Evidence of novel fine-scale structural variation at autism spectrum disorder candidate loci / Dale HEDGES in Molecular Autism, (April 2012)  

Public ISBD [article]  inMolecular Autism > (April 2012) . - 27 p. Titre : Evidence of novel fine-scale structural variation at autism spectrum disorder candidate loci Type de document : texte imprimé Auteurs : Dale HEDGES, Auteur ; Kara L. HAMILTON, Auteur ; Stephanie J. SACHAROW, Auteur ; Laura NATIONS, Auteur ; Gary W. BEECHAM, Auteur ; Zhanna M. KOZHEKBAEVA, Auteur ; Brittany L. BUTLER, Auteur ; Holly N. CUKIER, Auteur ; Patrice L. WHITEHEAD, Auteur ; Deqiong MA, Auteur ; James M. JAWORSKI, Auteur ; Lubov NATHANSON, Auteur ; Joycelyn M. LEE, Auteur ; Stephen L. HAUSER, Auteur ; Jorge R. OKSENBERG, Auteur ; Michael L. CUCCARO, Auteur ; Jonathan L. HAINES, Auteur ; John R. GILBERT, Auteur ; Margaret A.O. PERICAK-VANCE, Auteur Année de publication : 2012 Article en page(s) : 27 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorders (ASD) represent a group of neurodevelopmental disorders characterized by a core set of social-communicative and behavioral impairments. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting primarily via the GABA receptors (GABR). Multiple lines of evidence, including altered GABA and GABA receptor expression in autistic patients, indicate that the GABAergic system may be involved in the etiology of autism. Methods As copy number variations (CNVs), particularly rare and de novo CNVs, have now been implicated in ASD risk, we examined the GABA receptors and genes in related pathways for structural variation that may be associated with autism. We further extended our candidate gene set to include 19 genes and regions that had either been directly implicated in the autism literature or were directly related (via function or ancestry) to these primary candidates. For the high resolution CNV screen we employed custom-designed 244 k comparative genomic hybridization (CGH) arrays. Collectively, our probes spanned a total of 11 Mb of GABA-related and additional candidate regions with a density of approximately one probe every 200 nucleotides, allowing a theoretical resolution for detection of CNVs of approximately 1 kb or greater on average. One hundred and sixty-eight autism cases and 149 control individuals were screened for structural variants. Prioritized CNV events were confirmed using quantitative PCR, and confirmed loci were evaluated on an additional set of 170 cases and 170 control individuals that were not included in the original discovery set. Loci that remained interesting were subsequently screened via quantitative PCR on an additional set of 755 cases and 1,809 unaffected family members. Results Results include rare deletions in autistic individuals at JAKMIP1, NRXN1, Neuroligin4Y, OXTR, and ABAT. Common insertion/deletion polymorphisms were detected at several loci, including GABBR2 and NRXN3. Overall, statistically significant enrichment in affected vs. unaffected individuals was observed for NRXN1 deletions. En ligne : http://dx.doi.org/10.1186/2040-2392-3-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=155 [article] Evidence of novel fine-scale structural variation at autism spectrum disorder candidate loci [texte imprimé] / Dale HEDGES, Auteur ; Kara L. HAMILTON, Auteur ; Stephanie J. SACHAROW, Auteur ; Laura NATIONS, Auteur ; Gary W. BEECHAM, Auteur ; Zhanna M. KOZHEKBAEVA, Auteur ; Brittany L. BUTLER, Auteur ; Holly N. CUKIER, Auteur ; Patrice L. WHITEHEAD, Auteur ; Deqiong MA, Auteur ; James M. JAWORSKI, Auteur ; Lubov NATHANSON, Auteur ; Joycelyn M. LEE, Auteur ; Stephen L. HAUSER, Auteur ; Jorge R. OKSENBERG, Auteur ; Michael L. CUCCARO, Auteur ; Jonathan L. HAINES, Auteur ; John R. GILBERT, Auteur ; Margaret A.O. PERICAK-VANCE, Auteur . - 2012 . - 27 p. Langues : Anglais (eng) in Molecular Autism > (April 2012) . - 27 p. Index. décimale : PER Périodiques Résumé : Background Autism spectrum disorders (ASD) represent a group of neurodevelopmental disorders characterized by a core set of social-communicative and behavioral impairments. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, acting primarily via the GABA receptors (GABR). Multiple lines of evidence, including altered GABA and GABA receptor expression in autistic patients, indicate that the GABAergic system may be involved in the etiology of autism. Methods As copy number variations (CNVs), particularly rare and de novo CNVs, have now been implicated in ASD risk, we examined the GABA receptors and genes in related pathways for structural variation that may be associated with autism. We further extended our candidate gene set to include 19 genes and regions that had either been directly implicated in the autism literature or were directly related (via function or ancestry) to these primary candidates. For the high resolution CNV screen we employed custom-designed 244 k comparative genomic hybridization (CGH) arrays. Collectively, our probes spanned a total of 11 Mb of GABA-related and additional candidate regions with a density of approximately one probe every 200 nucleotides, allowing a theoretical resolution for detection of CNVs of approximately 1 kb or greater on average. One hundred and sixty-eight autism cases and 149 control individuals were screened for structural variants. Prioritized CNV events were confirmed using quantitative PCR, and confirmed loci were evaluated on an additional set of 170 cases and 170 control individuals that were not included in the original discovery set. Loci that remained interesting were subsequently screened via quantitative PCR on an additional set of 755 cases and 1,809 unaffected family members. Results Results include rare deletions in autistic individuals at JAKMIP1, NRXN1, Neuroligin4Y, OXTR, and ABAT. Common insertion/deletion polymorphisms were detected at several loci, including GABBR2 and NRXN3. Overall, statistically significant enrichment in affected vs. unaffected individuals was observed for NRXN1 deletions. En ligne : http://dx.doi.org/10.1186/2040-2392-3-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=155

Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders / Holly N. CUKIER in Molecular Autism, (January 2014)  

Public ISBD [article]  inMolecular Autism > (January 2014) Titre : Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders Type de document : texte imprimé Auteurs : Holly N. CUKIER, Auteur ; Nicole D. DUEKER, Auteur ; Susan SLIFER, Auteur ; Joycelyn M. LEE, Auteur ; Patrice L. WHITEHEAD, Auteur ; Eminisha LALANNE, Auteur ; Natalia LEYVA, Auteur ; Ioanna KONIDARI, Auteur ; Ryan GENTRY, Auteur ; William HULME, Auteur ; Derek BOOVEN, Auteur ; Vera MAYO, Auteur ; Natalia HOFMANN, Auteur ; Michael SCHMIDT, Auteur ; Eden R. MARTIN, Auteur ; Jonathan L. HAINES, Auteur ; Michael L. CUCCARO, Auteur ; John R. GILBERT, Auteur ; Margaret A.O. PERICAK-VANCE, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered. To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized. We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P=8.55 x 10-5). By studying these unique pedigrees, we have identified novel DNA variations related to ASD, demonstrated that exome sequencing in extended families is a powerful tool for ASD candidate gene discovery, and provided further evidence of an underlying genetic component to a wide range of neurodevelopmental and neuropsychiatric diseases. En ligne : http://dx.doi.org/10.1186/2040-2392-5-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Exome sequencing of extended families with autism reveals genes shared across neurodevelopmental and neuropsychiatric disorders [texte imprimé] / Holly N. CUKIER, Auteur ; Nicole D. DUEKER, Auteur ; Susan SLIFER, Auteur ; Joycelyn M. LEE, Auteur ; Patrice L. WHITEHEAD, Auteur ; Eminisha LALANNE, Auteur ; Natalia LEYVA, Auteur ; Ioanna KONIDARI, Auteur ; Ryan GENTRY, Auteur ; William HULME, Auteur ; Derek BOOVEN, Auteur ; Vera MAYO, Auteur ; Natalia HOFMANN, Auteur ; Michael SCHMIDT, Auteur ; Eden R. MARTIN, Auteur ; Jonathan L. HAINES, Auteur ; Michael L. CUCCARO, Auteur ; John R. GILBERT, Auteur ; Margaret A.O. PERICAK-VANCE, Auteur. Langues : Anglais (eng) in Molecular Autism > (January 2014) Index. décimale : PER Périodiques Résumé : Autism spectrum disorders (ASDs) comprise a range of neurodevelopmental conditions of varying severity, characterized by marked qualitative difficulties in social relatedness, communication, and behavior. Despite overwhelming evidence of high heritability, results from genetic studies to date show that ASD etiology is extremely heterogeneous and only a fraction of autism genes have been discovered. To help unravel this genetic complexity, we performed whole exome sequencing on 100 ASD individuals from 40 families with multiple distantly related affected individuals. All families contained a minimum of one pair of ASD cousins. Each individual was captured with the Agilent SureSelect Human All Exon kit, sequenced on the Illumina Hiseq 2000, and the resulting data processed and annotated with Burrows-Wheeler Aligner (BWA), Genome Analysis Toolkit (GATK), and SeattleSeq. Genotyping information on each family was utilized in order to determine genomic regions that were identical by descent (IBD). Variants identified by exome sequencing which occurred in IBD regions and present in all affected individuals within each family were then evaluated to determine which may potentially be disease related. Nucleotide alterations that were novel and rare (minor allele frequency, MAF, less than 0.05) and predicted to be detrimental, either by altering amino acids or splicing patterns, were prioritized. We identified numerous potentially damaging, ASD associated risk variants in genes previously unrelated to autism. A subset of these genes has been implicated in other neurobehavioral disorders including depression (SLIT3), epilepsy (CLCN2, PRICKLE1), intellectual disability (AP4M1), schizophrenia (WDR60), and Tourette syndrome (OFCC1). Additional alterations were found in previously reported autism candidate genes, including three genes with alterations in multiple families (CEP290, CSMD1, FAT1, and STXBP5). Compiling a list of ASD candidate genes from the literature, we determined that variants occurred in ASD candidate genes 1.65 times more frequently than in random genes captured by exome sequencing (P=8.55 x 10-5). By studying these unique pedigrees, we have identified novel DNA variations related to ASD, demonstrated that exome sequencing in extended families is a powerful tool for ASD candidate gene discovery, and provided further evidence of an underlying genetic component to a wide range of neurodevelopmental and neuropsychiatric diseases. En ligne : http://dx.doi.org/10.1186/2040-2392-5-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Family History of Eating Disorder and the Broad Autism Phenotype in Autism / Bianca A. BARRIONUEVO in Autism Research, 13-9 (September 2020)  

Public ISBD [article]  inAutism Research > 13-9 (September 2020) . - p.1573-1581 Titre : Family History of Eating Disorder and the Broad Autism Phenotype in Autism Type de document : texte imprimé Auteurs : Bianca A. BARRIONUEVO, Auteur ; Aneesa R. CHOWDHURY, Auteur ; Joycelyn M. LEE, Auteur ; Nicole D. DUEKER, Auteur ; Eden R. MARTIN, Auteur ; Margaret A.O. PERICAK-VANCE, Auteur ; Michael L. CUCCARO, Auteur Article en page(s) : p.1573-1581 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Abstract Autism features occur frequently among individuals with eating disorders (ED). This co-occurrence is not well understood but there is speculation that select traits (e.g., rigidity) are common to both autism and ED. To explore the co-occurrence of autistic traits and ED features, we used the Simons Simplex Collection (SSC; N = 2,623 families) to test whether first-degree relatives of individuals with autism with a history of ED features had more autism traits, as measured by the Broad Autism Phenotype Questionnaire (BAP-Q), compared to relatives with no history of ED. The frequency of individuals with ED features was 2.2% (N = 57) among mothers, <1% in siblings, and not present in fathers. We restricted our analyses to mothers. Compared to mothers with no history of ED, those with a history of ED had significantly higher scores on the BAP-Q Total Score and each of the three BAP-Q domains. More importantly, when the BAP-Q was used as a classification tool, we found that when compared to mothers with no history of ED, those with a history of ED were most likely to fall into the clinically significant range on the BAP-Q Rigid domain. Our results suggest that a history of ED features among mothers of individuals with autism is associated with the presence of autistic traits. This extends previous work showing a relationship between autism and ED and expands the range of neuropsychiatric traits that have relevance to the BAP among family members of individuals with autism. Lay Summary Using information from the Simons Simplex Collection we tested whether mothers of individuals with autism with a history of eating disorder had more autism traits (i.e., similar to those in autism but milder) compared to mothers with no history of eating disorder. The most striking difference between the groups was the presence of rigidity in mothers with a history of eating disorder. This extends previous work showing a relationship between autism and eating disorders and suggests the utility of studying eating disorders in future family studies of autism. Autism Res 2020, 13: 1573–1581. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.2378 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=431 [article] Family History of Eating Disorder and the Broad Autism Phenotype in Autism [texte imprimé] / Bianca A. BARRIONUEVO, Auteur ; Aneesa R. CHOWDHURY, Auteur ; Joycelyn M. LEE, Auteur ; Nicole D. DUEKER, Auteur ; Eden R. MARTIN, Auteur ; Margaret A.O. PERICAK-VANCE, Auteur ; Michael L. CUCCARO, Auteur . - p.1573-1581. Langues : Anglais (eng) in Autism Research > 13-9 (September 2020) . - p.1573-1581 Index. décimale : PER Périodiques Résumé : Abstract Autism features occur frequently among individuals with eating disorders (ED). This co-occurrence is not well understood but there is speculation that select traits (e.g., rigidity) are common to both autism and ED. To explore the co-occurrence of autistic traits and ED features, we used the Simons Simplex Collection (SSC; N = 2,623 families) to test whether first-degree relatives of individuals with autism with a history of ED features had more autism traits, as measured by the Broad Autism Phenotype Questionnaire (BAP-Q), compared to relatives with no history of ED. The frequency of individuals with ED features was 2.2% (N = 57) among mothers, <1% in siblings, and not present in fathers. We restricted our analyses to mothers. Compared to mothers with no history of ED, those with a history of ED had significantly higher scores on the BAP-Q Total Score and each of the three BAP-Q domains. More importantly, when the BAP-Q was used as a classification tool, we found that when compared to mothers with no history of ED, those with a history of ED were most likely to fall into the clinically significant range on the BAP-Q Rigid domain. Our results suggest that a history of ED features among mothers of individuals with autism is associated with the presence of autistic traits. This extends previous work showing a relationship between autism and ED and expands the range of neuropsychiatric traits that have relevance to the BAP among family members of individuals with autism. Lay Summary Using information from the Simons Simplex Collection we tested whether mothers of individuals with autism with a history of eating disorder had more autism traits (i.e., similar to those in autism but milder) compared to mothers with no history of eating disorder. The most striking difference between the groups was the presence of rigidity in mothers with a history of eating disorder. This extends previous work showing a relationship between autism and eating disorders and suggests the utility of studying eating disorders in future family studies of autism. Autism Res 2020, 13: 1573–1581. © 2020 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.2378 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=431

The Expanding Role of MBD Genes in Autism: Identification of a MECP2 Duplication and Novel Alterations in MBD5, MBD6, and SETDB1 / Holly N. CUKIER in Autism Research, 5-6 (December 2012)  

Public ISBD [article]  inAutism Research > 5-6 (December 2012) . - p.385-397 Titre : The Expanding Role of MBD Genes in Autism: Identification of a MECP2 Duplication and Novel Alterations in MBD5, MBD6, and SETDB1 Type de document : texte imprimé Auteurs : Holly N. CUKIER, Auteur ; Joycelyn M. LEE, Auteur ; Deqiong MA, Auteur ; Juan I. YOUNG, Auteur ; Vera MAYO, Auteur ; Brittany L. BUTLER, Auteur ; Sandhya S. RAMSOOK, Auteur ; Joseph A. RANTUS, Auteur ; Alexander J. ABRAMS, Auteur ; Patrice L. WHITEHEAD, Auteur ; Harry H. WRIGHT, Auteur ; Ruth K. ABRAMSON, Auteur ; Jonathan L. HAINES, Auteur ; Michael L. CUCCARO, Auteur ; Margaret A.O. PERICAK-VANCE, Auteur ; John R. GILBERT, Auteur Article en page(s) : p.385-397 Mots-clés : autism spectrum disorders (ASDs)  copy number variation (CNV)  methyl-CpG-binding domain (MBD)  Rett syndrome  single nucleotide polymorphism (SNP) Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1002/aur.1251 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=187 [article] The Expanding Role of MBD Genes in Autism: Identification of a MECP2 Duplication and Novel Alterations in MBD5, MBD6, and SETDB1 [texte imprimé] / Holly N. CUKIER, Auteur ; Joycelyn M. LEE, Auteur ; Deqiong MA, Auteur ; Juan I. YOUNG, Auteur ; Vera MAYO, Auteur ; Brittany L. BUTLER, Auteur ; Sandhya S. RAMSOOK, Auteur ; Joseph A. RANTUS, Auteur ; Alexander J. ABRAMS, Auteur ; Patrice L. WHITEHEAD, Auteur ; Harry H. WRIGHT, Auteur ; Ruth K. ABRAMSON, Auteur ; Jonathan L. HAINES, Auteur ; Michael L. CUCCARO, Auteur ; Margaret A.O. PERICAK-VANCE, Auteur ; John R. GILBERT, Auteur . - p.385-397. in Autism Research > 5-6 (December 2012) . - p.385-397 Mots-clés : autism spectrum disorders (ASDs)  copy number variation (CNV)  methyl-CpG-binding domain (MBD)  Rett syndrome  single nucleotide polymorphism (SNP) Index. décimale : PER Périodiques En ligne : http://dx.doi.org/10.1002/aur.1251 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=187

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