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Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder / Samira BAHL in Molecular Autism, (March 2013)
[article]
Titre : Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Samira BAHL, Auteur ; Colby CHIANG, Auteur ; Roberta L. BEAUCHAMP, Auteur ; Benjamin NEALE, Auteur ; Mark J. DALY, Auteur ; James GUSELLA, Auteur ; Michael E. TALKOWSKI, Auteur ; Vijaya RAMESH, Auteur Année de publication : 2013 Article en page(s) : 11 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Tuberous sclerosis complex Mammalian target of rapamycin Next-generation sequencing Rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND:Autism spectrum disorder (ASD) is reported in 30 to 60% of patients with tuberous sclerosis complex (TSC) but shared genetic mechanisms that exist between TSC-associated ASD and idiopathic ASD have yet to be determined. Through the small G-protein Rheb, the TSC proteins, hamartin and tuberin, negatively regulate mammalian target of rapamycin complex 1 (mTORC1) signaling. It is well established that mTORC1 plays a pivotal role in neuronal translation and connectivity, so dysregulation of mTORC1 signaling could be a common feature in many ASDs. Pam, an E3 ubiquitin ligase, binds to TSC proteins and regulates mTORC1 signaling in the CNS, and the FBXO45-Pam ubiquitin ligase complex plays an essential role in neurodevelopment by regulating synapse formation and growth. Since mounting evidence has established autism as a disorder of the synapses, we tested whether rare genetic variants in TSC1, TSC2, MYCBP2, RHEB and FBXO45, genes that regulate mTORC1 signaling and/or play a role in synapse development and function, contribute to the pathogenesis of idiopathic ASD.METHODS:Exons and splice junctions of TSC1, TSC2, MYCBP2, RHEB and FBXO45 were resequenced for 300 ASD trios from the Simons Simplex Collection (SSC) using a pooled PCR amplification and next-generation sequencing strategy, targeted to the discovery of deleterious coding variation. These detected, potentially functional, variants were confirmed by Sanger sequencing of the individual samples comprising the pools in which they were identified.RESULTS:We identified a total of 23 missense variants in MYCBP2, TSC1 and TSC2. These variants exhibited a near equal distribution between the proband and parental pools, with no statistical excess in ASD cases (P 0.05). All proband variants were inherited. No putative deleterious variants were confirmed in RHEB and FBXO45. Three intronic variants, identified as potential splice defects in MYCBP2 did not show aberrant splicing upon RNA assay. Overall, we did not find an over-representation of ASD causal variants in the genes studied to support them as contributors to autism susceptibility.CONCLUSIONS:We did not observe an enrichment of rare functional variants in TSC1 and TSC2 genes in our sample set of 300 trios. En ligne : http://dx.doi.org/10.1186/2040-2392-4-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202
in Molecular Autism > (March 2013) . - 11 p.[article] Lack of association of rare functional variants in TSC1/TSC2 genes with autism spectrum disorder [Texte imprimé et/ou numérique] / Samira BAHL, Auteur ; Colby CHIANG, Auteur ; Roberta L. BEAUCHAMP, Auteur ; Benjamin NEALE, Auteur ; Mark J. DALY, Auteur ; James GUSELLA, Auteur ; Michael E. TALKOWSKI, Auteur ; Vijaya RAMESH, Auteur . - 2013 . - 11 p.
Langues : Anglais (eng)
in Molecular Autism > (March 2013) . - 11 p.
Mots-clés : Autism spectrum disorder Tuberous sclerosis complex Mammalian target of rapamycin Next-generation sequencing Rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND:Autism spectrum disorder (ASD) is reported in 30 to 60% of patients with tuberous sclerosis complex (TSC) but shared genetic mechanisms that exist between TSC-associated ASD and idiopathic ASD have yet to be determined. Through the small G-protein Rheb, the TSC proteins, hamartin and tuberin, negatively regulate mammalian target of rapamycin complex 1 (mTORC1) signaling. It is well established that mTORC1 plays a pivotal role in neuronal translation and connectivity, so dysregulation of mTORC1 signaling could be a common feature in many ASDs. Pam, an E3 ubiquitin ligase, binds to TSC proteins and regulates mTORC1 signaling in the CNS, and the FBXO45-Pam ubiquitin ligase complex plays an essential role in neurodevelopment by regulating synapse formation and growth. Since mounting evidence has established autism as a disorder of the synapses, we tested whether rare genetic variants in TSC1, TSC2, MYCBP2, RHEB and FBXO45, genes that regulate mTORC1 signaling and/or play a role in synapse development and function, contribute to the pathogenesis of idiopathic ASD.METHODS:Exons and splice junctions of TSC1, TSC2, MYCBP2, RHEB and FBXO45 were resequenced for 300 ASD trios from the Simons Simplex Collection (SSC) using a pooled PCR amplification and next-generation sequencing strategy, targeted to the discovery of deleterious coding variation. These detected, potentially functional, variants were confirmed by Sanger sequencing of the individual samples comprising the pools in which they were identified.RESULTS:We identified a total of 23 missense variants in MYCBP2, TSC1 and TSC2. These variants exhibited a near equal distribution between the proband and parental pools, with no statistical excess in ASD cases (P 0.05). All proband variants were inherited. No putative deleterious variants were confirmed in RHEB and FBXO45. Three intronic variants, identified as potential splice defects in MYCBP2 did not show aberrant splicing upon RNA assay. Overall, we did not find an over-representation of ASD causal variants in the genes studied to support them as contributors to autism susceptibility.CONCLUSIONS:We did not observe an enrichment of rare functional variants in TSC1 and TSC2 genes in our sample set of 300 trios. En ligne : http://dx.doi.org/10.1186/2040-2392-4-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=202 A systematic variant annotation approach for ranking genes associated with autism spectrum disorders / E. LARSEN in Molecular Autism, 7 (2016)
[article]
Titre : A systematic variant annotation approach for ranking genes associated with autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : E. LARSEN, Auteur ; I. MENASHE, Auteur ; M. N. ZIATS, Auteur ; W. PEREANU, Auteur ; A. PACKER, Auteur ; Sharmila BANERJEE-BASU, Auteur Article en page(s) : 44p. Langues : Anglais (eng) Mots-clés : Algorithms Autism Spectrum Disorder/genetics/physiopathology DNA-Binding Proteins/genetics Databases, Genetic Datasets as Topic Gene Expression Genetic Predisposition to Disease Genetic Variation Homeodomain Proteins/genetics Humans Molecular Sequence Annotation Nerve Tissue Proteins/genetics Research Design Transcription Factors/genetics Autistic disorder Autosomal recessive Common variants Genetic variation Rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND: The search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function. A major challenge involves assessing the collective evidence in an unbiased, systematic manner for their functional relevance. METHODS: Here, we describe a scoring algorithm for prioritization of candidate genes based on the cumulative strength of evidence for each ASD-associated variant cataloged in AutDB (also known as SFARI Gene). We retrieved data from 889 publications to generate a dataset of 2187 rare and 711 common variants distributed across 461 genes implicated in ASD. Each individual variant was manually annotated with multiple attributes extracted from the original report, followed by score assignment using a set of standardized parameters yielding a single score for each gene. RESULTS: There was a wide variation in scores; SHANK3, CHD8, and ADNP had distinctly higher scores than all other genes in the dataset. Our gene scores were significantly correlated with other recently published rankings of ASD genes (RSpearman = 0.40-0.63; p< 0.0001), providing support for our scoring algorithm. CONCLUSIONS: This new resource, which is freely available, for the first time aggregates on one-platform variants identified from various study types (simplex, multiplex, multigenerational, and consanguineous families), from both common and rare variants, and also incorporates their putative functional consequences to arrive at a genetically and biologically driven ranking scheme. This work represents a major step in moving from simply cataloging autism variants to using data-driven approaches to gain insight into their significance. En ligne : http://dx.doi.org/10.1186/s13229-016-0103-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328
in Molecular Autism > 7 (2016) . - 44p.[article] A systematic variant annotation approach for ranking genes associated with autism spectrum disorders [Texte imprimé et/ou numérique] / E. LARSEN, Auteur ; I. MENASHE, Auteur ; M. N. ZIATS, Auteur ; W. PEREANU, Auteur ; A. PACKER, Auteur ; Sharmila BANERJEE-BASU, Auteur . - 44p.
Langues : Anglais (eng)
in Molecular Autism > 7 (2016) . - 44p.
Mots-clés : Algorithms Autism Spectrum Disorder/genetics/physiopathology DNA-Binding Proteins/genetics Databases, Genetic Datasets as Topic Gene Expression Genetic Predisposition to Disease Genetic Variation Homeodomain Proteins/genetics Humans Molecular Sequence Annotation Nerve Tissue Proteins/genetics Research Design Transcription Factors/genetics Autistic disorder Autosomal recessive Common variants Genetic variation Rare variants Index. décimale : PER Périodiques Résumé : BACKGROUND: The search for genetic factors underlying autism spectrum disorders (ASD) has led to the identification of hundreds of genes containing thousands of variants that differ in mode of inheritance, effect size, frequency, and function. A major challenge involves assessing the collective evidence in an unbiased, systematic manner for their functional relevance. METHODS: Here, we describe a scoring algorithm for prioritization of candidate genes based on the cumulative strength of evidence for each ASD-associated variant cataloged in AutDB (also known as SFARI Gene). We retrieved data from 889 publications to generate a dataset of 2187 rare and 711 common variants distributed across 461 genes implicated in ASD. Each individual variant was manually annotated with multiple attributes extracted from the original report, followed by score assignment using a set of standardized parameters yielding a single score for each gene. RESULTS: There was a wide variation in scores; SHANK3, CHD8, and ADNP had distinctly higher scores than all other genes in the dataset. Our gene scores were significantly correlated with other recently published rankings of ASD genes (RSpearman = 0.40-0.63; p< 0.0001), providing support for our scoring algorithm. CONCLUSIONS: This new resource, which is freely available, for the first time aggregates on one-platform variants identified from various study types (simplex, multiplex, multigenerational, and consanguineous families), from both common and rare variants, and also incorporates their putative functional consequences to arrive at a genetically and biologically driven ranking scheme. This work represents a major step in moving from simply cataloging autism variants to using data-driven approaches to gain insight into their significance. En ligne : http://dx.doi.org/10.1186/s13229-016-0103-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=328