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S Sayols-Baixeras, I Subirana, C Lluis-Ganella, F Civeira, J Roquer, A N Do, D Absher, D Muñoz, C Soriano-Tárraga, J Jiménez-Conde, J Ordovas, M Senti, S Aslibekyan, J Marrugat, D K Arnett, R Elosua
Lipid traits (total, low-density and high-density lipoprotein cholesterol, and triglycerides) are risk factors for cardiovascular disease. DNA methylation is an inherited but also modifiable epigenetic mark that has been related to cardiovascular risk factors. Our aim was to identify loci showing differential DNA methylation related to serum lipid levels. Blood DNA methylation was assessed using the Illumina HumanMethylation450 BeadChip. A two-stage epigenome-wide association study was performed, with a discovery sample in the REGICOR study (n=645) and validation in the Framingham Offspring Study (n=2,542)...
September 15, 2016: Human Molecular Genetics
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No abstract text is available yet for this article.
October 2016: Journal of Medical Genetics
Cyril J Peter, Laura K Fischer, Marija Kundakovic, Paras Garg, Mira Jakovcevski, Aslihan Dincer, Ana C Amaral, Edward I Ginns, Marzena Galdzicka, Cyralene P Bryce, Chana Ratner, Deborah P Waber, David Mokler, Gayle Medford, Frances A Champagne, Douglas L Rosene, Jill A McGaughy, Andrew J Sharp, Janina R Galler, Schahram Akbarian
BACKGROUND: Early childhood malnutrition affects 113 million children worldwide, impacting health and increasing vulnerability for cognitive and behavioral disorders later in life. Molecular signatures after childhood malnutrition, including the potential for intergenerational transmission, remain unexplored. METHODS: We surveyed blood DNA methylomes (~483,000 individual CpG sites) in 168 subjects across two generations, including 50 generation 1 individuals hospitalized during the first year of life for moderate to severe protein-energy malnutrition, then followed up to 48 years in the Barbados Nutrition Study...
November 15, 2016: Biological Psychiatry
Zhihui Xie, Jing Li, Jonathan Baker, Kathie L Eagleson, Marcelo P Coba, Pat Levitt
BACKGROUND: Atypical synapse development and plasticity are implicated in many neurodevelopmental disorders (NDDs). NDD-associated, high-confidence risk genes have been identified, yet little is known about functional relationships at the level of protein-protein interactions, which are the dominant molecular bases responsible for mediating circuit development. METHODS: Proteomics in three independent developing neocortical synaptosomal preparations identified putative interacting proteins of the ligand-activated MET receptor tyrosine kinase, an autism risk gene that mediates synapse development...
February 26, 2016: Biological Psychiatry
Cyril Mignot, Celina von Stülpnagel, Caroline Nava, Dorothée Ville, Damien Sanlaville, Gaetan Lesca, Agnès Rastetter, Benoit Gachet, Yannick Marie, G Christoph Korenke, Ingo Borggraefe, Dorota Hoffmann-Zacharska, Elżbieta Szczepanik, Mariola Rudzka-Dybała, Uluç Yiş, Hande Çağlayan, Arnaud Isapof, Isabelle Marey, Eleni Panagiotakaki, Christian Korff, Eva Rossier, Angelika Riess, Stefanie Beck-Woedl, Anita Rauch, Christiane Zweier, Juliane Hoyer, André Reis, Mikhail Mironov, Maria Bobylova, Konstantin Mukhin, Laura Hernandez-Hernandez, Bridget Maher, Sanjay Sisodiya, Marius Kuhn, Dieter Glaeser, Sarah Wechuysen, Candace T Myers, Heather C Mefford, Konstanze Hörtnagel, Saskia Biskup, Johannes R Lemke, Delphine Héron, Gerhard Kluger, Christel Depienne
OBJECTIVE: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations. METHODS: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed...
August 2016: Journal of Medical Genetics
Nallathambi Jeyabalan, James P Clement
A cardinal feature of early stages of human brain development centers on the sensory, cognitive, and emotional experiences that shape neuronal-circuit formation and refinement. Consequently, alterations in these processes account for many psychiatric and neurodevelopmental disorders. Neurodevelopment disorders affect 3-4% of the world population. The impact of these disorders presents a major challenge to clinicians, geneticists, and neuroscientists. Mutations that cause neurodevelopmental disorders are commonly found in genes encoding proteins that regulate synaptic function...
2016: Frontiers in Cellular Neuroscience
Stephanie A Barnes, Lasani S Wijetunge, Adam D Jackson, Danai Katsanevaki, Emily K Osterweil, Noboru H Komiyama, Seth G N Grant, Mark F Bear, U Valentin Nägerl, Peter C Kind, David J A Wyllie
UNLABELLED: Previous studies have hypothesized that diverse genetic causes of intellectual disability (ID) and autism spectrum disorders (ASDs) converge on common cellular pathways. Testing this hypothesis requires detailed phenotypic analyses of animal models with genetic mutations that accurately reflect those seen in the human condition (i.e., have structural validity) and which produce phenotypes that mirror ID/ASDs (i.e., have face validity). We show that SynGAP haploinsufficiency, which causes ID with co-occurring ASD in humans, mimics and occludes the synaptic pathophysiology associated with deletion of the Fmr1 gene...
November 11, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Juan F Codocedo, Carla Montecinos-Oliva, Nibaldo C Inestrosa
Wnt-5a is a synaptogenic factor that modulates glutamatergic synapses and generates neuroprotection against Aβ oligomers. It is known that Wnt-5a plays a key role in the adult nervous system and synaptic plasticity. Emerging evidence indicates that miRNAs are actively involved in the regulation of synaptic plasticity. Recently, we showed that Wnt-5a is able to control the expression of several miRNAs including miR-101b, which has been extensively studied in carcinogenesis. However, its role in brain is just beginning to be explored...
2015: Frontiers in Cellular Neuroscience
Celina von Stülpnagel, Claudia Funke, Caroline Haberl, Konstanze Hörtnagel, Jerome Jüngling, Yvonne G Weber, Martin Staudt, Gerhard Kluger
BACKGROUND: SYNGAP1, which encodes a RAS-GTPase-activating protein, is located on the short arm of chromosome 6. Heterozygous SYNGAP1 gene mutations have been associated with autism spectrum disorders, delay of psychomotor development, acquired microcephaly, and several forms of idiopathic generalized epilepsy. Here, we report a patient with a new SYNGAP1 stop mutation, and compare the phenotype with published cases with SYNGAP1 mutations and epilepsy. PATIENT: This 15-year-old nondysmorphic girl with intellectual disability developed drop attacks at the age of 2 years, later clonic and clonic-tonic as well as myoclonic seizures predominantly during sleep...
August 2015: Neuropediatrics
Michael J Parker, Alan E Fryer, Deborah J Shears, Katherine L Lachlan, Shane A McKee, Alex C Magee, Shehla Mohammed, Pradeep C Vasudevan, Soo-Mi Park, Valérie Benoit, Damien Lederer, Isabelle Maystadt, Ddd Study, David R FitzPatrick
De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase-activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi-gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss-of-function (3 nonsense; 3 frameshift; 1 whole gene deletion)...
October 2015: American Journal of Medical Genetics. Part A
Robert A Kozol, Holly N Cukier, Bing Zou, Vera Mayo, Silvia De Rubeis, Guiqing Cai, Anthony J Griswold, Patrice L Whitehead, Jonathan L Haines, John R Gilbert, Michael L Cuccaro, Eden R Martin, James D Baker, Joseph D Buxbaum, Margaret A Pericak-Vance, Julia E Dallman
Despite significant progress in the genetics of autism spectrum disorder (ASD), how genetic mutations translate to the behavioral changes characteristic of ASD remains largely unknown. ASD affects 1-2% of children and adults, and is characterized by deficits in verbal and non-verbal communication, and social interactions, as well as the presence of repetitive behaviors and/or stereotyped interests. ASD is clinically and etiologically heterogeneous, with a strong genetic component. Here, we present functional data from syngap1 and shank3 zebrafish loss-of-function models of ASD...
July 15, 2015: Human Molecular Genetics
Ca Tan, S Topper, D Del Gaudio, V Nelakuditi, O Shchelochkov, Mjm Nowaczyk, S Zeesman, L Brady, L Russell, N Meeks, S Sastry, K Arndt, F Kobiernicki, R Shaw, S Das
Genetic testing for non-specific intellectual disability (ID) presents challenges in daily clinical practice. Historically the focus of the genetic elucidation of non-specific ID has been on genes on the X-chromosome and recent research has brought attention to the growing contribution of autosomal genes. In addition, next generation sequencing (NGS) has greatly improved the ability to simultaneously analyze multiple genetic loci, making large panel testing a practical approach to testing for non-specific ID...
February 19, 2015: Clinical Genetics
Massimiliano Aceti, Thomas K Creson, Thomas Vaissiere, Camilo Rojas, Wen-Chin Huang, Ya-Xian Wang, Ronald S Petralia, Damon T Page, Courtney A Miller, Gavin Rumbaugh
BACKGROUND: Genetic haploinsufficiency of SYNGAP1/Syngap1 commonly occurs in developmental brain disorders, such as intellectual disability, epilepsy, schizophrenia, and autism spectrum disorder. Thus, studying mouse models of Syngap1 haploinsufficiency may uncover pathologic developmental processes common among distinct brain disorders. METHODS: A Syngap1 haploinsufficiency model was used to explore the relationship between critical period dendritic spine abnormalities, cortical circuit assembly, and the window for genetic rescue to understand how damaging mutations disrupt key substrates of mouse brain development...
May 1, 2015: Biological Psychiatry
B J O'Roak, H A Stessman, E A Boyle, K T Witherspoon, B Martin, C Lee, L Vives, C Baker, J B Hiatt, D A Nickerson, R Bernier, J Shendure, E E Eichler
Autism spectrum disorder (ASD) has a strong but complex genetic component. Here we report on the resequencing of 64 candidate neurodevelopmental disorder risk genes in 5,979 individuals: 3,486 probands and 2,493 unaffected siblings. We find a strong burden of de novo point mutations for these genes and specifically implicate nine genes. These include CHD2 and SYNGAP1, genes previously reported in related disorders, and novel genes TRIP12 and PAX5. We also show that mutation carriers generally have lower IQs and enrichment for seizures...
2014: Nature Communications
Claire Redin, Bénédicte Gérard, Julia Lauer, Yvan Herenger, Jean Muller, Angélique Quartier, Alice Masurel-Paulet, Marjolaine Willems, Gaétan Lesca, Salima El-Chehadeh, Stéphanie Le Gras, Serge Vicaire, Muriel Philipps, Michaël Dumas, Véronique Geoffroy, Claire Feger, Nicolas Haumesser, Yves Alembik, Magalie Barth, Dominique Bonneau, Estelle Colin, Hélène Dollfus, Bérénice Doray, Marie-Ange Delrue, Valérie Drouin-Garraud, Elisabeth Flori, Mélanie Fradin, Christine Francannet, Alice Goldenberg, Serge Lumbroso, Michèle Mathieu-Dramard, Dominique Martin-Coignard, Didier Lacombe, Gilles Morin, Anne Polge, Sylvie Sukno, Christel Thauvin-Robinet, Julien Thevenon, Martine Doco-Fenzy, David Genevieve, Pierre Sarda, Patrick Edery, Bertrand Isidor, Bernard Jost, Laurence Olivier-Faivre, Jean-Louis Mandel, Amélie Piton
BACKGROUND: Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. METHODS: We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern...
November 2014: Journal of Medical Genetics
D A Dyment, M Tétreault, C L Beaulieu, T Hartley, P Ferreira, J W Chardon, J Marcadier, S L Sawyer, S J Mosca, A M Innes, J S Parboosingh, D E Bulman, J Schwartzentruber, J Majewski, M Tarnopolsky, K M Boycott
Whole-exome sequencing (WES) has transformed our ability to detect mutations causing rare diseases. FORGE (Finding Of Rare disease GEnes) and Care4Rare Canada are nation-wide projects focused on identifying disease genes using WES and translating this technology to patient care. Rare forms of epilepsy are well-suited for WES and we retrospectively selected FORGE and Care4Rare families with clinical descriptions that included childhood-onset epilepsy or seizures not part of a recognizable syndrome or an early-onset encephalopathy where standard-of-care investigations were unrevealing...
July 2015: Clinical Genetics
William Warnica, Daniele Merico, Gregory Costain, Simon E Alfred, John Wei, Christian R Marshall, Stephen W Scherer, Anne S Bassett
BACKGROUND: MicroRNAs (miRNAs) are key regulators of gene expression in the human genome and may contribute to risk for neuropsychiatric disorders. miRNAs play an acknowledged role in the strongest of genetic risk factors for schizophrenia, 22q11.2 deletions. We hypothesized that in schizophrenia there would be an enrichment of other rare copy number variants (CNVs) that overlap miRNAs. METHODS: Using high-resolution genome-wide microarrays and rigorous methods, we compared the miRNA content of rare CNVs in well-characterized cohorts of schizophrenia cases (n = 420) and comparison subjects, excluding 22q11...
January 15, 2015: Biological Psychiatry
Emin D Ozkan, Thomas K Creson, Enikö A Kramár, Camilo Rojas, Ron R Seese, Alex H Babyan, Yulin Shi, Rocco Lucero, Xiangmin Xu, Jeffrey L Noebels, Courtney A Miller, Gary Lynch, Gavin Rumbaugh
Syngap1 haploinsufficiency is a common cause of sporadic intellectual disability. Syngap1 mutations disrupt developing pyramidal neurons, although it remains unclear if this process contributes to cognitive abnormalities. Here, we found that haploinsufficiency restricted to forebrain glutamatergic neurons was sufficient to disrupt cognition and removing mutations from this population prevented cognitive abnormalities. In contrast, manipulating Syngap1 function in GABAergic neurons had no effect on cognition, excitability, or neurotransmission, highlighting the specificity of Syngap1 mutations within forebrain excitatory neurons...
June 18, 2014: Neuron
Dmitry Velmeshev, Marco Magistri, Mohammad Ali Faghihi
BACKGROUND: Autism spectrum disorders (ASD) manifest with neurodevelopmental phenotypes including communicative, social and behavioral impairments that affect as many as 1 in 88 children. The majority of autism cases have no known genetic cause, suggesting complex genetics of the disorder, but a few genes of large effect have been identified. METHODS: In order to identify novel ASD genetic correlates, we investigated non-protein coding RNAs (ncRNAs) which are abundantly transcribed from the human genome, enriched in the brain, and have been implicated in neurodevelopmental disorders...
2013: Molecular Autism
James P Clement, Emin D Ozkan, Massimiliano Aceti, Courtney A Miller, Gavin Rumbaugh
Critical periods of developmental plasticity contribute to the refinement of neural connections that broadly shape brain development. These windows of plasticity are thought to be important for the maturation of perception, language, and cognition. Synaptic properties in cortical regions that underlie critical periods influence the onset and duration of windows, although it remains unclear how mechanisms that shape synapse development alter critical-period properties. In this study, we demonstrate that inactivation of a single copy of syngap1, which causes a surprisingly common form of sporadic, non-syndromic intellectual disability with autism in humans, induced widespread early functional maturation of excitatory connections in the mouse neocortex...
June 19, 2013: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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