.

March 12, 2016 - 8:06am
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Epigenetics of autism-related impairment: copy number variation and maternal infection.

J Dev Behav Pediatr. 2015 Feb-Mar;36(2):61-7

Authors: Mazina V, Gerdts J, Trinh S, Ankenman K, Ward T, Dennis MY, Girirajan S, Eichler EE, Bernier R

Abstract
OBJECTIVE: Epidemiological data have suggested maternal infection and fever to be associated with increased risk of autism spectrum disorder (ASD). Animal studies show that gestational infections perturb fetal brain development and result in offspring with the core features of autism and have demonstrated that behavioral effects of maternal immune activation are dependent on genetic susceptibility. The goal of this study was to explore the impact of ASD-associated copy number variants (CNVs) and prenatal maternal infection on clinical severity of ASD within a dataset of prenatal history and complete genetic and phenotypic findings.
METHODS: We analyzed data from the Simons Simplex Collection sample including 1971 children with a diagnosis of ASD aged 4 to 18 years who underwent array comparative genomic hybridization screening. Information on infection and febrile episodes during pregnancy was collected through parent interview. ASD severity was clinically measured through parent-reported interview and questionnaires.
RESULTS: We found significant interactive effects between the presence of CNVs and maternal infection during pregnancy on autistic symptomatology, such that individuals with CNVs and history of maternal infection demonstrated increased rates of social communicative impairments and repetitive/restricted behaviors. In contrast, no significant interactions were found between presence of CNVs and prenatal infections on cognitive and adaptive functioning of individuals with ASD.
CONCLUSIONS: Our findings support a gene-environment interaction model of autism impairment, in that individuals with ASD-associated CNVs are more susceptible to the effects of maternal infection and febrile episodes in pregnancy on behavioral outcomes and suggest that these effects are specific to ASD rather than to global neurodevelopment.

PMID: 25629966 [PubMed - indexed for MEDLINE]

Toward an immune-mediated subtype of autism spectrum disorder.

March 12, 2016 - 8:06am
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Toward an immune-mediated subtype of autism spectrum disorder.

Brain Res. 2015 Aug 18;1617:72-92

Authors: McDougle CJ, Landino SM, Vahabzadeh A, O'Rourke J, Zurcher NR, Finger BC, Palumbo ML, Helt J, Mullett JE, Hooker JM, Carlezon WA

Abstract
A role for immunological involvement in autism spectrum disorder (ASD) has long been hypothesized. This review includes four sections describing (1) evidence for a relationship between familial autoimmune disorders and ASD; (2) results from post-mortem and neuroimaging studies that investigated aspects of neuroinflammation in ASD; (3) findings from animal model work in ASD involving inflammatory processes; and (4) outcomes from trials of anti-inflammatory/immune-modulating drugs in ASD that have appeared in the literature. Following each section, ideas are provided for future research, suggesting paths forward in the continuing effort to define the role of immune factors and inflammation in the pathophysiology of a subtype of ASD. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

PMID: 25445995 [PubMed - indexed for MEDLINE]

The role of immune mechanisms in Tourette syndrome.

March 12, 2016 - 8:06am
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The role of immune mechanisms in Tourette syndrome.

Brain Res. 2015 Aug 18;1617:126-43

Authors: Martino D, Zis P, Buttiglione M

Abstract
Tourette syndrome (TS) is a childhood-onset tic disorder associated with abnormal development of brain networks involved in the sensory and motor processing. An involvement of immune mechanisms in its pathophysiology has been proposed. Animal models based on active immunization with bacterial or viral mimics, direct injection of cytokines or patients' serum anti-neuronal antibodies, and transgenic approaches replicated stereotyped behaviors observed in human TS. A crucial role of microglia in the neural-immune crosstalk within TS and related disorders has been proposed by animal models and confirmed by recent post mortem studies. With analogy to autism, genetic and early life environmental factors could foster the involvement of immune mechanisms to the abnormal developmental trajectories postulated in TS, as well as lead to systemic immune dysregulation in this condition. Clinical studies demonstrate an association between TS and immune responses to pathogens like group A Streptococcus (GAS), although their role as risk-modifiers is still undefined. Overactivity of immune responses at a systemic level is suggested by clinical studies exploring cytokine and immunoglobulin levels, immune cell subpopulations, and gene expression profiling of peripheral lymphocytes. The involvement of autoantibodies, on the other hand, remains uncertain and warrants more work using live cell-based approaches. Overall, a body of evidence supports the hypothesis that disease mechanisms in TS, like other neurodevelopmental illnesses (e.g. autism), may involve dysfunctional neural-immune cross-talk, ultimately leading to altered maturation of brain pathways controlling different behavioral domains and, possibly, differences in organising immune and stress responses. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

PMID: 24845720 [PubMed - indexed for MEDLINE]

The complex behavioral phenotype of 15q13.3 microdeletion syndrome.

March 11, 2016 - 7:52am

The complex behavioral phenotype of 15q13.3 microdeletion syndrome.

Genet Med. 2016 Mar 10;

Authors: Ziats MN, Goin-Kochel RP, Berry LN, Ali M, Ge J, Guffey D, Rosenfeld JA, Bader P, Gambello MJ, Wolf V, Penney LS, Miller R, Lebel RR, Kane J, Bachman K, Troxell R, Clark G, Minard CG, Stankiewicz P, Beaudet A, Schaaf CP

Abstract
BACKGROUND: Chromosome 15q13.3 represents a hotspot for genomic rearrangements due to repetitive sequences mediating nonallelic homologous recombination. Deletions of 15q13.3 have been identified in the context of multiple neurological and psychiatric disorders, but a prospective clinical and behavioral assessment of affected individuals has not yet been reported.
METHODS: Eighteen subjects with 15q13.3 microdeletion underwent a series of behavioral assessments, along with clinical history and physical examination, to comprehensively define their behavioral phenotypes.
RESULTS: Cognitive deficits are the most prevalent feature in 15q13.3 deletion syndrome, with an average nonverbal IQ of 60 among the patients studied. Autism spectrum disorder was highly penetrant, with 31% of patients meeting clinical criteria and exceeding cutoff scores on both ADOS-2 and ADI-R. Affected individuals exhibited a complex pattern of behavioral abnormalities, most notably hyperactivity, attention problems, withdrawal, and externalizing symptoms, as well as impairments in functional communication, leadership, adaptive skills, and activities of daily living.
CONCLUSIONS: The 15q13.3 deletion syndrome encompasses a heterogeneous behavioral phenotype that poses a major challenge to parents, caregivers, and treating providers. Further work to more clearly delineate genotype-phenotype relationships in 15q13.3 deletions will be important for anticipatory guidance and development of targeted therapies.Genet Med advance online publication 10 March 2016Genetics in Medicine (2016); doi:10.1038/gim.2016.9.

PMID: 26963284 [PubMed - as supplied by publisher]

MAGEL2 and Oxytocin-Implications in Prader-Willi Syndrome and Beyond.

March 11, 2016 - 7:52am
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MAGEL2 and Oxytocin-Implications in Prader-Willi Syndrome and Beyond.

Biol Psychiatry. 2015 Jul 15;78(2):78-80

Authors: Fountain MD, Schaaf CP

PMID: 26092431 [PubMed - indexed for MEDLINE]

Gain-of-function missense variant in SLC12A2, encoding the bumetanide-sensitive NKCC1 cotransporter, identified in human schizophrenia.

March 10, 2016 - 7:30am
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Gain-of-function missense variant in SLC12A2, encoding the bumetanide-sensitive NKCC1 cotransporter, identified in human schizophrenia.

J Psychiatr Res. 2016 Feb 27;77:22-26

Authors: Merner ND, Mercado A, Khanna AR, Hodgkinson A, Bruat V, Awadalla P, Gamba G, Rouleau GA, Kahle KT

Abstract
Perturbations of γ-aminobutyric acid (GABA) neurotransmission in the human prefrontal cortex have been implicated in the pathogenesis of schizophrenia (SCZ), but the mechanisms are unclear. NKCC1 (SLC12A2) is a Cl(-)-importing cation-Cl(-) cotransporter that contributes to the maintenance of depolarizing GABA activity in immature neurons, and variation in SLC12A2 has been shown to increase the risk for schizophrenia via alterations of NKCC1 mRNA expression. However, no disease-causing mutations or functional variants in NKCC1 have been identified in human patients with SCZ. Here, by sequencing three large French-Canadian (FC) patient cohorts of SCZ, autism spectrum disorders (ASD), and intellectual disability (ID), we identified a novel heterozygous NKCC1 missense variant (p.Y199C) in SCZ. This variant is located in an evolutionarily conserved residue in the critical N-terminal regulatory domain and exhibits high predicted pathogenicity. No NKCC1 variants were detected in ASD or ID, and no KCC3 variants were identified in any of the three neurodevelopmental disorder cohorts. Functional experiments show Y199C is a gain-of-function variant, increasing Cl(-)-dependent and bumetanide-sensitive NKCC1 activity even in conditions in which the transporter is normally functionally silent (hypotonicity). These data are the first to describe a functional missense variant in SLC12A2 in human SCZ, and suggest that genetically encoded dysregulation of NKCC1 may be a risk factor for, or contribute to the pathogenesis of, human SCZ.

PMID: 26955005 [PubMed - as supplied by publisher]

Broader Autism Phenotype in Siblings of Children with ASD--A Review.

March 10, 2016 - 7:30am
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Broader Autism Phenotype in Siblings of Children with ASD--A Review.

Int J Mol Sci. 2015;16(6):13217-58

Authors: Pisula E, Ziegart-Sadowska K

Abstract
Although less pronounced, social, cognitive, and personality characteristics associated with autism spectrum disorders (ASD) may be present in people who do not meet ASD diagnostic criteria, especially in first-degree relatives of individuals with ASD. Research on these characteristics, referred to as broader autism phenotype (BAP), provides valuable data on potential expressions of autism-specific deficits in the context of family relations. This paper offers a review of research on BAP in siblings of individuals with ASD, focusing on reports regarding social, communication, and cognitive deficits, published from 1993 to 2014. The studies are divided into two groups based on participants' age: papers on preschool and older siblings of individuals with ASD; and publications on infants at risk for ASD. On the basis of this review, suggestions are offered for further research and its significance for our understanding of the genetic determinants of autism.

PMID: 26068453 [PubMed - indexed for MEDLINE]

Meta-analysis of differentially expressed genes in autism based on gene expression data.

March 10, 2016 - 7:30am
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Meta-analysis of differentially expressed genes in autism based on gene expression data.

Genet Mol Res. 2015;14(1):2146-55

Authors: Ning LF, Yu YQ, GuoJi ET, Kou CG, Wu YH, Shi JP, Ai LZ, Yu Q

Abstract
The purpose of this study was to identify differentially expressed (DE) genes and biological processes associated with changes in gene expression in autism. We performed a meta-analysis using new publicly available Gene Expression Omnibus (GEO) datasets of autism. We performed Gene Ontology (GO) enrichment analyses and pathway analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG). Ten GEO datasets, including 364 cases and 248 controls, were available for the meta-analysis. We identified 3105 genes that were consistently DE in autism (1425 upregulated and 1680 downregulated genes). We also found that 7 genes were associated with phospholipase A2 (PLA2), including LYPLA2P1, PLA2G4D, PNPLA2, LYPLA2, PLA2G6, PLA2G7, and PLA2G5. We found GO terms for molecular functions significantly enriched in structural constituent of ribosome (GO: 0003735, P = 1.87-E06) and transcription regulator activity (GO: 0030528, P = 8.86E-04), while for biological processes, the enriched GO terms were involved in translational elongation (GO: 0006414, P = 1.74E-12) and the response to cytokine stimuli (GO: 0034097, P = 2.76E-05). The most significant pathway in our KEGG analysis was the ribosome pathway (P = 7.90E-12). Our meta-analysis identified genes that were consistently DE and biological pathways associated with gene expression changes in autism.

PMID: 25867362 [PubMed - indexed for MEDLINE]

Neuroanatomical Diversity of Corpus Callosum and Brain Volume in Autism: Meta-analysis, Analysis of the Autism Brain Imaging Data Exchange Project, and Simulation.

March 10, 2016 - 7:30am
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Neuroanatomical Diversity of Corpus Callosum and Brain Volume in Autism: Meta-analysis, Analysis of the Autism Brain Imaging Data Exchange Project, and Simulation.

Biol Psychiatry. 2015 Jul 15;78(2):126-34

Authors: Lefebvre A, Beggiato A, Bourgeron T, Toro R

Abstract
BACKGROUND: Patients with autism have been often reported to have a smaller corpus callosum (CC) than control subjects.
METHODS: We conducted a meta-analysis of the literature, analyzed the CC in 694 subjects of the Autism Brain Imaging Data Exchange project, and performed computer simulations to study the effect of different analysis strategies.
RESULTS: Our meta-analysis suggested a group difference in CC size; however, the studies were heavily underpowered (20% power to detect Cohen's d = .3). In contrast, we did not observe significant differences in the Autism Brain Imaging Data Exchange cohort, despite having achieved 99% power. However, we observed that CC scaled nonlinearly with brain volume (BV): large brains had a proportionally smaller CC. Our simulations showed that because of this nonlinearity, CC normalization could not control for eventual BV differences, but using BV as a covariate in a linear model would. We also observed a weaker correlation of IQ and BV in cases compared with control subjects. Our simulations showed that matching populations by IQ could then induce artifactual BV differences.
CONCLUSIONS: The lack of statistical power in the previous literature prevents us from establishing the reality of the claims of a smaller CC in autism, and our own analyses did not find any. However, the nonlinear relationship between CC and BV and the different correlation between BV and IQ in cases and control subjects may induce artifactual differences. Overall, our results highlight the necessity for open data sharing to provide a more solid ground for the discovery of neuroimaging biomarkers within the context of the wide human neuroanatomical diversity.

PMID: 25850620 [PubMed - indexed for MEDLINE]

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