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Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder / A. MUNNICH in Molecular Autism, 10 (2019)
[article]
Titre : Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : A. MUNNICH, Auteur ; Caroline DEMILY, Auteur ; L. FRUGERE, Auteur ; C. DUWIME, Auteur ; V. MALAN, Auteur ; Giulia BARCIA, Auteur ; C. VIDAL, Auteur ; E. THROO, Auteur ; C. BESMOND, Auteur ; L. HUBERT, Auteur ; G. ROLAND-MANUEL, Auteur ; J. P. MALEN, Auteur ; M. FERRERI, Auteur ; S. HANEIN, Auteur ; J. C. THALABARD, Auteur ; Nathalie BODDAERT, Auteur ; Moïse ASSOULINE, Auteur Article en page(s) : 33 p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Copy number variant Fragile X syndrome Gene panel Genetic counseling Genetic diagnosis Microarray Next-generation sequencing Sequence variant Index. décimale : PER Périodiques Résumé : Background: Neurogenetics investigations and diagnostic yield in patients with autism spectrum disorder (ASD) have significantly improved over the last few years. Yet, many patients still fail to be systematically investigated. Methods: To improve access to services, an ambulatory team has been established since 1998, delivering on-site clinical genetics consultations and gradually upgrading services to 502 children and young adults with ASD in their standard environment across 26 day-care hospitals and specialized institutions within the Greater Paris region. The evaluation included a clinical genetics consultation, screening for fragile X syndrome, metabolic workup, chromosomal microarray analysis, and, in a proportion of patients, next-generation sequencing of genes reported in ASD and other neurodevelopmental disorders. Results: Fragile X syndrome and pathogenic copy number variants (CNVs) accounted for the disease in 10% of cases, including 4/312 (1.3%) with fragile X syndrome and 34/388 (8.8%) with pathogenic CNVs (19 de novo and 4 inherited). Importantly, adding high-throughput resequencing of reported intellectual disability/ASD genes to the screening procedure had a major impact on diagnostic yield in the 141 patients examined most recently. Pathogenic or likely pathogenic sequence variants in 27 disease genes were identified in 33/141 patients (23.4%; 23 were de novo and 10 inherited, including five X-linked and five recessive compound heterozygous variants). Diagnosed cases presented atypical and/or syndromic ASD with moderate to severe intellectual disability. The diagnostic yield of fragile X syndrome and array CGH testing combined with next-generation sequencing was significantly higher than fragile X syndrome and array CGH alone (p value 0.009). No inborn errors of metabolism were detected with the metabolic screening. Conclusion: Based on the diagnostic rate observed in this cohort, we suggest that a stepwise procedure be considered, first screening pathogenic CNVs and a limited number of disease genes in a much larger number of patients, especially those with syndromic ASD and intellectual disability. En ligne : https://dx.doi.org/10.1186/s13229-019-0284-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408
in Molecular Autism > 10 (2019) . - 33 p.[article] Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder [Texte imprimé et/ou numérique] / A. MUNNICH, Auteur ; Caroline DEMILY, Auteur ; L. FRUGERE, Auteur ; C. DUWIME, Auteur ; V. MALAN, Auteur ; Giulia BARCIA, Auteur ; C. VIDAL, Auteur ; E. THROO, Auteur ; C. BESMOND, Auteur ; L. HUBERT, Auteur ; G. ROLAND-MANUEL, Auteur ; J. P. MALEN, Auteur ; M. FERRERI, Auteur ; S. HANEIN, Auteur ; J. C. THALABARD, Auteur ; Nathalie BODDAERT, Auteur ; Moïse ASSOULINE, Auteur . - 33 p.
Langues : Anglais (eng)
in Molecular Autism > 10 (2019) . - 33 p.
Mots-clés : Autism spectrum disorder Copy number variant Fragile X syndrome Gene panel Genetic counseling Genetic diagnosis Microarray Next-generation sequencing Sequence variant Index. décimale : PER Périodiques Résumé : Background: Neurogenetics investigations and diagnostic yield in patients with autism spectrum disorder (ASD) have significantly improved over the last few years. Yet, many patients still fail to be systematically investigated. Methods: To improve access to services, an ambulatory team has been established since 1998, delivering on-site clinical genetics consultations and gradually upgrading services to 502 children and young adults with ASD in their standard environment across 26 day-care hospitals and specialized institutions within the Greater Paris region. The evaluation included a clinical genetics consultation, screening for fragile X syndrome, metabolic workup, chromosomal microarray analysis, and, in a proportion of patients, next-generation sequencing of genes reported in ASD and other neurodevelopmental disorders. Results: Fragile X syndrome and pathogenic copy number variants (CNVs) accounted for the disease in 10% of cases, including 4/312 (1.3%) with fragile X syndrome and 34/388 (8.8%) with pathogenic CNVs (19 de novo and 4 inherited). Importantly, adding high-throughput resequencing of reported intellectual disability/ASD genes to the screening procedure had a major impact on diagnostic yield in the 141 patients examined most recently. Pathogenic or likely pathogenic sequence variants in 27 disease genes were identified in 33/141 patients (23.4%; 23 were de novo and 10 inherited, including five X-linked and five recessive compound heterozygous variants). Diagnosed cases presented atypical and/or syndromic ASD with moderate to severe intellectual disability. The diagnostic yield of fragile X syndrome and array CGH testing combined with next-generation sequencing was significantly higher than fragile X syndrome and array CGH alone (p value 0.009). No inborn errors of metabolism were detected with the metabolic screening. Conclusion: Based on the diagnostic rate observed in this cohort, we suggest that a stepwise procedure be considered, first screening pathogenic CNVs and a limited number of disease genes in a much larger number of patients, especially those with syndromic ASD and intellectual disability. En ligne : https://dx.doi.org/10.1186/s13229-019-0284-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408 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 Experimental Tools for the Identification of Specific Genes in Autism Spectrum Disorders and Intellectual Disability / Yiping SHEN
in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA
Titre : Experimental Tools for the Identification of Specific Genes in Autism Spectrum Disorders and Intellectual Disability Type de document : Texte imprimé et/ou numérique Auteurs : Yiping SHEN, Auteur ; Xiaohong GONG, Auteur Année de publication : 2016 Importance : p.3-12 Langues : Anglais (eng) Mots-clés : Autozygosity mapping Balanced translocation breakpoint mapping Candidate gene approach Copy number variations Exome sequencing Linkage analysis Next-generation sequencing Positional mapping Whole-genome sequencing Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Technological advancements for interrogating genomic variants continue to facilitate discoveries of the genetic causes of intellectual disability (ID) and autism spectrum disorders (ASD), both of which are neurodevelopmental disorders known to have a strong genetic basis. In this chapter we discuss the major methods and approaches that have had significant roles in revealing genes and genomic regions associated with ID and ASD. Linkage analysis followed by candidate gene sequencing and positional cloning in patients with genomic rearrangements have been largely responsible for the success of identifying X-linked and autosomal dominant ID/ASD genes. Autozygosity mapping has a unique role in identifying recessive ID/ASD genes. Exome and whole-genome sequencing has provided unprecedented power for genotyping, and the data have provided us with a broader understanding of the association of de novo variants with ID and ASD. We believe that a better understanding of the genetic underpinnings will lead to better diagnosis, management, and treatment for patients with ID and ASD. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00001-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 Experimental Tools for the Identification of Specific Genes in Autism Spectrum Disorders and Intellectual Disability [Texte imprimé et/ou numérique] / Yiping SHEN, Auteur ; Xiaohong GONG, Auteur . - 2016 . - p.3-12.
in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability / Carlo SALA
Langues : Anglais (eng)
Mots-clés : Autozygosity mapping Balanced translocation breakpoint mapping Candidate gene approach Copy number variations Exome sequencing Linkage analysis Next-generation sequencing Positional mapping Whole-genome sequencing Index. décimale : SCI-D SCI-D - Neurosciences Résumé : Technological advancements for interrogating genomic variants continue to facilitate discoveries of the genetic causes of intellectual disability (ID) and autism spectrum disorders (ASD), both of which are neurodevelopmental disorders known to have a strong genetic basis. In this chapter we discuss the major methods and approaches that have had significant roles in revealing genes and genomic regions associated with ID and ASD. Linkage analysis followed by candidate gene sequencing and positional cloning in patients with genomic rearrangements have been largely responsible for the success of identifying X-linked and autosomal dominant ID/ASD genes. Autozygosity mapping has a unique role in identifying recessive ID/ASD genes. Exome and whole-genome sequencing has provided unprecedented power for genotyping, and the data have provided us with a broader understanding of the association of de novo variants with ID and ASD. We believe that a better understanding of the genetic underpinnings will lead to better diagnosis, management, and treatment for patients with ID and ASD. En ligne : http://dx.doi.org/10.1016/B978-0-12-800109-7.00001-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=301 Exemplaires
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