pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 1 hour 16 min ago

A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism.

March 7, 2015 - 7:55am
Related Articles

A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism.

Transl Psychiatry. 2014;4:e354

Authors: Wittkowski KM, Sonakya V, Bigio B, Tonn MK, Shic F, Ascano M, Nasca C, Gold-Von Simson G

Abstract
The prevalence of autism spectrum disorders (ASDs) has increased 20-fold over the past 50 years to >1% of US children. Although twin studies attest to a high degree of heritability, the genetic risk factors are still poorly understood. We analyzed data from two independent populations using u-statistics for genetically structured wide-locus data and added data from unrelated controls to explore epistasis. To account for systematic, but disease-unrelated differences in (non-randomized) genome-wide association studies (GWAS), a correlation between P-values and minor allele frequency with low granularity data and for conducting multiple tests in overlapping genetic regions, we present a novel study-specific criterion for 'genome-wide significance'. From recent results in a comorbid disease, childhood absence epilepsy, we had hypothesized that axonal guidance and calcium signaling are involved in autism as well. Enrichment of the results in both studies with related genes confirms this hypothesis. Additional ASD-specific variations identified in this study suggest protracted growth factor signaling as causing more severe forms of ASD. Another cluster of related genes suggests chloride and potassium ion channels as additional ASD-specific drug targets. The involvement of growth factors suggests the time of accelerated neuronal growth and pruning at 9-24 months of age as the period during which treatment with ion channel modulators would be most effective in preventing progression to more severe forms of autism. By extension, the same computational biostatistics approach could yield profound insights into the etiology of many common diseases from the genetic data collected over the last decade.

PMID: 24473445 [PubMed - indexed for MEDLINE]

Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum.

March 7, 2015 - 7:55am
Related Articles

Increased binding of MeCP2 to the GAD1 and RELN promoters may be mediated by an enrichment of 5-hmC in autism spectrum disorder (ASD) cerebellum.

Transl Psychiatry. 2014;4:e349

Authors: Zhubi A, Chen Y, Dong E, Cook EH, Guidotti A, Grayson DR

Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by symptoms related to altered social interactions/communication and restricted and repetitive behaviors. In addition to genetic risk, epigenetic mechanisms (which include DNA methylation/demethylation) are thought to be important in the etiopathogenesis of ASD. We studied epigenetic mechanisms underlying the transcriptional regulation of candidate genes in cerebella of ASD patients, including the binding of MeCP2 (methyl CpG binding protein-2) to the glutamic acid decarboxylase 67 (GAD1), glutamic acid decarboxylase 65 (GAD2), and Reelin (RELN) promoters and gene bodies. Moreover, we performed methyl DNA immunoprecipitation (MeDIP) and hydroxymethyl DNA immunoprecipitation (hMeDIP) to measure total 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the same regions of these genes. The enrichment of 5-hmC and decrease in 5-mC at the GAD1 or RELN promoters detected by 5-hmC and 5-mC antibodies was confirmed by Tet-assisted bisulfite (TAB) pyrosequencing. The results showed a marked and significant increase in MeCP2 binding to the promoter regions of GAD1 and RELN, but not to the corresponding gene body regions in cerebellar cortex of ASD patients. Moreover, we detected a significant increase in TET1 expression and an enrichment in the level of 5-hmC, but not 5-mC, at the promoters of GAD1 and RELN in ASD when compared with CON. Moreover, there was increased TET1 binding to these promoter regions. These data are consistent with the hypothesis that an increase of 5-hmC (relative to 5-mC) at specific gene domains enhances the binding of MeCP2 to 5-hmC and reduces expression of the corresponding target genes in ASD cerebella.

PMID: 24448211 [PubMed - indexed for MEDLINE]

First case report of Rett syndrome in the Azeri Turkish population and brief review of the literature.

March 5, 2015 - 8:02am

First case report of Rett syndrome in the Azeri Turkish population and brief review of the literature.

Epilepsy Behav Case Rep. 2015;3:15-9

Authors: Gharesouran J, Khalili AF, Azari NS, Vahedi L

Abstract
Rett syndrome is a dominant X-linked male-lethal disorder largely caused by mutations in the gene encoding methyl-CpG binding protein 2 (MECP2). Clinical manifestations include neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and abnormal electroencephalograms. Afflicted females show normal development until the age of 6 to 18 months, followed by gradual loss of speech abilities, microcephaly, social impairment, ataxia, and stereotypic hand movements. We report a 7-year-old girl who was born of a nonconsanguineous marriage presenting with mental retardation and delayed development. Physical examination revealed loss of speech, repetitive hand-wringing movement, short stature (120 cm), strabismus, microcephaly, and autistic behavior. The diagnosis was confirmed by sequencing MECP2 gene with heterozygous mutation C385A in exon 2. The current study aimed to report the first case of Rett syndrome in the Azeri Turkish population.

PMID: 25737965 [PubMed]

Syndromic X-linked intellectual disability segregating with a missense variant in RLIM.

March 5, 2015 - 8:02am

Syndromic X-linked intellectual disability segregating with a missense variant in RLIM.

Eur J Hum Genet. 2015 Mar 4;

Authors: Tønne E, Holdhus R, Stansberg C, Stray-Pedersen A, Petersen K, Brunner HG, Gilissen C, Hoischen A, Prescott T, Steen VM, Fiskerstrand T

Abstract
We describe a three-generation Norwegian family with a novel X-linked intellectual disability (XLID) syndrome characterized by subtle facial dysmorphism, autism and severe feeding problems. By exome sequencing we detected a rare missense variant (c.1067A>G, p.(Tyr356Cys)) in the RLIM gene, in two affected male second cousins. Sanger sequencing confirmed the presence of the variant in the four affected males (none of whom were siblings) and in three mothers available for testing. The variant was not present in 100 normal Norwegian controls, has not been reported in variant databases and is deleterious according to in silico prediction tools. The clinical phenotype and the variant co-segregate, yielding a LOD score of 3.0 for linkage to the shared region (36.09 Mb), which contains 242 genes. No other shared rare variants on the X chromosome were detected in the two affected exome-sequenced individuals, and all female carriers had an extremely skewed X-chromosome inactivation pattern. RLIM encodes RING zinc finger protein 12 (RNF12), an ubiquitin ligase that is essential for X inactivation in mice and that acts as a co-regulator of a range of transcription factors, particularly those containing a LIM homeodomain. Tyrosine in position 356 in RNF12 is located within a highly conserved domain essential for binding such transcription factors. Expression of RNF12 is widespread during embryogenesis, and is particularly high in the outer layers of the cerebral cortex. Functional studies are needed to prove a definite causal relationship between the variant and the phenotype. Subsequent reports may confirm a role for RLIM variants in patients with XLID.European Journal of Human Genetics advance online publication, 4 March 2015; doi:10.1038/ejhg.2015.30.

PMID: 25735484 [PubMed - as supplied by publisher]

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

March 5, 2015 - 8:02am

CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms.

Eur J Hum Genet. 2015 Mar 4;

Authors: Damaj L, Lupien-Meilleur A, Lortie A, Riou É, Ospina LH, Gagnon L, Vanasse C, Rossignol E

Abstract
CACNA1A loss-of-function mutations classically present as episodic ataxia type 2 (EA2), with brief episodes of ataxia and nystagmus, or with progressive spinocerebellar ataxia (SCA6). A minority of patients carrying CACNA1A mutations develops epilepsy. Non-motor symptoms associated with these mutations are often overlooked. In this study, we report 16 affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual deficiency, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia. Sequencing revealed one CACNA1A gene deletion, two deleterious CACNA1A point mutations including one known stop-gain and one new frameshift variant and a new splice-site variant. This report illustrates the phenotypic heterogeneity of CACNA1A loss-of-function mutations and stresses the cognitive and epileptic manifestations caused by the loss of CaV2.1 channels function, presumably affecting cerebellar, cortical and limbic networks.European Journal of Human Genetics advance online publication, 4 March 2015; doi:10.1038/ejhg.2015.21.

PMID: 25735478 [PubMed - as supplied by publisher]

Blood manganese concentrations in Jamaican children with and without autism spectrum disorders.

March 5, 2015 - 8:02am
Related Articles

Blood manganese concentrations in Jamaican children with and without autism spectrum disorders.

Environ Health. 2014;13:69

Authors: Rahbar MH, Samms-Vaughan M, Dickerson AS, Loveland KA, Ardjomand-Hessabi M, Bressler J, Shakespeare-Pellington S, Grove ML, Pearson DA, Boerwinkle E

Abstract
BACKGROUND: Manganese is an essential element for human health and development. Previous studies have shown neurotoxic effects in children exposed to higher levels of manganese. Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that impairs social interaction and communication. Several studies have hypothesized that ASD is caused through environmental exposures during crucial stages in brain development. We investigated the possible association between blood manganese concentrations (BMC) and ASD. We also identified factors associated with BMC in typically developing (TD) Jamaican children.
METHODS: We used data from 109 ASD cases with their 1:1 age- and sex-matched TD controls to compare mean BMC in Jamaican children (2-8 years of age) with and without ASD. We administered a pre-tested questionnaire to assess demographic and socioeconomic information, medical history, and potential exposure to manganese. Finally, we collected 2 mL of whole blood from each child for analysis of manganese levels. Using General Linear Models (GLM), we assessed the association between BMC and ASD status. Furthermore, we used two independent sample t-tests to identify factors associated with BMC in TD children.
RESULTS: In univariable GLM analysis, we found no significant association between BMC and ASD, (10.9 μg/L for cases vs. 10.5 μg/L for controls; P = 0.29). In a multivariable GLM adjusting for paternal age, parental education, place of child's birth (Kingston parish), consumption of root vegetables, cabbage, saltwater fish, and cakes/buns, there was still no significant association between BMC and ASD status, (11.5 μg/L for cases vs. 11.9 μg/L for controls; P = 0.48). Our findings also indicated TD children who ate fresh water fish had a higher BMC than children who did not (11.0 μg/L vs. 9.9 μg/L; P = 0.03) as younger TD children (i.e., 2 ≤ age ≤4), (12.0 μg/L vs. 10.2 μg/L; P = 0.01).
CONCLUSIONS: While these results cannot be used to assess early exposure at potentially more susceptible time period, our findings suggest that there is no significant association between manganese exposures and ASD case status in Jamaica. Our findings also indicate that BMC in Jamaican children resemble those of children in the developed world and are much lower than those in the developing countries.

PMID: 25149876 [PubMed - indexed for MEDLINE]

Enhanced extinction of contextual fear conditioning in ClockΔ19 mutant mice.

March 5, 2015 - 8:02am
Related Articles

Enhanced extinction of contextual fear conditioning in ClockΔ19 mutant mice.

Behav Neurosci. 2014 Aug;128(4):468-73

Authors: Bernardi RE, Spanagel R

Abstract
Clock genes have been implicated in several disorders, such as schizophrenia, bipolar disorder, autism spectrum disorders, and drug dependence. However, few studies to date have examined the role of clock genes in fear-related behaviors. The authors used mice with the ClockΔ19 mutation to assess the involvement of this gene in contextual fear conditioning. Male wild-type (WT) and ClockΔ19 mutant mice underwent a single session of contextual fear conditioning (12 min, 4 unsignaled shocks), followed by daily 12-min retention trials. There were no differences between mutant and WT mice in the acquisition of contextual fear, and WT and mutant mice demonstrated similar freezing during the first retention session. However, extinction of contextual fear was accelerated in mutant mice across the remaining retention sessions, as compared to WT mice, suggesting a role for Clock in extinction following aversive learning. Because the ClockΔ19 mutation has previously been demonstrated to result in an increase in dopamine signaling, the authors confirmed the role of dopamine in extinction learning using preretention session administration of a low dose of the dopamine transport reuptake inhibitor modafinil (0.75 mg/kg), which resulted in decreased freezing across retention sessions. These findings are consistent with an emerging portrayal of the importance of Clock genes in noncircadian functions, as well as the important role of dopamine in extinction learning.

PMID: 24865659 [PubMed - indexed for MEDLINE]

Dissociable genetic contributions to error processing: a multimodal neuroimaging study.

March 4, 2015 - 7:28am
Related Articles

Dissociable genetic contributions to error processing: a multimodal neuroimaging study.

PLoS One. 2014;9(7):e101784

Authors: Agam Y, Vangel M, Roffman JL, Gallagher PJ, Chaponis J, Haddad S, Goff DC, Greenberg JL, Wilhelm S, Smoller JW, Manoach DS

Abstract
BACKGROUND: Neuroimaging studies reliably identify two markers of error commission: the error-related negativity (ERN), an event-related potential, and functional MRI activation of the dorsal anterior cingulate cortex (dACC). While theorized to reflect the same neural process, recent evidence suggests that the ERN arises from the posterior cingulate cortex not the dACC. Here, we tested the hypothesis that these two error markers also have different genetic mediation.
METHODS: We measured both error markers in a sample of 92 comprised of healthy individuals and those with diagnoses of schizophrenia, obsessive-compulsive disorder or autism spectrum disorder. Participants performed the same task during functional MRI and simultaneously acquired magnetoencephalography and electroencephalography. We examined the mediation of the error markers by two single nucleotide polymorphisms: dopamine D4 receptor (DRD4) C-521T (rs1800955), which has been associated with the ERN and methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133), which has been associated with error-related dACC activation. We then compared the effects of each polymorphism on the two error markers modeled as a bivariate response.
RESULTS: We replicated our previous report of a posterior cingulate source of the ERN in healthy participants in the schizophrenia and obsessive-compulsive disorder groups. The effect of genotype on error markers did not differ significantly by diagnostic group. DRD4 C-521T allele load had a significant linear effect on ERN amplitude, but not on dACC activation, and this difference was significant. MTHFR C677T allele load had a significant linear effect on dACC activation but not ERN amplitude, but the difference in effects on the two error markers was not significant.
CONCLUSIONS: DRD4 C-521T, but not MTHFR C677T, had a significant differential effect on two canonical error markers. Together with the anatomical dissociation between the ERN and error-related dACC activation, these findings suggest that these error markers have different neural and genetic mediation.

PMID: 25010186 [PubMed - indexed for MEDLINE]

Cannabinoid receptor type 1 receptors on GABAergic vs. glutamatergic neurons differentially gate sex-dependent social interest in mice.

March 4, 2015 - 7:28am
Related Articles

Cannabinoid receptor type 1 receptors on GABAergic vs. glutamatergic neurons differentially gate sex-dependent social interest in mice.

Eur J Neurosci. 2014 Jul;40(1):2293-8

Authors: Terzian AL, Micale V, Wotjak CT

Abstract
Abnormalities in social behavior are found in almost all psychiatric disorders, such as anxiety, depression, autism, and schizophrenia. Thus, comprehension of the neurobiological basis of social interaction is important for a better understanding of numerous pathologies and improved treatments. Several findings have suggested that an alteration of cannabinoid receptor type 1 (CB1) receptor function could be involved in the pathophysiology of such disorders. However, the role of CB1 receptors is still unclear, and their localisation on different neuronal subpopulations may produce distinct outcomes. To dissect the role of CB1 receptors in different neuronal populations, we used male knockout mice and their respective control littermates [total deletion (CB1(-/-) ); specific deletion on cortical glutamatergic neurons (Glu-CB1(-/-) ) or on GABAergic interneurons (GABA-CB1(-/-) ), and wild-type (WT) mice treated with the CB1 antagonist/inverse agonist SR141716A (3 mg/kg). Mice were required to perform different social tasks - direct social interaction and social investigation. Direct interaction of two male mice was not modified in any group; however, when they were paired with females, Glu-CB1(-/-) mice showed reduced interaction. Also, exploration of the male stimulus subject in the three-chamber social investigation test was almost unaffected. The situation was completely different when a female was used as the stimulus subject. In this case, Glu-CB1(-/-) mice showed reduced interest in the social stimulus, mimicking the phenotype of CB1(-/-) or WT mice treated with SR141716A. GABA-CB1(-/-) mice showed the opposite phenotype, by spending more time investigating the social stimulus. In conclusion, we provide evidence that CB1 receptors specifically modulate the social investigation of female mice in a neuronal subtype-specific manner.

PMID: 24698342 [PubMed - indexed for MEDLINE]

Recent update of autism spectrum disorders.

March 3, 2015 - 6:10am

Recent update of autism spectrum disorders.

Korean J Pediatr. 2015 Jan;58(1):8-14

Authors: Kim SK

Abstract
In patients with a language developmental delay, it is necessary to make a differential diagnosis for autism spectrum disorders (ASDs), specific language impairment, and mental retardation. It is important that pediatricians recognize the signs and symptoms of ASDs, as many patients with language developmental delays are ultimately diagnosed with ASDs. Pediatricians play an important role in the early recognition of ASDs, because they are usually the first point of contact for children with ASDs. A revision of the diagnostic criteria of ASDs was proposed in the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) that was released in May 2013. The autism spectrum describes a range of conditions classified as neurodevelopmental disorders in the fifth edition of the DSM. The new diagnostic criteria encompasses previous elements from the diagnosis of autistic disorder, Asperger disorder, childhood disintegrative disorder, and pervasive developmental disorder-not otherwise specified. An additional change to the DSM includes synthesizing the section on social and communication deficits into one domain. In ASD patients, the appropriate behavioral therapies and rehabilitation treatments significantly affect the prognosis. Therefore, this makes early diagnosis and treatment very important. In conclusion, pediatricians need to be able to recognize the signs and symptoms of ASDs and be attentive to them in order to make an early diagnosis and provide treatment.

PMID: 25729393 [PubMed]

Social responsiveness, an autism endophenotype: genomewide significant linkage to two regions on chromosome 8.

March 3, 2015 - 6:10am

Social responsiveness, an autism endophenotype: genomewide significant linkage to two regions on chromosome 8.

Am J Psychiatry. 2015 Mar 1;172(3):266-75

Authors: Lowe JK, Werling DM, Constantino JN, Cantor RM, Geschwind DH

Abstract
OBJECTIVE: Autism spectrum disorder is characterized by deficits in social function and the presence of repetitive and restrictive behaviors. Following a previous test of principle, the authors adopted a quantitative approach to discovering genes contributing to the broader autism phenotype by using social responsiveness as an endophenotype for autism spectrum disorder.
METHOD: Linkage analyses using scores from the Social Responsiveness Scale were performed in 590 families from the Autism Genetic Resource Exchange, a largely multiplex autism spectrum disorder cohort. Regional and genomewide association analyses were performed to search for common variants contributing to social responsiveness.
RESULTS: Social Responsiveness Scale scores were unimodally distributed in male offspring from multiplex autism families, in contrast with a bimodal distribution observed in female offspring. In correlated analyses differing by Social Responsiveness Scale respondent, genomewide significant linkage for social responsiveness was identified at chr8p21.3 (multipoint LOD=4.11; teacher/parent scores) and chr8q24.22 (multipoint LOD=4.54; parent-only scores), respectively. Genomewide or linkage-directed association analyses did not detect common variants contributing to social responsiveness.
CONCLUSIONS: The sex-differential distributions of Social Responsiveness Scale scores in multiplex autism families likely reflect mechanisms contributing to the sex ratio for autism observed in the general population and form a quantitative signature of reduced penetrance of inherited liability to autism spectrum disorder among females. The identification of two strong loci for social responsiveness validates the endophenotype approach for the identification of genetic variants contributing to complex traits such as autism spectrum disorder. While causal mutations have yet to be identified, these findings are consistent with segregation of rare genetic variants influencing social responsiveness and underscore the increasingly recognized role of rare inherited variants in the genetic architecture of autism spectrum disorder.

PMID: 25727539 [PubMed - in process]

Identification of candidate single-nucleotide polymorphisms in NRXN1 related to antipsychotic treatment response in patients with schizophrenia.

March 3, 2015 - 6:10am
Related Articles

Identification of candidate single-nucleotide polymorphisms in NRXN1 related to antipsychotic treatment response in patients with schizophrenia.

Neuropsychopharmacology. 2014 Aug;39(9):2170-8

Authors: Jenkins A, Apud JA, Zhang F, Decot H, Weinberger DR, Law AJ

Abstract
Neurexins are presynaptic neuronal adhesion molecules that interact with postsynaptic neuroligins to form an inter-synaptic complex required for synaptic specification and efficient neurotransmission. Deletions and point mutations in the neurexin 1 (NRXN1) gene are associated with a broad spectrum of neuropsychiatric and neurodevelopmental disorders, including autism, intellectual disability, epilepsy, developmental delay, and schizophrenia. Recently, small nucleotide polymorphisms in NRXN1 have been associated with antipsychotic drug response in patients with schizophrenia. Based on previous suggestive evidence of an impact on clozapine response in patients with schizophrenia, we conducted an association study of NRXN1 polymorphisms (rs12467557 and rs10490162) with antipsychotic treatment response in 54 patients with schizophrenia in a double blind, placebo-controlled NIMH inpatient crossover trial and examined for association with risk for schizophrenia in independent case-control and family-based clinical cohorts. Pharmacogenetic analysis in the placebo controlled trial revealed significant association of rs12467557and rs10490162 with drug response, whereby individuals homozygous for the A allele, at either SNP, showed significant improvement in positive symptoms, general psychopathology, thought disturbance, and negative symptoms, whereas patients carrying the G allele showed no overall response. Although we did not find evidence of the same NRXN1 SNPs being associated with results of the NIMH sponsored CATIE trial, other SNPs showed weakly positive signals. The family and case-control analyses for schizophrenia risk were negative. Our results provide confirmatory evidence of genetically determined differences in drug response in patients with schizophrenia related to NRXN1 variation. Furthermore, these findings potentially implicate NRXN1 in the therapeutic actions of antipsychotic drugs.

PMID: 24633560 [PubMed - indexed for MEDLINE]

Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity.

March 3, 2015 - 6:10am
Related Articles

Autistic-like syndrome in mu opioid receptor null mice is relieved by facilitated mGluR4 activity.

Neuropsychopharmacology. 2014 Aug;39(9):2049-60

Authors: Becker JA, Clesse D, Spiegelhalter C, Schwab Y, Le Merrer J, Kieffer BL

Abstract
The etiology of Autism Spectrum Disorders (ASDs) remains largely unknown. Identifying vulnerability genes for autism represents a major challenge in the field and allows the development of animal models for translational research. Mice lacking the mu opioid receptor gene (Oprm1(-/-)) were recently proposed as a monogenic mouse model of autism, based on severe deficits in social behavior and communication skills. We confirm this hypothesis by showing that adult Oprm1(-/-) animals recapitulate core and multiple comorbid behavioral symptoms of autism and also display anatomical, neurochemical, and genetic landmarks of the disease. Chronic facilitation of mGluR4 signaling, which we identified as a novel pharmacological target in ASDs in these mice, was more efficient in alleviating behavioral deficits than the reference molecule risperidone. Altogether, our data provide first evidence that disrupted mu opioid receptor signaling is sufficient to trigger a comprehensive autistic syndrome, maybe through blunted social reward processes, and this mouse model opens promising avenues for therapeutic innovation.

PMID: 24619243 [PubMed - indexed for MEDLINE]

Asthma and Allergies in Children With Autism Spectrum Disorders: Results From the CHARGE Study.

February 28, 2015 - 1:44pm

Asthma and Allergies in Children With Autism Spectrum Disorders: Results From the CHARGE Study.

Autism Res. 2015 Feb 26;

Authors: Lyall K, Van de Water J, Ashwood P, Hertz-Picciotto I

Abstract
Immune aberrations are often noted in children with autism spectrum disorder (ASD), but whether asthma and allergy are related to ASD is not well defined. This study examined asthma and allergies in association with ASD and phenotypic subsets. Participants were 560 children with confirmed ASD and 391 typically developing children from the CHildhood Autism Risks from Genetics and the Environment study. Maternally reported child asthma and allergy was compared between cases and controls, and in association with cognitive and behavioral test scores. Prevalence of asthma and overall allergies did not differ between cases and controls, but overall allergy in children with ASD was associated with higher stereotypy scores as measured by the Aberrant Behavior Checklist. In addition, reported food allergies were significantly associated with ASD (adjusted odds ratio = 2.23, 95% confidence interval 1.28, 3.89). Our results suggest food allergies and sensitivities may be more common in children with ASD, and that these issues may correlate with other behaviors. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 25722050 [PubMed - as supplied by publisher]

Meta-Analysis of Gene Expression in Autism Spectrum Disorder.

February 28, 2015 - 1:44pm

Meta-Analysis of Gene Expression in Autism Spectrum Disorder.

Autism Res. 2015 Feb 26;

Authors: Ch'ng C, Kwok W, Rogic S, Pavlidis P

Abstract
Autism spectrum disorders (ASD) are clinically heterogeneous and biologically complex. In general it remains unclear, what biological factors lead to changes in the brains of autistic individuals. A considerable number of transcriptome analyses have been performed in attempts to address this question, but their findings lack a clear consensus. As a result, each of these individual studies has not led to any significant advance in understanding the autistic phenotype as a whole. Here, we report a meta-analysis of more than 1000 microarrays across twelve independent studies on expression changes in ASD compared to unaffected individuals, in both blood and brain tissues. We identified a number of known and novel genes that are consistently differentially expressed across three studies of the brain (71 samples in total). A subset of the highly ranked genes is suggestive of effects on mitochondrial function. In blood, consistent changes were more difficult to identify, despite individual studies tending to exhibit larger effects than the brain studies. Our results are the strongest evidence to date of a common transcriptome signature in the brains of individuals with ASD. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.

PMID: 25720351 [PubMed - as supplied by publisher]

Ultrasonic vocalizations in Shank mouse models for autism spectrum disorders: detailed spectrographic analyses and developmental profiles.

February 28, 2015 - 1:44pm
Related Articles

Ultrasonic vocalizations in Shank mouse models for autism spectrum disorders: detailed spectrographic analyses and developmental profiles.

Neurosci Biobehav Rev. 2014 Jun;43:199-212

Authors: Wöhr M

Abstract
Autism spectrum disorders (ASD) are a class of neurodevelopmental disorders characterized by persistent deficits in social behavior and communication across multiple contexts, together with repetitive patterns of behavior, interests, or activities. The high concordance rate between monozygotic twins supports a strong genetic component. Among the most promising candidate genes for ASD is the SHANK gene family, including SHANK1, SHANK2 (ProSAP1), and SHANK3 (ProSAP2). SHANK genes are therefore important candidates for modeling ASD in mice and various genetic models were generated within the last few years. As the diagnostic criteria for ASD are purely behaviorally defined, the validity of mouse models for ASD strongly depends on their behavioral phenotype. Behavioral phenotyping is therefore a key component of the current translational approach and requires sensitive behavioral test paradigms with high relevance to each diagnostic symptom category. While behavioral phenotyping assays for social deficits and repetitive patterns of behavior, interests, or activities are well-established, the development of sensitive behavioral test paradigms to assess communication deficits in mice is a daunting challenge. Measuring ultrasonic vocalizations (USV) appears to be a promising strategy. In the first part of the review, an overview on the different types of mouse USV and their communicative functions will be provided. The second part is devoted to studies on the emission of USV in Shank mouse models for ASD. Evidence for communication deficits was obtained in Shank1, Shank2, and Shank3 genetic mouse models for ASD, often paralleled by behavioral phenotypes relevant to social deficits seen in ASD.

PMID: 24726578 [PubMed - indexed for MEDLINE]

Commentary: We've only just begun: unravelling the underlying genetics of neurodevelopmental disorders - a commentary on Kiser et al. ().

February 26, 2015 - 7:00am

Commentary: We've only just begun: unravelling the underlying genetics of neurodevelopmental disorders - a commentary on Kiser et al. ().

J Child Psychol Psychiatry. 2015 Mar;56(3):296-298

Authors: Coghill D

Abstract
Kiser and colleagues (this issue) have presented us with a comprehensive and bold review that describes current understanding of the genetic influences that underpin three of the most important neurodevelopmental disorders: attention deficit hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and intellectual disability (ID), and explores several new avenues of thinking that are opening up based on this knowledge. Based on phenotypic overlap, comorbidity and a sharing of genetic and environmental risks they propose that ADHD, ASD and ID together form part of a continuum. The idea that disorders we have traditionally seen as being separate are in fact inter-related is, of course, not an entirely new one and indeed has similarly been proposed for the developmental disorders by Gillberg and in a more general way as a part of the NIMH Research Domain Criteria (RDoC) project. Where this review differs is in the authors' attempts to look at several possible mechanisms for these.

PMID: 25714739 [PubMed - as supplied by publisher]

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

February 26, 2015 - 7:00am

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

Am J Med Genet A. 2015 Feb 25;

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. © 2015 Wiley Periodicals, Inc.

PMID: 25712757 [PubMed - as supplied by publisher]

Genetic Changes Shaping the Human Brain.

February 25, 2015 - 9:02am

Genetic Changes Shaping the Human Brain.

Dev Cell. 2015 Feb 23;32(4):423-434

Authors: Bae BI, Jayaraman D, Walsh CA

Abstract
The development and function of our brain are governed by a genetic blueprint, which reflects dynamic changes over the history of evolution. Recent progress in genetics and genomics, facilitated by next-generation sequencing and single-cell sorting, has identified numerous genomic loci that are associated with a neuroanatomical or neurobehavioral phenotype. Here, we review some of the genetic changes in both protein-coding and noncoding regions that affect brain development and evolution, as well as recent progress in brain transcriptomics. Understanding these genetic changes may provide novel insights into neurological and neuropsychiatric disorders, such as autism and schizophrenia.

PMID: 25710529 [PubMed - as supplied by publisher]

Searching for a minimal set of behaviors for autism detection through feature selection-based machine learning.

February 25, 2015 - 9:02am

Searching for a minimal set of behaviors for autism detection through feature selection-based machine learning.

Transl Psychiatry. 2015;5:e514

Authors: Kosmicki JA, Sochat V, Duda M, Wall DP

Abstract
Although the prevalence of autism spectrum disorder (ASD) has risen sharply in the last few years reaching 1 in 68, the average age of diagnosis in the United States remains close to 4-well past the developmental window when early intervention has the largest gains. This emphasizes the importance of developing accurate methods to detect risk faster than the current standards of care. In the present study, we used machine learning to evaluate one of the best and most widely used instruments for clinical assessment of ASD, the Autism Diagnostic Observation Schedule (ADOS) to test whether only a subset of behaviors can differentiate between children on and off the autism spectrum. ADOS relies on behavioral observation in a clinical setting and consists of four modules, with module 2 reserved for individuals with some vocabulary and module 3 for higher levels of cognitive functioning. We ran eight machine learning algorithms using stepwise backward feature selection on score sheets from modules 2 and 3 from 4540 individuals. We found that 9 of the 28 behaviors captured by items from module 2, and 12 of the 28 behaviors captured by module 3 are sufficient to detect ASD risk with 98.27% and 97.66% accuracy, respectively. A greater than 55% reduction in the number of behaviorals with negligible loss of accuracy across both modules suggests a role for computational and statistical methods to streamline ASD risk detection and screening. These results may help enable development of mobile and parent-directed methods for preliminary risk evaluation and/or clinical triage that reach a larger percentage of the population and help to lower the average age of detection and diagnosis.

PMID: 25710120 [PubMed - as supplied by publisher]

Pages