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Integrating multiple genomic data to predict disease-causing nonsynonymous single nucleotide variants in exome sequencing studies.

March 22, 2014 - 8:20am
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Integrating multiple genomic data to predict disease-causing nonsynonymous single nucleotide variants in exome sequencing studies.

PLoS Genet. 2014 Mar;10(3):e1004237

Authors: Wu J, Li Y, Jiang R

Abstract
Exome sequencing has been widely used in detecting pathogenic nonsynonymous single nucleotide variants (SNVs) for human inherited diseases. However, traditional statistical genetics methods are ineffective in analyzing exome sequencing data, due to such facts as the large number of sequenced variants, the presence of non-negligible fraction of pathogenic rare variants or de novo mutations, and the limited size of affected and normal populations. Indeed, prevalent applications of exome sequencing have been appealing for an effective computational method for identifying causative nonsynonymous SNVs from a large number of sequenced variants. Here, we propose a bioinformatics approach called SPRING (Snv PRioritization via the INtegration of Genomic data) for identifying pathogenic nonsynonymous SNVs for a given query disease. Based on six functional effect scores calculated by existing methods (SIFT, PolyPhen2, LRT, MutationTaster, GERP and PhyloP) and five association scores derived from a variety of genomic data sources (gene ontology, protein-protein interactions, protein sequences, protein domain annotations and gene pathway annotations), SPRING calculates the statistical significance that an SNV is causative for a query disease and hence provides a means of prioritizing candidate SNVs. With a series of comprehensive validation experiments, we demonstrate that SPRING is valid for diseases whose genetic bases are either partly known or completely unknown and effective for diseases with a variety of inheritance styles. In applications of our method to real exome sequencing data sets, we show the capability of SPRING in detecting causative de novo mutations for autism, epileptic encephalopathies and intellectual disability. We further provide an online service, the standalone software and genome-wide predictions of causative SNVs for 5,080 diseases at http://bioinfo.au.tsinghua.edu.cn/spring.

PMID: 24651380 [PubMed - in process]

Branched-Chain Amino Acid Metabolism: From Rare Mendelian Diseases to More Common Disorders.

March 22, 2014 - 8:20am
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Branched-Chain Amino Acid Metabolism: From Rare Mendelian Diseases to More Common Disorders.

Hum Mol Genet. 2014 Mar 20;

Authors: Burrage LC, Nagamani SC, Campeau PM, Lee BH

Abstract
Branched-chain amino acid (BCAA) metabolism plays a central role in the pathophysiology of both rare inborn errors of metabolism and the more common multi-factorial diseases. Although deficiency of the branched-chain ketoacid dehydrogenase (BCKDC) and associated elevations in the BCAAs and their ketoacids have been recognized as the cause of maple syrup urine disease (MSUD) for decades, treatment options for this disorder have been limited to dietary interventions. In recent years, the discovery of improved leucine tolerance after liver transplantation has resulted in a new therapeutic strategy for this disorder. Likewise, targeting the regulation of the BCKDC activity may be an alternative potential treatment strategy for MSUD. The regulation of the BCKDC by the branched-chain ketoacid dehydrogenase kinase (BCKDK) has also been implicated in a new inborn error of metabolism characterized by autism, intellectual disability, and seizures. Lastly, there is a growing body of literature implicating BCAA metabolism in more common disorders such as the metabolic syndrome, cancer, and hepatic disease. This review surveys the knowledge acquired on the topic over the past 50 years and focuses on recent developments in the field of BCAA metabolism.

PMID: 24651065 [PubMed - as supplied by publisher]

Genetic Evidence for the Adhesion Protein IgSF9/Dasm1 to Regulate Inhibitory Synapse Development Independent of its Intracellular Domain.

March 22, 2014 - 8:20am
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Genetic Evidence for the Adhesion Protein IgSF9/Dasm1 to Regulate Inhibitory Synapse Development Independent of its Intracellular Domain.

J Neurosci. 2014 Mar 19;34(12):4187-99

Authors: Mishra A, Traut MH, Becker L, Klopstock T, Stein V, Klein R

Abstract
Normal brain function requires balanced development of excitatory and inhibitory synapses. An imbalance in synaptic transmission underlies many brain disorders such as epilepsy, schizophrenia, and autism. Compared with excitatory synapses, relatively little is known about the molecular control of inhibitory synapse development. We used a genetic approach in mice to identify the Ig superfamily member IgSF9/Dasm1 as a candidate homophilic synaptic adhesion protein that regulates inhibitory synapse development. IgSF9 is expressed in pyramidal cells and subsets of interneurons in the CA1 region of hippocampus. Electrophysiological recordings of acute hippocampal slices revealed that genetic inactivation of the IgSF9 gene resulted in fewer functional inhibitory synapses; however, the strength of the remaining synapses was unaltered. These physiological abnormalities were correlated with decreased expression of inhibitory synapse markers in IgSF9(-/-) mice, providing anatomical evidence for a reduction in inhibitory synapse numbers, whereas excitatory synapse development was normal. Surprisingly, knock-in mice expressing a mutant isoform of IgSF9 lacking the entire cytoplasmic domain (IgSF9(ΔC/ΔC) mice) had no defects in inhibitory synapse development, providing genetic evidence that IgSF9 regulates synapse development via ectodomain interactions rather than acting itself as a signaling receptor. Further, we found that IgSF9 mediated homotypic binding and cell aggregation, but failed to induce synapse formation, suggesting that IgSF9 acts as a cell adhesion molecule (CAM) to maintain synapses. Juvenile IgSF9(-/-) mice exhibited increased seizure susceptibility indicative of an imbalance in synaptic excitation and inhibition. These results provide genetic evidence for a specific role of IgSF9 in inhibitory synapse development/maintenance, presumably by its CAM-like activity.

PMID: 24647940 [PubMed - in process]

Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.

March 22, 2014 - 8:20am
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Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model.

Genes Dev. 2014 Feb 1;28(3):273-89

Authors: Lim CS, Hoang ET, Viar KE, Stornetta RL, Scott MM, Zhu JJ

Abstract
Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. Using a tractable animal model, we investigated mechanisms of action of a few FDA-approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients. Here we report that compounds activating serotonin (5HT) subtype 2B receptors (5HT2B-Rs) or dopamine (DA) subtype 1-like receptors (D1-Rs) and/or those inhibiting 5HT2A-Rs or D2-Rs moderately enhance Ras-PI3K/PKB signaling input, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Unexpectedly, combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras-PI3K/PKB signal transduction and GluA1-dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects. These findings suggest that properly dosed and combined FDA-approved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome.

PMID: 24493647 [PubMed - indexed for MEDLINE]

[Circadian rhythm disruption and human development].

March 22, 2014 - 8:20am
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[Circadian rhythm disruption and human development].

Nihon Rinsho. 2013 Dec;71(12):2082-8

Authors: Kohyama J

Abstract
Ontogenetic developments of rest-activity, sleep-wakefulness, temperature and several hormone rhythms in humans were reviewed. The reported effects of environment on these alterations were also summarized. Then, disorders or conditions which often encounter during early stage of life and reveal circadian rhythm disruptions were described. These disorders or conditions included severe brain damage, visual disturbance, developmental disorders(autistic spectrum disorder and attention deficit/hyperactivity disorder), Rett syndrome, Angelman syndrome, Smith-Magenis syndrome, epilepsy, Yonaki, and inadequate sleep hygiene. Finally, it was emphasized that we should pay special attention on the development of youngsters who showed sleep disturbance during early stage of life with special reference to the later occurrence of developmental disorders.

PMID: 24437259 [PubMed - indexed for MEDLINE]

Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes.

March 22, 2014 - 8:20am
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Integrated model of de novo and inherited genetic variants yields greater power to identify risk genes.

PLoS Genet. 2013;9(8):e1003671

Authors: He X, Sanders SJ, Liu L, De Rubeis S, Lim ET, Sutcliffe JS, Schellenberg GD, Gibbs RA, Daly MJ, Buxbaum JD, State MW, Devlin B, Roeder K

Abstract
De novo mutations affect risk for many diseases and disorders, especially those with early-onset. An example is autism spectrum disorders (ASD). Four recent whole-exome sequencing (WES) studies of ASD families revealed a handful of novel risk genes, based on independent de novo loss-of-function (LoF) mutations falling in the same gene, and found that de novo LoF mutations occurred at a twofold higher rate than expected by chance. However successful these studies were, they used only a small fraction of the data, excluding other types of de novo mutations and inherited rare variants. Moreover, such analyses cannot readily incorporate data from case-control studies. An important research challenge in gene discovery, therefore, is to develop statistical methods that accommodate a broader class of rare variation. We develop methods that can incorporate WES data regarding de novo mutations, inherited variants present, and variants identified within cases and controls. TADA, for Transmission And De novo Association, integrates these data by a gene-based likelihood model involving parameters for allele frequencies and gene-specific penetrances. Inference is based on a Hierarchical Bayes strategy that borrows information across all genes to infer parameters that would be difficult to estimate for individual genes. In addition to theoretical development we validated TADA using realistic simulations mimicking rare, large-effect mutations affecting risk for ASD and show it has dramatically better power than other common methods of analysis. Thus TADA's integration of various kinds of WES data can be a highly effective means of identifying novel risk genes. Indeed, application of TADA to WES data from subjects with ASD and their families, as well as from a study of ASD subjects and controls, revealed several novel and promising ASD candidate genes with strong statistical support.

PMID: 23966865 [PubMed - indexed for MEDLINE]

Synthesis and bioassay of a new class of furanyl-1,3,4-oxadiazole derivatives.

March 22, 2014 - 8:20am
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Synthesis and bioassay of a new class of furanyl-1,3,4-oxadiazole derivatives.

Molecules. 2013;18(7):8550-62

Authors: El Sadek MM, Hassan SY, Abdelwahab HE, Yacout GA

Abstract
Tyrosinase enzyme is a monophenol monoxygenase enzyme, which plays an important role in human as a rate limiting step enzyme for different specific metabolic pathways, as well as its useful application in industry and agriculture. So this study was carried out to test the effect of newly prepared compounds containing 1,3,4-oxadiazoles with different substituted groups on tyrosinase enzyme activity, hoping to use them in the treatment of some diseases arising from tyrosinase activity disorders such as Parkinson's disease, schizophrenia, autism, attention deficit, hyperactivity disorder, and cancer.

PMID: 23877049 [PubMed - indexed for MEDLINE]

Epileptic spasms in tuberous sclerosis complex.

March 22, 2014 - 8:20am
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Epileptic spasms in tuberous sclerosis complex.

Epilepsy Res. 2013 Sep;106(1-2):200-10

Authors: Hsieh DT, Jennesson MM, Thiele EA

Abstract
PURPOSE: To characterize epileptic spasms (ES) occurring after the age of two years in patients with tuberous sclerosis complex (TSC), particularly treatment response to vigabatrin (VGB), which is extremely effective for infantile spasms (IS) in TSC.
METHODS: The authors retrospectively reviewed 19 patients with TSC and ES. Medical records were assessed for clinical and treatment data, neurocognitive, EEG, MRI data, and genetic analyses.
RESULTS: Of 391 patients with TSC, 19 (4.8%) had ES. Of those with detailed clinical data, six had infantile spasms that persisted after 2 years old, six recurred after an initial remission of infantile spasms (range 2-24 years old), and four occurred de novo over the age of two (range 2-20 years old). All concurrently had other seizure types. One had hypsarrhythmia on EEG. All had brain MRI stigmata typical of TSC. Thirteen had a mutation in TSC2, and one in TSC1. Six patients became spasm-free with medication treatment, including four with VGB, one with VGB in combination with the low glycemic index dietary treatment, and one with felbamate. Five became spasm-free after epilepsy surgery. VGB was not effective for seven patients. The majority continued to have refractory epilepsy.
CONCLUSIONS: ES are not uncommon in patients with TSC, especially those with TSC2 mutations. ES in TSC occur in the setting of other seizure types and refractory epilepsy. Hypsarrhythmia is rare. VGB can be effective, but the success of VGB for ES in TSC is not equivalent to that of IS in TSC.

PMID: 23796861 [PubMed - indexed for MEDLINE]

Cancer and copy number variants in an autism diagnostic clinic.

March 22, 2014 - 8:20am
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Cancer and copy number variants in an autism diagnostic clinic.

J Dev Behav Pediatr. 2013 Jun;34(5):379-81

Authors: Gannon WT, Martinez JE, Anderson SJ, Swingle HM

PMID: 23751890 [PubMed - indexed for MEDLINE]

Head circumferences in twins with and without Autism Spectrum Disorders.

March 22, 2014 - 8:20am
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Head circumferences in twins with and without Autism Spectrum Disorders.

J Autism Dev Disord. 2013 Sep;43(9):2026-37

Authors: Froehlich W, Cleveland S, Torres A, Phillips J, Cohen B, Torigoe T, Miller J, Fedele A, Collins J, Smith K, Lotspeich L, Croen LA, Ozonoff S, Lajonchere C, Grether JK, Hallmayer J

Abstract
To determine the genetic relationship between head circumference (HC) and Autism Spectrum Disorders (ASDs). Twin pairs with at least one twin with an ASD were assessed. HCs in affected and unaffected individuals were compared, as were HC correlations in monozygotic and dizygotic pairs. 404 subjects, ages 4-18, were included. 20 % of males and 27 % of females with an ASD had macrocephaly. Unaffected co-twins showed similar rates (16 % of males and 22 % of females). Statistical analysis revealed no significant difference in HCs between affected and unaffected twins. Twins with ASDs and unaffected co-twins have similar HCs and increased rates of macrocephaly. Correlations demonstrated partial inheritance of HCs. Thus, macrocephaly may represent an endophenotype in ASDs.

PMID: 23321801 [PubMed - indexed for MEDLINE]

Ethical considerations in conducting research on autism spectrum disorders in low and middle income countries.

March 22, 2014 - 8:20am
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Ethical considerations in conducting research on autism spectrum disorders in low and middle income countries.

J Autism Dev Disord. 2013 Sep;43(9):2002-14

Authors: Daley TC, Singhal N, Krishnamurthy V

Abstract
Autism spectrum disorder (ASD) is being identified in an ever-increasing number of countries, including many that are low or middle income (LMIC). Research conducted in these countries requires awareness of unique ethical issues. Drawing on the experience of two organizations that have been involved in conducting and collaborating in ASD research in India, we describe specific considerations in conducting epidemiological, genetic and treatment studies as well as general principles from the field of multinational clinical research as they apply to the conduct of ASD research. We argue that greater attention to ethical concerns will result in quality studies conducted in LMICs that are also of greatest relevance for families and children with ASD.

PMID: 23283629 [PubMed - indexed for MEDLINE]

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

March 20, 2014 - 7:34am

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 - as supplied by publisher]

Genetics of childhood-onset schizophrenia.

March 19, 2014 - 7:22am
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Genetics of childhood-onset schizophrenia.

Child Adolesc Psychiatr Clin N Am. 2013 Oct;22(4):675-87

Authors: Asarnow RF, Forsyth JK

Abstract
Schizophrenia is a heritable disorder. The genetic architecture of schizophrenia is complex and heterogeneous. This article discusses genetic studies of childhood-onset schizophrenia (COS) and compares findings in familial aggregation, common allele, and rare allele studies of COS with those for adult-onset schizophrenia (AOS). COS seems to be a rare variant of AOS with greater familial aggregation of schizophrenia spectrum disorders and higher occurrence of rare allelic variants. The usefulness of genetic screening for diagnosis and individualized treatment is limited; however, identifying common pathways through which multiple genes adversely affect neural systems offers great promise toward developing novel pharmacologic interventions.

PMID: 24012080 [PubMed - indexed for MEDLINE]

Increased susceptibility to mild neonatal stress in MTHFR deficient mice.

March 19, 2014 - 7:22am
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Increased susceptibility to mild neonatal stress in MTHFR deficient mice.

Behav Brain Res. 2013 Sep 15;253:240-52

Authors: Kezurer N, Galron D, Golan HM

Abstract
Early life stress is shown to have a life-span outcome on human and animal behavior, increasing the risk for psychopathology. The gene methylenetetrahydrofolate reductase (MTHFR), which encodes for a key enzyme in one carbon metabolism, shows a high prevalence of polymorphism in patients with developmental disorders. Here we examined the hypothesis that MTHFR deficiency results in an increased susceptibility of the developing brain to mild neonatal stress (NS). Mild NS failed to alter corticosterone levels in young and adult Wt mice. However, an elevated level of corticosterone was found in the MTHFR deficient-NS female, exemplifying enhanced sensitivity to NS. Behavioral phenotyping of Wt and MTHFR deficient mice provides evidence that the effect of mild NS may be amplified by the MTHFR deficient genotype. Distinct behavioral characteristics were altered in male and female mice. In general, three patterns of influence on mice behavior were observed: (1) an additive suppressive effect of NS and MTHFR deficiency on exploration and activity was evident in females; (2) stress related parameters were significantly sensitive to genotype in females, presenting an interaction between genotype and sex; (3) various aspects of behavior in a social setting were modified preferably in males by genotype, NS and the interaction between the two, while females exhibited a smaller effect that was restricted to NS with no genotype effect. Overall, our results support an interaction between mild NS, the MTHFR genotype and sex. We suggest using this animal model to study the molecular mechanism linking these two risk factors and their involvement in neurodevelopmental disorders such as schizophrenia and autism.

PMID: 23896051 [PubMed - indexed for MEDLINE]

Biomarkers for personalised treatment in psychiatric diseases.

March 19, 2014 - 7:22am
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Biomarkers for personalised treatment in psychiatric diseases.

Expert Opin Med Diagn. 2013 Sep;7(5):417-22

Authors: Bagdy G, Juhasz G

Abstract
Biomarker research of psychiatric disorders is delayed by symptom pattern-related diagnostic categories that are only distantly associated with biological mechanisms. In neuropsychiatric disorders that have high heritability (schizophrenia, autism, Alzheimer's disease), genomic research led to significant genome-wide association study (GWAS) results by increasing the number of subjects in case-control studies, and thus provided new hypotheses regarding the aetiology of these disorders and possible targets for research of new treatment approaches. In contrast, in moderately heritable psychiatric disorders (anxiety disorders, unipolar major depression), the development of symptoms, in addition to risk genes, is more dependent on the presence of specific environmental risk factors. Thus, controlling for heterogeneity, and not simply increasing the number of subjects, is crucial for further significant psychiatric GWAS findings that warrant the collection of more detailed individual phenotypic data and information about relevant previous environmental exposures. Gene-gene interactions (epistasis) and intermediate phenotypes or psychiatric and somatic co-morbidities, by identifying similar cases within a diagnostic category, could further increase the generally weak effects of individual genes that limit their usefulness as biomarkers. In conclusion, we argue that methods that are suitable to identify biologically more homogeneous subgroups within a given psychiatric disorder are necessary to advance biomarker research.

PMID: 23875948 [PubMed - indexed for MEDLINE]

Delayed myelination in a mouse model of fragile X syndrome.

March 19, 2014 - 7:22am
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Delayed myelination in a mouse model of fragile X syndrome.

Hum Mol Genet. 2013 Oct 1;22(19):3920-30

Authors: Pacey LK, Xuan IC, Guan S, Sussman D, Henkelman RM, Chen Y, Thomsen C, Hampson DR

Abstract
Fragile X Syndrome is the most common inherited cause of autism. Fragile X mental retardation protein (FMRP), which is absent in fragile X, is an mRNA binding protein that regulates the translation of hundreds of different mRNA transcripts. In the adult brain, FMRP is expressed primarily in the neurons; however, it is also expressed in developing glial cells, where its function is not well understood. Here, we show that fragile X (Fmr1) knockout mice display abnormalities in the myelination of cerebellar axons as early as the first postnatal week, corresponding roughly to the equivalent time in human brain development when symptoms of the syndrome first become apparent (1-3 years of age). At postnatal day (PND) 7, diffusion tensor magnetic resonance imaging showed reduced volume of the Fmr1 cerebellum compared with wild-type mice, concomitant with an 80-85% reduction in the expression of myelin basic protein, fewer myelinated axons and reduced thickness of myelin sheaths, as measured by electron microscopy. Both the expression of the proteoglycan NG2 and the number of PDGFRα+/NG2+ oligodendrocyte precursor cells were reduced in the Fmr1 cerebellum at PND 7. Although myelin proteins were still depressed at PND 15, they regained wild-type levels by PND 30. These findings suggest that impaired maturation or function of oligodendrocyte precursor cells induces delayed myelination in the Fmr1 mouse brain. Our results bolster an emerging recognition that white matter abnormalities in early postnatal brain development represent an underlying neurological deficit in Fragile X syndrome.

PMID: 23740941 [PubMed - indexed for MEDLINE]

The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells.

March 19, 2014 - 7:22am
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The functional genetic link of NLGN4X knockdown and neurodevelopment in neural stem cells.

Hum Mol Genet. 2013 Sep 15;22(18):3749-60

Authors: Shi L, Chang X, Zhang P, Coba MP, Lu W, Wang K

Abstract
Genetic mutations in NLGN4X (neuroligin 4), including point mutations and copy number variants (CNVs), have been associated with susceptibility to autism spectrum disorders (ASDs). However, it is unclear how mutations in NLGN4X result in neurodevelopmental defects. Here, we used neural stem cells (NSCs) as in vitro models to explore the impacts of NLGN4X knockdown on neurodevelopment. Using two shRNAmir-based vectors targeting NLGN4X and one control shRNAmir vector, we modulated NLGN4X expression and differentiated these NSCs into mature neurons. We monitored the neurodevelopmental process at Weeks 0, 0.5, 1, 2, 4 and 6, based on morphological analysis and whole-genome gene expression profiling. At the cellular level, in NSCs with NLGN4X knockdown, we observed increasingly delayed neuronal development and compromised neurite formation, starting from Week 2 through Week 6 post differentiation. At the molecular level, we identified multiple pathways, such as neurogenesis, neuron differentiation and muscle development, which are increasingly disturbed in cells with NLGN4X knockdown. Notably, several postsynaptic genes, including DLG4, NLGN1 and NLGN3, also have decreased expression. Based on in vitro models, NLGN4X knockdown directly impacts neurodevelopmental process during the formation of neurons and their connections. Our functional genomics study highlights the utility of NSCs models in understanding the functional roles of CNVs in affecting neurodevelopment and conferring susceptibility to neurodevelopmental diseases.

PMID: 23710042 [PubMed - indexed for MEDLINE]

Variant in OXTR gene and functional connectivity of the hypothalamus in normal subjects.

March 19, 2014 - 7:22am
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Variant in OXTR gene and functional connectivity of the hypothalamus in normal subjects.

Neuroimage. 2013 Nov 1;81:199-204

Authors: Wang J, Qin W, Liu B, Wang D, Zhang Y, Jiang T, Yu C

Abstract
The oxytocin receptor gene (OXTR) rs53576A has been associated with autism spectrum disorders (ASDs). A smaller hypothalamic volume has been reported in healthy male A-allele carriers than in male GG homozygotes and in patients with ASDs than in healthy controls. These findings prompt the hypothesis that male AA homozygotes may have weaker hypothalamic functional connectivity when compared to male G-allele carriers. We calculated local functional connectivity density (FCD) using a voxel-wise data-driven approach based on resting-state functional MRI data in 270 young healthy subjects. Both the main effect of genotype and the gender-by-genotype interaction were considered. Of the whole brain, only the local FCD of the hypothalamus exhibited the main effect of genotype. Post-hoc testing revealed significantly lower local FCD in male AA homozygotes compared to male G-allele carriers although there was only a trend of significance in the gender-by-genotype interaction. We further analyzed the resting-state functional connectivity (rsFC) of the hypothalamic region that demonstrating significant genotype differences in local FCD. We found a significant gender-by-genotype interaction in rsFC between the hypothalamic region and the left dorsolateral prefrontal cortex, but no significant main effect of genotype was found. Post-hoc testing revealed that this rsFC was significantly weaker in male AA homozygotes compared to male G-allele carriers. Our findings identify gender-dependent mechanisms of OXTR rs53576 gene variation impacting the functional connectivity of the hypothalamus in healthy individuals and suggest that these mechanisms are important for understanding ASDs.

PMID: 23684879 [PubMed - indexed for MEDLINE]

Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability.

March 16, 2014 - 9:10pm
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Environmental and state-level regulatory factors affect the incidence of autism and intellectual disability.

PLoS Comput Biol. 2014 Mar;10(3):e1003518

Authors: Rzhetsky A, Bagley SC, Wang K, Lyttle CS, Cook EH, Altman RB, Gibbons RD

Abstract
Many factors affect the risks for neurodevelopmental maladies such as autism spectrum disorders (ASD) and intellectual disability (ID). To compare environmental, phenotypic, socioeconomic and state-policy factors in a unified geospatial framework, we analyzed the spatial incidence patterns of ASD and ID using an insurance claims dataset covering nearly one third of the US population. Following epidemiologic evidence, we used the rate of congenital malformations of the reproductive system as a surrogate for environmental exposure of parents to unmeasured developmental risk factors, including toxins. Adjusted for gender, ethnic, socioeconomic, and geopolitical factors, the ASD incidence rates were strongly linked to population-normalized rates of congenital malformations of the reproductive system in males (an increase in ASD incidence by 283% for every percent increase in incidence of malformations, 95% CI: [91%, 576%], p<6×10-5). Such congenital malformations were barely significant for ID (94% increase, 95% CI: [1%, 250%], p = 0.0384). Other congenital malformations in males (excluding those affecting the reproductive system) appeared to significantly affect both phenotypes: 31.8% ASD rate increase (CI: [12%, 52%], p<6×10-5), and 43% ID rate increase (CI: [23%, 67%], p<6×10-5). Furthermore, the state-mandated rigor of diagnosis of ASD by a pediatrician or clinician for consideration in the special education system was predictive of a considerable decrease in ASD and ID incidence rates (98.6%, CI: [28%, 99.99%], p = 0.02475 and 99% CI: [68%, 99.99%], p = 0.00637 respectively). Thus, the observed spatial variability of both ID and ASD rates is associated with environmental and state-level regulatory factors; the magnitude of influence of compound environmental predictors was approximately three times greater than that of state-level incentives. The estimated county-level random effects exhibited marked spatial clustering, strongly indicating existence of as yet unidentified localized factors driving apparent disease incidence. Finally, we found that the rates of ASD and ID at the county level were weakly but significantly correlated (Pearson product-moment correlation 0.0589, p = 0.00101), while for females the correlation was much stronger (0.197, p<2.26×10-16).

PMID: 24625521 [PubMed - in process]

Additional post-natal diagnoses following antenatal diagnosis of isolated cleft lip +/- palate.

March 16, 2014 - 9:10pm
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Additional post-natal diagnoses following antenatal diagnosis of isolated cleft lip +/- palate.

Arch Dis Child Fetal Neonatal Ed. 2014 Mar 13;

Authors: Burnell L, Verchere C, Pugash D, Loock C, Robertson S, Lehman A

Abstract
INTRODUCTION: Cleft lip with or without palate (CLP) can be diagnosed antenatally through ultrasound, and may be categorised as apparently isolated versus associated with other malformations. Limited data exist on the long-term outcomes following antenatal diagnosis of apparently isolated CLP.
AIM: This study examined the long-term post-natal outcomes of CLP when found in isolation antenatally, in order to determine the rates of unexpected additional anomalies, developmental delay or genetic syndromes.
PATIENTS AND METHODS: A retrospective chart review of antenatal and post-natal medical charts was completed for a ten-year period between January 2000 and December 2009. At least 2 years of available post-natal clinical information was required for inclusion in the study.
RESULTS: A total of 97 cases of antenatally isolated CLP were ascertained. Fifteen pregnancies were terminated. Follow-up data were available for 81 liveborns, though 4 were lost to follow-up prior to 2 years of age. Twelve of the 77 children meeting study criteria were identified to have other major malformations and/or developmental disability either later in the pregnancy or post-natally. Findings included familial clefting syndromes, trisomy 21, autism spectrum disorders, brain malformations, fetal alcohol syndrome and Kabuki syndrome, among other findings. Another 11 children had additional anomalies of minor impact. Examples of findings include a perimembranous ventricular septal defect, mild unilateral optic nerve hypoplasia, mild pulmonary artery stenosis with a small atrial septal defect, and transient delays in fine and gross motor skills. No children with clefting of the lip only had major additional diagnoses.
CONCLUSIONS: The frequency of an associated complex developmental disorder following an otherwise reassuring fetal ultrasound is around 15%. A few diagnoses could be suspected at the antenatal assessment based on family history or exposures. Our study is lacking comprehensive assessment on the yield of genomic microarray testing for this population.

PMID: 24625434 [PubMed - as supplied by publisher]

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