pubmed: autism and genetics

Subscribe to pubmed: autism and genetics feed pubmed: autism and genetics
NCBI: db=pubmed; Term=autism AND genetics
Updated: 2 hours 10 min ago

A longitudinal twin study of the association between childhood autistic traits and psychotic experiences in adolescence.

July 23, 2015 - 7:27am
Related Articles

A longitudinal twin study of the association between childhood autistic traits and psychotic experiences in adolescence.

Mol Autism. 2015;6:44

Authors: Taylor MJ, Robinson EB, Happé F, Bolton P, Freeman D, Ronald A

Abstract
BACKGROUND: This twin study investigated whether autistic traits during childhood were associated with adolescent psychotic experiences.
METHODS: Data were collected from a community sample of approximately 5000 twin pairs, which included 32 individuals with diagnosed autism spectrum conditions (ASC). Parents rated autistic traits in the twins at four points between ages 8-16 years. Positive, negative, and cognitive psychotic experiences were assessed at age 16 years using self- and parent-report scales. Longitudinal twin analyses tested the associations between these measures.
RESULTS: Autistic traits correlated weakly or nonsignificantly with positive psychotic experiences (paranoia, hallucinations, and grandiosity), and modestly with cognitive psychotic experiences (cognitive disorganisation). Higher correlations were observed for parent-rated negative symptoms and self-reported anhedonia, although the proportion of variance in both accounted for by autistic traits was low (10 and 31 %, respectively). The majority of the genetic influences on negative symptoms and anhedonia were independent of autistic traits. Additionally, individuals with ASC displayed significantly more negative symptoms, anhedonia, and cognitive disorganisation than controls.
CONCLUSIONS: Autistic traits do not appear to be strongly associated with psychotic experiences in adolescence; associations were also largely restricted to negative symptoms. Of note, the degree to which the genetic and environmental causes of autistic traits influenced psychotic experiences was limited. These findings thus support a phenotypic and etiological distinction between autistic traits and psychotic experiences.

PMID: 26199714 [PubMed]

Prenatal mercury exposure, autism, and developmental delay, using pharmacokinetic combination of newborn blood concentrations and questionnaire data: a case control study.

July 23, 2015 - 7:27am
Related Articles

Prenatal mercury exposure, autism, and developmental delay, using pharmacokinetic combination of newborn blood concentrations and questionnaire data: a case control study.

Environ Health. 2015;14(1):62

Authors: McKean SJ, Bartell SM, Hansen RL, Barfod GH, Green PG, Hertz-Picciotto I

Abstract
BACKGROUND: Methylmercury (MeHg), known for well over a century as a neurotoxin in adults, has more recently been studied for potential detrimental effects during early brain development. While several studies have estimated mercury exposure, they usually rely on either a single biomarker or questionnaire data, each of which has limitations. The goal of this paper was to develop a toxicokinetic model that incorporates both biomarker and questionnaire data to estimate the cumulative exposure to MeHg through seafood consumption using data collected from the Childhood Autism Risks from Genetics and the Environment (CHARGE) study.
METHODS: We utilized a previously described discrete-time model that estimates blood MeHg concentration given a piecewise-constant ingestion rate and single-compartment pharmacokinetics. We measured newborn bloodspot Hg concentrations and obtained information pertaining to maternal fish consumption using a questionnaire. Using MeHg concentration estimates from the toxicokinetic model, cumulative MeHg exposure was estimated in children with autism, children with developmental delay, and typically developing children. Median estimated cumulative MeHg was compared among diagnostic groups using the Kruskal-Wallis Test. Multinomial logistic regression models were constructed to assess the association between cumulative MeHg concentration and the risk of autism and developmental delay (vs. typical development).
RESULTS: The estimated average MeHg concentration of for all fish species consumed by mothers was 42 ppb. Median cumulative MeHg over gestation was similar across diagnostic groups (p-values raged from 0.91 to 0.98). After adjusting for potential confounding, we found no association between cumulative MeHg exposure and the risk of autism (OR = 0.95, 95 % CI: 0.95, 1.12) or developmental delay (OR = 1.00, 95 % CI: 0.89, 1.13).
CONCLUSIONS: The toxicokinetic model described in this paper yielded fish MeHg concentration estimates that are consistent with fish species containing lower levels of MeHg. Overall, cumulative MeHg exposure does not appear to detectably elevate the risk of autism or developmental delay. Based on the regression standard error for the association between ASD and TD, we would have reported statistical significance for an adjusted odds ratio of 1.09 or larger. This method can easily be extended to other epidemiologic studies in which there is a biomarker measurement and questionnaire data regarding exposure.

PMID: 26198445 [PubMed - as supplied by publisher]

Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders.

July 23, 2015 - 7:27am
Related Articles

Genetic epidemiology and insights into interactive genetic and environmental effects in autism spectrum disorders.

Biol Psychiatry. 2015 Jan 1;77(1):66-74

Authors: Kim YS, Leventhal BL

Abstract
Understanding the pathogenesis of neurodevelopmental disorders has proven to be challenging. Using autism spectrum disorder (ASD) as a paradigmatic neurodevelopmental disorder, this article reviews the existing literature on the etiological substrates of ASD and explores how genetic epidemiology approaches including gene-environment interactions (G×E) can play a role in identifying factors associated with ASD etiology. New genetic and bioinformatics strategies have yielded important clues to ASD genetic substrates. The next steps for understanding ASD pathogenesis require significant effort to focus on how genes and environment interact with one another in typical development and its perturbations. Along with larger sample sizes, future study designs should include sample ascertainment that is epidemiologic and population-based to capture the entire ASD spectrum with both categorical and dimensional phenotypic characterization; environmental measurements with accuracy, validity, and biomarkers; statistical methods to address population stratification, multiple comparisons, and G×E of rare variants; animal models to test hypotheses; and new methods to broaden the capacity to search for G×E, including genome-wide and environment-wide association studies, precise estimation of heritability using dense genetic markers, and consideration of G×E both as the disease cause and a disease course modifier. Although examination of G×E appears to be a daunting task, tremendous recent progress in gene discovery has opened new horizons for advancing our understanding of the role of G×E in the pathogenesis of ASD and ultimately identifying the causes, treatments, and even preventive measures for ASD and other neurodevelopmental disorders.

PMID: 25483344 [PubMed - indexed for MEDLINE]

Leveraging genetics and genomics to define the causes of mental illness.

July 23, 2015 - 7:27am
Related Articles

Leveraging genetics and genomics to define the causes of mental illness.

Biol Psychiatry. 2015 Jan 1;77(1):3-5

Authors: State MW, Geschwind DH

PMID: 25483342 [PubMed - indexed for MEDLINE]

HyDRA: gene prioritization via hybrid distance-score rank aggregation.

July 22, 2015 - 6:29am
Related Articles

HyDRA: gene prioritization via hybrid distance-score rank aggregation.

Bioinformatics. 2015 Apr 1;31(7):1034-43

Authors: Kim M, Farnoud F, Milenkovic O

Abstract
UNLABELLED: Gene prioritization refers to a family of computational techniques for inferring disease genes through a set of training genes and carefully chosen similarity criteria. Test genes are scored based on their average similarity to the training set, and the rankings of genes under various similarity criteria are aggregated via statistical methods. The contributions of our work are threefold: (i) first, based on the realization that there is no unique way to define an optimal aggregate for rankings, we investigate the predictive quality of a number of new aggregation methods and known fusion techniques from machine learning and social choice theory. Within this context, we quantify the influence of the number of training genes and similarity criteria on the diagnostic quality of the aggregate and perform in-depth cross-validation studies; (ii) second, we propose a new approach to genomic data aggregation, termed HyDRA (Hybrid Distance-score Rank Aggregation), which combines the advantages of score-based and combinatorial aggregation techniques. We also propose incorporating a new top-versus-bottom (TvB) weighting feature into the hybrid schemes. The TvB feature ensures that aggregates are more reliable at the top of the list, rather than at the bottom, since only top candidates are tested experimentally; (iii) third, we propose an iterative procedure for gene discovery that operates via successful augmentation of the set of training genes by genes discovered in previous rounds, checked for consistency.
MOTIVATION: Fundamental results from social choice theory, political and computer sciences, and statistics have shown that there exists no consistent, fair and unique way to aggregate rankings. Instead, one has to decide on an aggregation approach using predefined set of desirable properties for the aggregate. The aggregation methods fall into two categories, score- and distance-based approaches, each of which has its own drawbacks and advantages. This work is motivated by the observation that merging these two techniques in a computationally efficient manner, and by incorporating additional constraints, one can ensure that the predictive quality of the resulting aggregation algorithm is very high.
RESULTS: We tested HyDRA on a number of gene sets, including autism, breast cancer, colorectal cancer, endometriosis, ischaemic stroke, leukemia, lymphoma and osteoarthritis. Furthermore, we performed iterative gene discovery for glioblastoma, meningioma and breast cancer, using a sequentially augmented list of training genes related to the Turcot syndrome, Li-Fraumeni condition and other diseases. The methods outperform state-of-the-art software tools such as ToppGene and Endeavour. Despite this finding, we recommend as best practice to take the union of top-ranked items produced by different methods for the final aggregated list.
AVAILABILITY AND IMPLEMENTATION: The HyDRA software may be downloaded from: http://web.engr.illinois.edu/∼mkim158/HyDRA.zip.
SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

PMID: 25411330 [PubMed - indexed for MEDLINE]

Cerebral visual impairment, autism, and pancreatitis associated with a 9 Mbp deletion on 10p12.

July 22, 2015 - 6:29am
Related Articles

Cerebral visual impairment, autism, and pancreatitis associated with a 9 Mbp deletion on 10p12.

Clin Dysmorphol. 2015 Jan;24(1):34-7

Authors: Bosch DG, Boonstra FN, Pfundt R, Cremers FP, de Vries BB

PMID: 25356883 [PubMed - indexed for MEDLINE]

Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.

July 22, 2015 - 6:29am
Related Articles

Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology.

Nat Commun. 2014;5:4692

Authors: Orosco LA, Ross AP, Cates SL, Scott SE, Wu D, Sohn J, Pleasure D, Pleasure SJ, Adamopoulos IE, Zarbalis KS

Abstract
Autism spectrum disorders (ASDs) are complex and heterogeneous developmental disabilities affecting an ever-increasing number of children worldwide. The diverse manifestations and complex, largely genetic aetiology of ASDs pose a major challenge to the identification of unifying neuropathological features. Here we describe the neurodevelopmental defects in mice that carry deleterious alleles of the Wdfy3 gene, recently recognized as causative in ASDs. Loss of Wdfy3 leads to a regionally enlarged cerebral cortex resembling early brain overgrowth described in many children on the autism spectrum. In addition, affected mouse mutants display migration defects of cortical projection neurons, a recognized cause of epilepsy, which is significantly comorbid with autism. Our analysis of affected mouse mutants defines an important role for Wdfy3 in regulating neural progenitor divisions and neural migration in the developing brain. Furthermore, Wdfy3 is essential for cerebral expansion and functional organization while its loss-of-function results in pathological changes characteristic of ASDs.

PMID: 25198012 [PubMed - indexed for MEDLINE]

Epigenetic regulation of memory: implications in human cognitive disorders.

July 22, 2015 - 6:29am
Related Articles

Epigenetic regulation of memory: implications in human cognitive disorders.

Biomol Concepts. 2013 Feb;4(1):1-12

Authors: Kramer JM

Abstract
Epigenetic modification of chromatin structure is an important mechanism in the regulation of gene expression. Recent studies have shown that dynamic regulation of chromatin structure occurs in response to neuronal stimulation associated with learning and memory. Learning-induced chromatin modifications include DNA methylation, histone acetylation, histone phosphorylation and histone methylation. Studies in animal models have used genetic and pharmacological methods to manipulate the epigenetic machinery in the brain during learning and memory formation. In general, these studies suggest that epigenetic regulation of chromatin structure is essential for long term memory (LTM) consolidation, which is known to require new gene transcription. Analysis of animal models has also implicated epigenetic mechanisms in impaired cognition associated with aging, neurodegenerative disease, and intellectual disability (ID). Recently, it has been shown that a subset of ID disorders and autism are caused by disruption of specific chromatin modification complexes that are involved in nuclear hormone receptor mediated transcriptional regulation. This review provides an overview of chromatin modifications that are implicated in learning and memory and discusses the role of chromatin modifying proteins in learning-induced transcriptional regulation and human cognitive disorders.

PMID: 25436561 [PubMed - indexed for MEDLINE]

In vivo synaptic transmission and morphology in mouse models of Tuberous sclerosis, Fragile X syndrome, Neurofibromatosis type 1, and Costello syndrome.

July 21, 2015 - 7:43am
Related Articles

In vivo synaptic transmission and morphology in mouse models of Tuberous sclerosis, Fragile X syndrome, Neurofibromatosis type 1, and Costello syndrome.

Front Cell Neurosci. 2015;9:234

Authors: Wang T, de Kok L, Willemsen R, Elgersma Y, Borst JG

Abstract
Defects in the rat sarcoma viral oncogene homolog (Ras)/extracellular-signal-regulated kinase and the phosphatidylinositol 3-kinase-mammalian target of rapamycin (mTOR) signaling pathways are responsible for several neurodevelopmental disorders. These disorders are an important cause for intellectual disability; additional manifestations include autism spectrum disorder, seizures, and brain malformations. Changes in synaptic function are thought to underlie the neurological conditions associated with these syndromes. We therefore studied morphology and in vivo synaptic transmission of the calyx of Held synapse, a relay synapse in the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem, in mouse models of tuberous sclerosis complex (TSC), Fragile X syndrome (FXS), Neurofibromatosis type 1 (NF1), and Costello syndrome. Calyces from both Tsc1(+/-) and from Fmr1 knock-out (KO) mice showed increased volume and surface area compared to wild-type (WT) controls. In addition, in Fmr1 KO animals a larger fraction of calyces showed complex morphology. In MNTB principal neurons of Nf1 (+/) (-) mice the average delay between EPSPs and APs was slightly smaller compared to WT controls, which could indicate an increased excitability. Otherwise, no obvious changes in synaptic transmission, or short-term plasticity were observed during juxtacellular recordings in any of the four lines. Our results in these four mutants thus indicate that abnormalities of mTOR or Ras signaling do not necessarily result in changes in in vivo synaptic transmission.

PMID: 26190969 [PubMed]

Genetics and genomics of autism spectrum disorder: Embracing complexity.

July 19, 2015 - 8:14am
Related Articles

Genetics and genomics of autism spectrum disorder: Embracing complexity.

Hum Mol Genet. 2015 Jul 17;

Authors: De Rubeis S, Buxbaum JD

Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impairments in social communication and social interaction, and the presence of repetitive behaviors and/or restricted interests. ASD has profound etiological and clinical heterogeneity, which has impeded the identification of risk factors and pathophysiological processes underlying the disorder. A constellation of (a) types of genetic variation, (b) modes of inheritance, and (c) specific genomic loci and genes have all recently been implicated in ASD risk, and these findings are currently being extended with functional analyses in model organisms and genotype-phenotype correlation studies. The overlap of risk loci between ASD and other neurodevelopmental disorders raises intriguing questions around the mechanisms of risk. In this review, we will touch upon these aspects of ASD and how they might be addressed.

PMID: 26188008 [PubMed - as supplied by publisher]

FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.

July 18, 2015 - 6:49am

FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.

Cell. 2015 Jul 16;162(2):375-390

Authors: Mariani J, Coppola G, Zhang P, Abyzov A, Provini L, Tomasini L, Amenduni M, Szekely A, Palejev D, Wilson M, Gerstein M, Grigorenko EL, Chawarska K, Pelphrey KA, Howe JR, Vaccarino FM

Abstract
Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of re-enacting human brain development has precluded understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from induced pluripotent stem cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. While no known underlying genomic mutation could be identified, transcriptome and gene network analyses revealed upregulation of genes involved in cell proliferation, neuronal differentiation, and synaptic assembly. ASD-derived organoids exhibit an accelerated cell cycle and overproduction of GABAergic inhibitory neurons. Using RNA interference, we show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons. Altered expression of gene network modules and FOXG1 are positively correlated with symptom severity. Our data suggest that a shift toward GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD.

PMID: 26186191 [PubMed - as supplied by publisher]

Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants.

July 18, 2015 - 6:49am
Related Articles

Targeted massively parallel sequencing of autism spectrum disorder-associated genes in a case control cohort reveals rare loss-of-function risk variants.

Mol Autism. 2015;6:43

Authors: Griswold AJ, Dueker ND, Van Booven D, Rantus JA, Jaworski JM, Slifer SH, Schmidt MA, Hulme W, Konidari I, Whitehead PL, Cuccaro ML, Martin ER, Haines JL, Gilbert JR, Hussman JP, Pericak-Vance MA

Abstract
BACKGROUND: Autism spectrum disorder (ASD) is highly heritable, yet genome-wide association studies (GWAS), copy number variation screens, and candidate gene association studies have found no single factor accounting for a large percentage of genetic risk. ASD trio exome sequencing studies have revealed genes with recurrent de novo loss-of-function variants as strong risk factors, but there are relatively few recurrently affected genes while as many as 1000 genes are predicted to play a role. As such, it is critical to identify the remaining rare and low-frequency variants contributing to ASD.
METHODS: We have utilized an approach of prioritization of genes by GWAS and follow-up with massively parallel sequencing in a case-control cohort. Using a previously reported ASD noise reduction GWAS analyses, we prioritized 837 RefSeq genes for custom targeting and sequencing. We sequenced the coding regions of those genes in 2071 ASD cases and 904 controls of European white ancestry. We applied comprehensive annotation to identify single variants which could confer ASD risk and also gene-based association analysis to identify sets of rare variants associated with ASD.
RESULTS: We identified a significant over-representation of rare loss-of-function variants in genes previously associated with ASD, including a de novo premature stop variant in the well-established ASD candidate gene RBFOX1. Furthermore, ASD cases were more likely to have two damaging missense variants in candidate genes than controls. Finally, gene-based rare variant association implicates genes functioning in excitatory neurotransmission and neurite outgrowth and guidance pathways including CACNAD2, KCNH7, and NRXN1.
CONCLUSIONS: We find suggestive evidence that rare variants in synaptic genes are associated with ASD and that loss-of-function mutations in ASD candidate genes are a major risk factor, and we implicate damaging mutations in glutamate signaling receptors and neuronal adhesion and guidance molecules. Furthermore, the role of de novo mutations in ASD remains to be fully investigated as we identified the first reported protein-truncating variant in RBFOX1 in ASD. Overall, this work, combined with others in the field, suggests a convergence of genes and molecular pathways underlying ASD etiology.

PMID: 26185613 [PubMed - as supplied by publisher]

Deletion of α-neurexin II results in autism-related behaviors in mice.

July 18, 2015 - 6:49am
Related Articles

Deletion of α-neurexin II results in autism-related behaviors in mice.

Transl Psychiatry. 2014;4:e484

Authors: Dachtler J, Glasper J, Cohen RN, Ivorra JL, Swiffen DJ, Jackson AJ, Harte MK, Rodgers RJ, Clapcote SJ

Abstract
Autism is a common and frequently disabling neurodevelopmental disorder with a strong genetic basis. Human genetic studies have discovered mutations disrupting exons of the NRXN2 gene, which encodes the synaptic adhesion protein α-neurexin II (Nrxn2α), in two unrelated individuals with autism, but a causal link between NRXN2 and the disorder remains unclear. To begin to test the hypothesis that Nrxn2α deficiency contributes to the symptoms of autism, we employed Nrxn2α knockout (KO) mice that genetically model Nrxn2α deficiency in vivo. We report that Nrxn2α KO mice displayed deficits in sociability and social memory when exposed to novel conspecifics. In tests of exploratory activity, Nrxn2α KO mice displayed an anxiety-like phenotype in comparison with wild-type littermates, with thigmotaxis in an open field, less time spent in the open arms of an elevated plus maze, more time spent in the enclosure of an emergence test and less time spent exploring novel objects. However, Nrxn2α KO mice did not exhibit any obvious changes in prepulse inhibition or in passive avoidance learning. Real-time PCR analysis of the frontal cortex and hippocampus revealed significant decreases in the mRNA levels of genes encoding proteins involved in both excitatory and inhibitory transmission. Quantification of protein expression revealed that Munc18-1, encoded by Stxbp1, was significantly decreased in the hippocampus of Nrxn2α KO mice, which is suggestive of deficiencies in presynaptic vesicular release. Our findings demonstrate a causal role for the loss of Nrxn2α in the genesis of autism-related behaviors in mice.

PMID: 25423136 [PubMed - indexed for MEDLINE]

The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders.

July 18, 2015 - 6:49am
Related Articles

The serotonin-N-acetylserotonin-melatonin pathway as a biomarker for autism spectrum disorders.

Transl Psychiatry. 2014;4:e479

Authors: Pagan C, Delorme R, Callebert J, Goubran-Botros H, Amsellem F, Drouot X, Boudebesse C, Le Dudal K, Ngo-Nguyen N, Laouamri H, Gillberg C, Leboyer M, Bourgeron T, Launay JM

Abstract
Elevated whole-blood serotonin and decreased plasma melatonin (a circadian synchronizer hormone that derives from serotonin) have been reported independently in patients with autism spectrum disorders (ASDs). Here, we explored, in parallel, serotonin, melatonin and the intermediate N-acetylserotonin (NAS) in a large cohort of patients with ASD and their relatives. We then investigated the clinical correlates of these biochemical parameters. Whole-blood serotonin, platelet NAS and plasma melatonin were assessed in 278 patients with ASD, their 506 first-degree relatives (129 unaffected siblings, 199 mothers and 178 fathers) and 416 sex- and age-matched controls. We confirmed the previously reported hyperserotonemia in ASD (40% (35-46%) of patients), as well as the deficit in melatonin (51% (45-57%)), taking as a threshold the 95th or 5th percentile of the control group, respectively. In addition, this study reveals an increase of NAS (47% (41-54%) of patients) in platelets, pointing to a disruption of the serotonin-NAS-melatonin pathway in ASD. Biochemical impairments were also observed in the first-degree relatives of patients. A score combining impairments of serotonin, NAS and melatonin distinguished between patients and controls with a sensitivity of 80% and a specificity of 85%. In patients the melatonin deficit was only significantly associated with insomnia. Impairments of melatonin synthesis in ASD may be linked with decreased 14-3-3 proteins. Although ASDs are highly heterogeneous, disruption of the serotonin-NAS-melatonin pathway is a very frequent trait in patients and may represent a useful biomarker for a large subgroup of individuals with ASD.

PMID: 25386956 [PubMed - indexed for MEDLINE]

Epidemiologic and Molecular Relationship Between Vaccine Manufacture and Autism Spectrum Disorder Prevalence.

July 17, 2015 - 7:50am
Related Articles

Epidemiologic and Molecular Relationship Between Vaccine Manufacture and Autism Spectrum Disorder Prevalence.

Issues Law Med. 2015;30(1):47-70

Authors: Deisher TA, Doan NV, Koyama K, Bwabye S

Abstract
OBJECTIVES: To assess the public health consequences of fetal cell line manufactured vaccines that contain residual human fetal DNA fragments utilizing laboratory and ecological approaches including statistics, molecular biology and genomics.
METHOD: MMR coverage and autism disorder or autism spectrum disorder prevalence data for Norway, Sweden and the UK were obtained from public and government websites as well as peer reviewed published articles. Biologically, the size and quantity of the contaminating fetal DNA in Meruvax II and Havrix as well as the propensity of various cell lines for cellular and nuclear uptake of primitive human DNA fragments were measured and quantified using gel electrophoresis, fluorescence microscopy and fluorometry. Lastly, genomic analysis identified the specific sites where fetal DNA fragment integration into a child's genome is most likely to occur.
RESULTS: The average MMR coverage for the three countries fell below 90% after Dr. Wakefield's infamous 1998 publication but started to recover slowly after 2001 until reaching over 90% coverage again by 2004. During the same time period, the average autism spectrum disorder prevalence in the United Kingdom, Norway and Sweden dropped substantially after birth year 1998 and gradually increased again after birth year 2000. Average single stranded DNA and double stranded DNA in Meruvax II were 142.05 ng/vial and 35.00 ng/vial, respectively, and 276.00 ng/vial and 35.74 ng/vial in Havrix respectively. The size of the fetal DNA fragments in Meruvax II was approximately 215 base pairs. There was spontaneous cellular and nuclear DNA uptake in HFF1 and NCCIT cells. Genes that have been linked to autism (autism associated genes; AAGs) have a more concentrated susceptibility for insults to genomic stability in comparison to the group of all genes contained within the human genome. Of the X chromosome AAGs, 15 of 19 have double strand break motifs less than 100 kilobases away from the center of a meiotic recombination hotspot located within an exon.
CONCLUSION: Vaccines manufactured in human fetal cell lines contain unacceptably high levels of fetal DNA fragment contaminants. The human genome naturally contains regions that are susceptible to double strand break formation and DNA insertional mutagenesis. The "Wakefield Scare" created a natural experiment that may demonstrate a causal relationship between fetal cell-line manufactured vaccines and ASD prevalence.

PMID: 26103708 [PubMed - indexed for MEDLINE]

Zinc inhibits Hedgehog autoprocessing: linking zinc deficiency with Hedgehog activation.

July 17, 2015 - 7:50am
Related Articles

Zinc inhibits Hedgehog autoprocessing: linking zinc deficiency with Hedgehog activation.

J Biol Chem. 2015 May 1;290(18):11591-600

Authors: Xie J, Owen T, Xia K, Singh AV, Tou E, Li L, Arduini B, Li H, Wan LQ, Callahan B, Wang C

Abstract
Zinc is an essential trace element with wide-ranging biological functions, whereas the Hedgehog (Hh) signaling pathway plays crucial roles in both development and disease. Here we show that there is a mechanistic link between zinc and Hh signaling. The upstream activator of Hh signaling, the Hh ligand, originates from Hh autoprocessing, which converts the Hh precursor protein to the Hh ligand. In an in vitro Hh autoprocessing assay we show that zinc inhibits Hh autoprocessing with a Ki of 2 μm. We then demonstrate that zinc inhibits Hh autoprocessing in a cellular environment with experiments in primary rat astrocyte culture. Solution NMR reveals that zinc binds the active site residues of the Hh autoprocessing domain to inhibit autoprocessing, and isothermal titration calorimetry provided the thermodynamics of the binding. In normal physiology, zinc likely acts as a negative regulator of Hh autoprocessing and inhibits the generation of Hh ligand and Hh signaling. In many diseases, zinc deficiency and elevated level of Hh ligand co-exist, including prostate cancer, lung cancer, ovarian cancer, and autism. Our data suggest a causal relationship between zinc deficiency and the overproduction of Hh ligand.

PMID: 25787080 [PubMed - indexed for MEDLINE]

Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies.

July 17, 2015 - 7:50am
Related Articles

Folinic acid treatment for schizophrenia associated with folate receptor autoantibodies.

Mol Genet Metab. 2014 Dec;113(4):307-14

Authors: Ramaekers VT, Thöny B, Sequeira JM, Ansseau M, Philippe P, Boemer F, Bours V, Quadros EV

Abstract
BACKGROUND: Auto-antibodies against folate receptor alpha (FRα) at the choroid plexus that block N(5)-methyltetrahydrofolate (MTHF) transfer to the brain were identified in catatonic schizophrenia. Acoustic hallucinations disappeared following folinic acid treatment. Folate transport to the CNS prevents homocysteine accumulation and delivers one-carbon units for methyl-transfer reactions and synthesis of purines. The guanosine derivative tetrahydrobiopterin acts as common co-factor for the enzymes producing dopamine, serotonin and nitric oxide.
METHODS: Our study selected patients with schizophrenia unresponsive to conventional treatment. Serum from these patients with normal plasma homocysteine, folate and vitamin B12 was tested for FR autoantibodies of the blocking type on serial samples each week. Spinal fluid was analyzed for MTHF and the metabolites of pterins, dopamine and serotonin. The clinical response to folinic acid treatment was evaluated.
RESULTS: Fifteen of 18 patients (83.3%) had positive serum FR auto-antibodies compared to only 1 in 30 controls (3.3%) (χ(2)=21.6; p<0.0001). FRα antibody titers in patients fluctuated over time varying between negative and high titers, modulating folate flux to the CNS, which explained low CSF folate values in 6 and normal values in 7 patients. The mean±SD for CSF MTHF was diminished compared to previously established controls (t-test: 3.90; p=0.0002). A positive linear correlation existed between CSF MTHF and biopterin levels. CSF dopamine and serotonin metabolites were low or in the lower normal range. Administration of folinic acid (0.3-1mg/kg/day) to 7 participating patients during at least six months resulted in clinical improvement.
CONCLUSION: Assessment of FR auto-antibodies in serum is recommended for schizophrenic patients. Clinical negative or positive symptoms are speculated to be influenced by the level and evolution of FRα antibody titers which determine folate flux to the brain with up- or down-regulation of brain folate intermediates linked to metabolic processes affecting homocysteine levels, synthesis of tetrahydrobiopterin and neurotransmitters. Folinic acid intervention appears to stabilize the disease process.

PMID: 25456743 [PubMed - indexed for MEDLINE]

Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy.

July 16, 2015 - 6:24am
Related Articles

Extending the phenotypic spectrum of RBFOX1 deletions: Sporadic focal epilepsy.

Epilepsia. 2015 Jul 15;

Authors: Lal D, Pernhorst K, Klein KM, Reif P, Tozzi R, Toliat MR, Winterer G, Neubauer B, Nürnberg P, Rosenow F, Becker F, Lerche H, Kunz WS, Kurki MI, Hoffmann P, Becker AJ, Perucca E, Zara F, Sander T, Weber YG

Abstract
Partial deletions of the RBFOX1 gene encoding the neuronal splicing regulator have been reported in a range of neurodevelopmental diseases including idiopathic/genetic generalized epilepsy (IGE/GGE), childhood focal epilepsy, and self-limited childhood benign epilepsy with centrotemporal spikes (BECTS, rolandic epilepsy), and autism. The protein regulates alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. Herein, we examined whether structural deletions affecting RBFOX1 exons confer susceptibility to common forms of juvenile and adult focal epilepsy syndromes. We screened 807 unrelated patients with sporadic focal epilepsy, and we identified seven hemizygous exonic RBFOX1 deletions in patients with sporadic focal epilepsy (0.9%) in comparison to one deletion found in 1,502 controls. The phenotypes of the patients carrying RBFOX1 deletions comprise magnetic resonance imaging (MRI)-negative epilepsy of unknown etiology with frontal and temporal origin (n = 5) and two patients with temporal lobe epilepsy with hippocampal sclerosis. The epilepsies were largely pharmacoresistant but not associated with intellectual disability. Our study extends the phenotypic spectrum of RBFOX1 deletions as a risk factor for focal epilepsy and suggests that exonic RBFOX1 deletions are involved in the broad spectrum of focal and generalized epilepsies.

PMID: 26174448 [PubMed - as supplied by publisher]

Genetic Testing for Developmental Disabilities, Intellectual Disability, and Autism Spectrum Disorder

July 10, 2015 - 6:45pm

Genetic Testing for Developmental Disabilities, Intellectual Disability, and Autism Spectrum Disorder

Book. 2015 06

Authors: Sun F, Oristaglio J, Levy SE, Hakonarson H, Sullivan N, Fontanarosa J, Schoelles KM

Abstract
BACKGROUND: Genetics research in recent decades has discovered numerous genetic variants that help explain the etiology of developmental disabilities (DDs). Genetic tests (e.g., array comparative genomic hybridization, sequencing) are rapidly diffusing into clinical practice for diagnosing DDs or, more often, for determining their genetic etiology. An urgent need exists for a better understanding of these tests and their clinical utility.
PURPOSE: This Technical Brief collects and summarizes information on genetic tests clinically available in the United States to detect genetic markers that predispose to DDs. It also identifies, but does not systematically review, existing evidence addressing the tests' clinical utility. This Brief primarily focuses on patients with idiopathic or unexplained DDs, particularly intellectual disability, global developmental delay, and autism spectrum disorder. Several better-defined DD syndromes, including Angelman syndrome, fragile X syndrome, Prader-Willi syndrome, Rett syndrome, Rubinstein-Taybi syndrome, Smith-Magenis syndrome, velocardiofacial syndrome, and Williams syndrome are also included. Patient-centered health outcomes (e.g., functional or symptomatic improvement) and intermediate outcomes (e.g., changes in clinical decisions or family reproductive decisions, the tests' diagnostic accuracy and analytic validity) are examined.
METHODS: We sought input from nine Key Informants to identify important clinical, technology, and policy issues from different perspectives. We searched the National Center for Biotechnology Information's Genetic Testing Registry (GTR) to identify genetic tests. A structured search of studies published since 2000 was performed to identify available evidence that addresses genetic tests' clinical utility.
FINDINGS: Our search of the GTR database identified 672 laboratory-developed tests offered by 63 providers in 29 States. We also identified one test cleared by the U.S. Food and Drug Administration. Common genetic testing methods used include array comparative genomic hybridization, microarray, DNA sequencing (the Sanger method or next-generation sequencing), and polymerase chain reaction. We did not identify any studies that directly assessed the impact of genetic testing on health outcomes. Most of the clinical studies identified for indirect assessment of clinical utility are case series reporting on a test's diagnostic yield.


PMID: 26158183

An ontology for Autism Spectrum Disorder (ASD) to infer ASD phenotypes from Autism Diagnostic Interview-Revised data.

July 8, 2015 - 7:33am

An ontology for Autism Spectrum Disorder (ASD) to infer ASD phenotypes from Autism Diagnostic Interview-Revised data.

J Biomed Inform. 2015 Jul 4;

Authors: Mugzach O, Peleg M, Bagley SC, Guter SJ, Cook EH, Altman RB

Abstract
OBJECTIVE: Our goal is to create an ontology that will allow data integration and reasoning with subject data to classify subjects, and based on this classification, to infer new knowledge on Autism Spectrum Disorder (ASD) and related neurodevelopmental disorders (NDD). We take a first step toward this goal by extending an existing autism ontology to allow automatic inference of ASD phenotypes and Diagnostic & Statistical Manual of Mental Disorders (DSM) criteria based on subjects' Autism Diagnostic Interview-Revised (ADI-R) assessment data.
MATERIALS AND METHODS: Knowledge regarding diagnostic instruments, ASD phenotypes and risk factors was added to augment an existing autism ontology via Ontology Web Language class definitions and semantic web rules. We developed a custom Protégé plugin for enumerating combinatorial OWL axioms to support the many-to-many relations of ADI-R items to diagnostic categories in the DSM. We utilized a reasoner to infer whether 2642 subjects, whose data was obtained from the Simons Foundation Autism Research Initiative, meet DSM-IV-TR (DSM-IV) and DSM-5 diagnostic criteria based on their ADI-R data.
RESULTS: We extended the ontology by adding 443 classes and 632 rules that represent phenotypes, along with their synonyms, environmental risk factors, and frequency of comorbidities. Applying the rules on the data set showed that the method produced accurate results: the true positive and true negative rates for inferring autistic disorder diagnosis according to DSM-IV criteria were 1 and 0.065, respectively; the true positive rate for inferring ASD based on DSM-5 criteria was 0.94.
DISCUSSION: The ontology allows automatic inference of subjects' disease phenotypes and diagnosis with high accuracy.
CONCLUSION: The ontology may benefit future studies by serving as a knowledge base for ASD. In addition, by adding knowledge of related NDDs, commonalities and differences in manifestations and risk factors could be automatically inferred, contributing to the understanding of ASD pathophysiology.

PMID: 26151311 [PubMed - as supplied by publisher]

Pages