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DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores.

March 7, 2015 - 7:55am
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DUF1220 copy number is linearly associated with increased cognitive function as measured by total IQ and mathematical aptitude scores.

Hum Genet. 2015 Jan;134(1):67-75

Authors: Davis JM, Searles VB, Anderson N, Keeney J, Raznahan A, Horwood LJ, Fergusson DM, Kennedy MA, Giedd J, Sikela JM

Abstract
DUF1220 protein domains exhibit the greatest human lineage-specific copy number expansion of any protein-coding sequence in the genome, and variation in DUF1220 copy number has been linked to both brain size in humans and brain evolution among primates. Given these findings, we examined associations between DUF1220 subtypes CON1 and CON2 and cognitive aptitude. We identified a linear association between CON2 copy number and cognitive function in two independent populations of European descent. In North American males, an increase in CON2 copy number corresponded with an increase in WISC IQ (R (2) = 0.13, p = 0.02), which may be driven by males aged 6-11 (R (2) = 0.42, p = 0.003). We utilized ddPCR in a subset as a confirmatory measurement. This group had 26-33 copies of CON2 with a mean of 29, and each copy increase of CON2 was associated with a 3.3-point increase in WISC IQ (R (2) = 0.22, p = 0.045). In individuals from New Zealand, an increase in CON2 copy number was associated with an increase in math aptitude ability (R (2) = 0.10 p = 0.018). These were not confounded by brain size. To our knowledge, this is the first study to report a replicated association between copy number of a gene coding sequence and cognitive aptitude. Remarkably, dosage variations involving DUF1220 sequences have now been linked to human brain expansion, autism severity and cognitive aptitude, suggesting that such processes may be genetically and mechanistically inter-related. The findings presented here warrant expanded investigations in larger, well-characterized cohorts.

PMID: 25287832 [PubMed - indexed for MEDLINE]

Impairment of translation in neurons as a putative causative factor for autism.

March 7, 2015 - 7:55am
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Impairment of translation in neurons as a putative causative factor for autism.

Biol Direct. 2014;9:16

Authors: Poliakov E, Koonin EV, Rogozin IB

Abstract
BACKGROUND: A dramatic increase in the prevalence of autism and Autistic Spectrum Disorders (ASD) has been observed over the last two decades in USA, Europe and Asia. Given the accumulating data on the possible role of translation in the etiology of ASD, we analyzed potential effects of rare synonymous substitutions associated with ASD on mRNA stability, splicing enhancers and silencers, and codon usage.
PRESENTATION OF THE HYPOTHESIS: We hypothesize that subtle impairment of translation, resulting in dosage imbalance of neuron-specific proteins, contributes to the etiology of ASD synergistically with environmental neurotoxins.
TESTING THE HYPOTHESIS: A statistically significant shift from optimal to suboptimal codons caused by rare synonymous substitutions associated with ASD was detected whereas no effect on other analyzed characteristics of transcripts was identified. This result suggests that the impact of rare codons on the translation of genes involved in neuron development, even if slight in magnitude, could contribute to the pathogenesis of ASD in the presence of an aggressive chemical background. This hypothesis could be tested by further analysis of ASD-associated mutations, direct biochemical characterization of their effects, and assessment of in vivo effects on animal models.
IMPLICATIONS OF THE HYPOTHESIS: It seems likely that the synergistic action of environmental hazards with genetic variations that in themselves have limited or no deleterious effects but are potentiated by the environmental factors is a general principle that underlies the alarming increase in the ASD prevalence.
REVIEWERS: This article was reviewed by Andrey Rzhetsky, Neil R. Smalheiser, and Shamil R. Sunyaev.

PMID: 25011470 [PubMed - indexed for MEDLINE]

Towards a molecular characterization of autism spectrum disorders: an exome sequencing and systems approach.

March 7, 2015 - 7:55am
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Towards a molecular characterization of autism spectrum disorders: an exome sequencing and systems approach.

Transl Psychiatry. 2014;4:e394

Authors: An JY, Cristino AS, Zhao Q, Edson J, Williams SM, Ravine D, Wray J, Marshall VM, Hunt A, Whitehouse AJ, Claudianos C

Abstract
The hypothetical 'AXAS' gene network model that profiles functional patterns of heterogeneous DNA variants overrepresented in autism spectrum disorder (ASD), X-linked intellectual disability, attention deficit and hyperactivity disorder and schizophrenia was used in this current study to analyze whole exome sequencing data from an Australian ASD cohort. An optimized DNA variant filtering pipeline was used to identify loss-of-function DNA variations. Inherited variants from parents with a broader autism phenotype and de novo variants were found to be significantly associated with ASD. Gene ontology analysis revealed that putative rare causal variants cluster in key neurobiological processes and are overrepresented in functions involving neuronal development, signal transduction and synapse development including the neurexin trans-synaptic complex. We also show how a complex gene network model can be used to fine map combinations of inherited and de novo variations in families with ASD that converge in the L1CAM pathway. Our results provide an important step forward in the molecular characterization of ASD with potential for developing a tool to analyze the pathogenesis of individual affected families.

PMID: 24893065 [PubMed - indexed for MEDLINE]

Association of CDH11 with non-syndromic ASD.

March 7, 2015 - 7:55am
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Association of CDH11 with non-syndromic ASD.

Am J Med Genet B Neuropsychiatr Genet. 2014 Jul;165B(5):391-8

Authors: Crepel A, De Wolf V, Brison N, Ceulemans B, Walleghem D, Peuteman G, Lambrechts D, Steyaert J, Noens I, Devriendt K, Peeters H

Abstract
We report a sporadic patient with Autism Spectrum Disorder (ASD), mild intellectual disability and attention deficit hyperactivity disorder (ADHD) with a de novo partial deletion of CADHERIN 11 (CDH11). The deletion is associated with one of the breakpoints of a de novo complex chromosomal rearrangement 46,XY,t(3;16;5)(q29;q22;q15)inv4(p14;q21)ins(4;5)(q21;q14.3q15). Cadherins are cell adhesion molecules involved in synaptic plasticity. Since genetic evidence points towards a role for cadherins in ASD, we studied the possible contribution of CDH11 to ASD. A case-control association study for 14 SNP variants in 519 ASD cases and 1,192 controls showed significant overrepresentation of rs7187376C/C genotypes in the patient group [P = 0.0049 (Chi-square = 7.90 1 df) and O.R. 3.88 C.I. = 1.403-10.733]. There was no association for C/T versus T/T [P = 0.6772 (Chi-square = 0.17 1 df)] nor was there association at the allelic level [P = 0.4373 (Chi-square = 0.6 1 df)]. In addition to the association of common variants in CDH11 with ASD, we studied the possible contribution of rare variants by sequencing CDH11 in 247 patients, and found three novel variants in the coding region of CDH1, of which two variants were unlikely to be causal. Targeted CNV screening in these 247 patients did not reveal copy number variation in CDH11. In conclusion, the data provide evidence for the involvement of CDH11 in ASD which is consistent with the association of other cadherins with ASD and neuropsychiatric diseases.

PMID: 24839052 [PubMed - indexed for MEDLINE]

Grand-paternal age and the development of autism-like symptoms in mice progeny.

March 7, 2015 - 7:55am
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Grand-paternal age and the development of autism-like symptoms in mice progeny.

Transl Psychiatry. 2014;4:e386

Authors: Sampino S, Juszczak GR, Zacchini F, Swiergiel AH, Modlinski JA, Loi P, Ptak GE

Abstract
Advanced paternal age (APA) contributes to the risk of autism spectrum disorders (ASDs) in children. In this study, we used a mouse model to investigate the effects of APA on behavioral features related to autistic syndromes (that is, social deficits, communication impairments and stereotypic/repetitive behaviors). We also examined whether such effects are transmitted across generations. To do this, males aged 15 months (APA) and 4 months (control) were bred with 4-month-old females, and the resulting offspring (F1) and their progeny (F2; conceived by 4-month-old parents) were tested for the presence and severity of ASD-like behaviors. Our results indicate that APA resulted in offspring that displayed distinctive symptoms of ASD. We found that both F1 conceived from old fathers and F2 derived from old grandfathers displayed increased ultrasound vocalization (USV) activity, decreased sociability, increased grooming activity and increased anxiety-like responses. Moreover, such abnormalities were partially transmitted to the second generation of mice, having APA grandfathers. In conclusion, our study suggests that the risk of ASD could develop over generations, consistent with heritable mutations and/or epigenetic alterations associated with APA.

PMID: 24780920 [PubMed - indexed for MEDLINE]

Etiologies underlying sex differences in Autism Spectrum Disorders.

March 7, 2015 - 7:55am
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Etiologies underlying sex differences in Autism Spectrum Disorders.

Front Neuroendocrinol. 2014 Aug;35(3):255-71

Authors: Schaafsma SM, Pfaff DW

Abstract
The male predominance of Autism Spectrum Disorders (ASD) is one of the best-known, and at the same time, one of the least understood characteristics of these disorders. In this paper we review genetic, epigenetic, hormonal, and environmental mechanisms underlying this male preponderance. Sex-specific effects of Y-linked genes (including SRY expression leading to testicular development), balanced and skewed X-inactivation, genes that escape X-inactivation, parent-of-origin allelic imprinting, and the hypothetical heterochromatin sink are reviewed. These mechanisms likely contribute to etiology, instead of being simply causative to ASD. Environments, both internal and external, also play important roles in ASD's etiology. Early exposure to androgenic hormones and early maternal immune activation comprise environmental factors affecting sex-specific susceptibility to ASD. The gene-environment interactions underlying ASD, suggested here, implicate early prenatal stress as being especially detrimental to boys with a vulnerable genotype.

PMID: 24705124 [PubMed - indexed for MEDLINE]

Sex differences in attention Deficit Hyperactivity Disorder: candidate genetic and endocrine mechanisms.

March 7, 2015 - 7:55am
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Sex differences in attention Deficit Hyperactivity Disorder: candidate genetic and endocrine mechanisms.

Front Neuroendocrinol. 2014 Aug;35(3):331-46

Authors: Davies W

Abstract
Attention Deficit Hyperactivity Disorder (ADHD) is a developmental condition characterised by severe inattention, pathological impulsivity and hyperactivity; it is relatively common affecting up to 6% of children, and is associated with a risk of long-term adverse educational and social consequences. Males are considerably more likely to be diagnosed with ADHD than females; the course of the disorder and its associated co-morbidities also appear to be sensitive to sex. Here, I discuss fundamental biological (genetic and endocrine) mechanisms that have been shown to, or could theoretically, contribute towards these sexually dimorphic phenomena. Greater understanding of how and why the sexes differ with respect to ADHD vulnerability should allow us to identify and characterise novel protective and risk factors for the disorder, and should ultimately facilitate improved diagnosis, prognosis and treatment.

PMID: 24680800 [PubMed - indexed for MEDLINE]

The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.

March 7, 2015 - 7:55am
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The autism and schizophrenia associated gene CYFIP1 is critical for the maintenance of dendritic complexity and the stabilization of mature spines.

Transl Psychiatry. 2014;4:e374

Authors: Pathania M, Davenport EC, Muir J, Sheehan DF, López-Doménech G, Kittler JT

Abstract
Copy number variation (CNV) at the 15q11.2 region has been identified as a significant risk locus for neurological and neuropsychiatric conditions such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the individual roles for genes at this locus in nervous system development, function and connectivity remain poorly understood. Haploinsufficiency of one gene in this region, Cyfip1, may provide a model for 15q11.2 CNV-associated neuropsychiatric phenotypes. Here we show that altering CYFIP1 expression levels in neurons both in vitro and in vivo influences dendritic complexity, spine morphology, spine actin dynamics and synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor lateral diffusion. CYFIP1 is highly enriched at synapses and its overexpression in vitro leads to increased dendritic complexity. Neurons derived from Cyfip1 heterozygous animals on the other hand, possess reduced dendritic complexity, increased mobile F-actin and enhanced GluA2-containing AMPA receptor mobility at synapses. Interestingly, Cyfip1 overexpression or haploinsufficiency increased immature spine number, whereas activity-dependent changes in spine volume were occluded in Cyfip1 haploinsufficient neurons. In vivo, Cyfip1 heterozygous animals exhibited deficits in dendritic complexity as well as an altered ratio of immature-to-mature spines in hippocampal CA1 neurons. In summary, we provide evidence that dysregulation of CYFIP1 expression levels leads to pathological changes in CNS maturation and neuronal connectivity, both of which may contribute to the development of the neurological symptoms seen in ASD and SCZ.

PMID: 24667445 [PubMed - indexed for MEDLINE]

Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study.

March 7, 2015 - 7:55am
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Glutamate/glutamine and neuronal integrity in adults with ADHD: a proton MRS study.

Transl Psychiatry. 2014;4:e373

Authors: Maltezos S, Horder J, Coghlan S, Skirrow C, O'Gorman R, Lavender TJ, Mendez MA, Mehta M, Daly E, Xenitidis K, Paliokosta E, Spain D, Pitts M, Asherson P, Lythgoe DJ, Barker GJ, Murphy DG

Abstract
There is increasing evidence that abnormalities in glutamate signalling may contribute to the pathophysiology of attention-deficit hyperactivity disorder (ADHD). Proton magnetic resonance spectroscopy ([1H]MRS) can be used to measure glutamate, and also its metabolite glutamine, in vivo. However, few studies have investigated glutamate in the brain of adults with ADHD naive to stimulant medication. Therefore, we used [1H]MRS to measure the combined signal of glutamate and glutamine (Glu+Gln; abbreviated as Glx) along with other neurometabolites such as creatine (Cr), N-acetylaspartate (NAA) and choline. Data were acquired from three brain regions, including two implicated in ADHD-the basal ganglia (caudate/striatum) and the dorsolateral prefrontal cortex (DLPFC)-and one 'control' region-the medial parietal cortex. We compared 40 adults with ADHD, of whom 24 were naive for ADHD medication, whereas 16 were currently on stimulants, against 20 age, sex and IQ-matched healthy controls. We found that compared with controls, adult ADHD participants had a significantly lower concentration of Glx, Cr and NAA in the basal ganglia and Cr in the DLPFC, after correction for multiple comparisons. There were no differences between stimulant-treated and treatment-naive ADHD participants. In people with untreated ADHD, lower basal ganglia Glx was significantly associated with more severe symptoms of inattention. There were no significant differences in the parietal 'control' region. We suggest that subcortical glutamate and glutamine have a modulatory role in ADHD adults; and that differences in glutamate-glutamine levels are not explained by use of stimulant medication.

PMID: 24643164 [PubMed - indexed for MEDLINE]

Environmental toxicants and autism spectrum disorders: a systematic review.

March 7, 2015 - 7:55am
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Environmental toxicants and autism spectrum disorders: a systematic review.

Transl Psychiatry. 2014;4:e360

Authors: Rossignol DA, Genuis SJ, Frye RE

Abstract
Although the involvement of genetic abnormalities in autism spectrum disorders (ASD) is well-accepted, recent studies point to an equal contribution by environmental factors, particularly environmental toxicants. However, these toxicant-related studies in ASD have not been systematically reviewed to date. Therefore, we compiled publications investigating potential associations between environmental toxicants and ASD and arranged these publications into the following three categories: (a) studies examining estimated toxicant exposures in the environment during the preconceptional, gestational and early childhood periods; (b) studies investigating biomarkers of toxicants; and (c) studies examining potential genetic susceptibilities to toxicants. A literature search of nine electronic scientific databases through November 2013 was performed. In the first category examining ASD risk and estimated toxicant exposures in the environment, the majority of studies (34/37; 92%) reported an association. Most of these studies were retrospective case-control, ecological or prospective cohort studies, although a few had weaker study designs (for example, case reports or series). Toxicants implicated in ASD included pesticides, phthalates, polychlorinated biphenyls (PCBs), solvents, toxic waste sites, air pollutants and heavy metals, with the strongest evidence found for air pollutants and pesticides. Gestational exposure to methylmercury (through fish exposure, one study) and childhood exposure to pollutants in water supplies (two studies) were not found to be associated with ASD risk. In the second category of studies investigating biomarkers of toxicants and ASD, a large number was dedicated to examining heavy metals. Such studies demonstrated mixed findings, with only 19 of 40 (47%) case-control studies reporting higher concentrations of heavy metals in blood, urine, hair, brain or teeth of children with ASD compared with controls. Other biomarker studies reported that solvent, phthalate and pesticide levels were associated with ASD, whereas PCB studies were mixed. Seven studies reported a relationship between autism severity and heavy metal biomarkers, suggesting evidence of a dose-effect relationship. Overall, the evidence linking biomarkers of toxicants with ASD (the second category) was weaker compared with the evidence associating estimated exposures to toxicants in the environment and ASD risk (the first category) because many of the biomarker studies contained small sample sizes and the relationships between biomarkers and ASD were inconsistent across studies. Regarding the third category of studies investigating potential genetic susceptibilities to toxicants, 10 unique studies examined polymorphisms in genes associated with increased susceptibilities to toxicants, with 8 studies reporting that such polymorphisms were more common in ASD individuals (or their mothers, 1 study) compared with controls (one study examined multiple polymorphisms). Genes implicated in these studies included paraoxonase (PON1, three of five studies), glutathione S-transferase (GSTM1 and GSTP1, three of four studies), δ-aminolevulinic acid dehydratase (one study), SLC11A3 (one study) and the metal regulatory transcription factor 1 (one of two studies). Notably, many of the reviewed studies had significant limitations, including lack of replication, limited sample sizes, retrospective design, recall and publication biases, inadequate matching of cases and controls, and the use of nonstandard tools to diagnose ASD. The findings of this review suggest that the etiology of ASD may involve, at least in a subset of children, complex interactions between genetic factors and certain environmental toxicants that may act synergistically or in parallel during critical periods of neurodevelopment, in a manner that increases the likelihood of developing ASD. Because of the limitations of many of the reviewed studies, additional high-quality epidemiological studies concerning environmental toxicants and ASD are warranted to confirm and clarify many of these findings.

PMID: 24518398 [PubMed - indexed for MEDLINE]

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

March 7, 2015 - 7:55am
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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
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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
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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
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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
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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
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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]

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