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 et/ou numérique 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 et/ou numérique] / 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 et/ou numérique Auteurs : Holly N. CUKIER, Auteur ; Nicole DUEKER, Auteur ; Susan SLIFER, Auteur ; Joycelyn 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 MARTIN, Auteur ; Jonathan L. HAINES, Auteur ; Michael L. CUCCARO, Auteur ; John 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 et/ou numérique] / Holly N. CUKIER, Auteur ; Nicole DUEKER, Auteur ; Susan SLIFER, Auteur ; Joycelyn 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 MARTIN, Auteur ; Jonathan L. HAINES, Auteur ; Michael L. CUCCARO, Auteur ; John 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

Identification of chromosome 7 inversion breakpoints in an autistic family narrows candidate region for autism susceptibility / Holly N. CUKIER in Autism Research, 2-5 (October 2009)  

Public ISBD [article]  inAutism Research > 2-5 (October 2009) . - p.258-266 Titre : Identification of chromosome 7 inversion breakpoints in an autistic family narrows candidate region for autism susceptibility Type de document : Texte imprimé et/ou numérique Auteurs : Holly N. CUKIER, Auteur ; Michael L. CUCCARO, Auteur ; John R. GILBERT, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur ; David A. SKAAR, Auteur ; Melissa Y. RAYNER-EVANS, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; James M. JAWORSKI, Auteur Année de publication : 2009 Article en page(s) : p.258-266 Langues : Anglais (eng) Mots-clés : molecular-genetics paracentric-inversion fluorescent-in-situ-hybridization-(FISH) genome-wide-association-study-(GWAS) Index. décimale : PER Périodiques Résumé : Chromosomal breaks and rearrangements have been observed in conjunction with autism and autistic spectrum disorders. A chromosomal inversion has been previously reported in autistic siblings, spanning the region from approximately 7q22.1 to 7q31. This family is distinguished by having multiple individuals with autism and associated disabilities. The region containing the inversion has been strongly implicated in autism by multiple linkage studies, and has been particularly associated with language defects in autism as well as in other disorders with language components. Mapping of the inversion breakpoints by FISH has localized the inversion to the region spanning approximately 99-108.75 Mb of chromosome 7. The proximal breakpoint has the potential to disrupt either the coding sequence or regulatory regions of a number of cytochrome P450 genes while the distal region falls in a relative gene desert. Copy number variant analysis of the breakpoint regions detected no duplication or deletion that could clearly be associated with disease status. Association analysis in our autism data set using single nucleotide polymorphisms located near the breakpoints showed no significant association with proximal breakpoint markers, but has identified markers near the distal breakpoint (108-110 Mb) with significant associations to autism. The chromosomal abnormality in this family strengthens the case for an autism susceptibility gene in the chromosome 7q22-31 region and targets a candidate region for further investigation. En ligne : http://dx.doi.org/10.1002/aur.96 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=938 [article] Identification of chromosome 7 inversion breakpoints in an autistic family narrows candidate region for autism susceptibility [Texte imprimé et/ou numérique] / Holly N. CUKIER, Auteur ; Michael L. CUCCARO, Auteur ; John R. GILBERT, Auteur ; Margaret A. O. PERICAK-VANCE, Auteur ; David A. SKAAR, Auteur ; Melissa Y. RAYNER-EVANS, Auteur ; Ioanna KONIDARI, Auteur ; Patrice L. WHITEHEAD, Auteur ; James M. JAWORSKI, Auteur . - 2009 . - p.258-266. Langues : Anglais (eng) in Autism Research > 2-5 (October 2009) . - p.258-266 Mots-clés : molecular-genetics paracentric-inversion fluorescent-in-situ-hybridization-(FISH) genome-wide-association-study-(GWAS) Index. décimale : PER Périodiques Résumé : Chromosomal breaks and rearrangements have been observed in conjunction with autism and autistic spectrum disorders. A chromosomal inversion has been previously reported in autistic siblings, spanning the region from approximately 7q22.1 to 7q31. This family is distinguished by having multiple individuals with autism and associated disabilities. The region containing the inversion has been strongly implicated in autism by multiple linkage studies, and has been particularly associated with language defects in autism as well as in other disorders with language components. Mapping of the inversion breakpoints by FISH has localized the inversion to the region spanning approximately 99-108.75 Mb of chromosome 7. The proximal breakpoint has the potential to disrupt either the coding sequence or regulatory regions of a number of cytochrome P450 genes while the distal region falls in a relative gene desert. Copy number variant analysis of the breakpoint regions detected no duplication or deletion that could clearly be associated with disease status. Association analysis in our autism data set using single nucleotide polymorphisms located near the breakpoints showed no significant association with proximal breakpoint markers, but has identified markers near the distal breakpoint (108-110 Mb) with significant associations to autism. The chromosomal abnormality in this family strengthens the case for an autism susceptibility gene in the chromosome 7q22-31 region and targets a candidate region for further investigation. En ligne : http://dx.doi.org/10.1002/aur.96 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=938

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 et/ou numérique 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 et/ou numérique] / 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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