4 recherche sur le mot-clé 'Whole-exome sequencing'

Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation / Zhu WEN in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 43p. Titre : Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation Type de document : texte imprimé Auteurs : Zhu WEN, Auteur ; Tian-Lin CHENG, Auteur ; Gai-Zhi LI, Auteur ; Shi-Bang SUN, Auteur ; Shun-Ying YU, Auteur ; Yi ZHANG, Auteur ; Ya-song DU, Auteur ; Zilong QIU, Auteur Article en page(s) : 43p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Methyl-CpG-binding protein-2 (MeCP2)  Neural development  Whole-exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Methyl-CpG-binding protein-2 (MeCP2) is a critical regulator for neural development. Either loss- or gain-of-function leads to severe neurodevelopmental disorders, such as Rett syndrome (RTT) and autism spectrum disorder (ASD). We set out to screen for MECP2 mutations in patients of ASD and determine whether these autism-related mutations may compromise the proper function of MeCP2. METHODS: Whole-exome sequencing was performed to screen MECP2 and other ASD candidate genes for 120 patients diagnosed with ASD. The parents of patients who were identified with MECP2 mutation were selected for further Sanger sequencing. Each patient accomplished the case report form including general information and clinical scales applied to assess their clinical features. Mouse cortical neurons and HEK-293 cells were cultured and transfected with MeCP2 wild-type (WT) or mutant to examine the function of autism-associated MeCP2 mutants. HEK-293 cells were used to examine the expression of MeCP2 mutant constructs with Western blot. Mouse cortical neurons were used to analyze neurites and axon outgrowth by immunofluorescence experiments. RESULTS: We identified three missense mutations of MECP2 from three autism patients by whole-exome sequencing: p.P152L (c.455C>T), p.P376S (c.1162C>T), and p.R294X (c.880C>T). Among these mutations, p.P152L and p.R294X were de novo mutations, whereas p.P376S was inherited maternally. The diagnosis of RTT was excluded in all three autism patients. Abnormalities of dendritic and axonal growth were found after autism-related MeCP2 mutants were expressed in mouse cortical neurons; suggesting that autism-related MECP2 mutations impair the proper development of neurons. CONCLUSIONS: Our study identified genetic mutations of the MECP2 gene in autism patients, which were previously considered to be associated primarily with RTT. This finding suggests that loss-of-function mutations of MECP2 may also lead to autism spectrum disorders. En ligne : http://dx.doi.org/10.1186/s13229-017-0157-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation [texte imprimé] / Zhu WEN, Auteur ; Tian-Lin CHENG, Auteur ; Gai-Zhi LI, Auteur ; Shi-Bang SUN, Auteur ; Shun-Ying YU, Auteur ; Yi ZHANG, Auteur ; Ya-song DU, Auteur ; Zilong QIU, Auteur . - 43p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 43p. Mots-clés : Autism spectrum disorder  Methyl-CpG-binding protein-2 (MeCP2)  Neural development  Whole-exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Methyl-CpG-binding protein-2 (MeCP2) is a critical regulator for neural development. Either loss- or gain-of-function leads to severe neurodevelopmental disorders, such as Rett syndrome (RTT) and autism spectrum disorder (ASD). We set out to screen for MECP2 mutations in patients of ASD and determine whether these autism-related mutations may compromise the proper function of MeCP2. METHODS: Whole-exome sequencing was performed to screen MECP2 and other ASD candidate genes for 120 patients diagnosed with ASD. The parents of patients who were identified with MECP2 mutation were selected for further Sanger sequencing. Each patient accomplished the case report form including general information and clinical scales applied to assess their clinical features. Mouse cortical neurons and HEK-293 cells were cultured and transfected with MeCP2 wild-type (WT) or mutant to examine the function of autism-associated MeCP2 mutants. HEK-293 cells were used to examine the expression of MeCP2 mutant constructs with Western blot. Mouse cortical neurons were used to analyze neurites and axon outgrowth by immunofluorescence experiments. RESULTS: We identified three missense mutations of MECP2 from three autism patients by whole-exome sequencing: p.P152L (c.455C>T), p.P376S (c.1162C>T), and p.R294X (c.880C>T). Among these mutations, p.P152L and p.R294X were de novo mutations, whereas p.P376S was inherited maternally. The diagnosis of RTT was excluded in all three autism patients. Abnormalities of dendritic and axonal growth were found after autism-related MeCP2 mutants were expressed in mouse cortical neurons; suggesting that autism-related MECP2 mutations impair the proper development of neurons. CONCLUSIONS: Our study identified genetic mutations of the MECP2 gene in autism patients, which were previously considered to be associated primarily with RTT. This finding suggests that loss-of-function mutations of MECP2 may also lead to autism spectrum disorders. En ligne : http://dx.doi.org/10.1186/s13229-017-0157-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Association between rare, genetic variants linked to autism and ultrasonography fetal anomalies in children with autism spectrum disorder / Ohad REGEV in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Association between rare, genetic variants linked to autism and ultrasonography fetal anomalies in children with autism spectrum disorder Type de document : texte imprimé Auteurs : Ohad REGEV, Auteur ; Apurba SHIL, Auteur ; Tal BRONSHTEIN, Auteur ; Amnon HADAR, Auteur ; Gal MEIRI, Auteur ; Dikla ZIGDON, Auteur ; Analya MICHAELOVSKI, Auteur ; Reli HERSHKOVITZ, Auteur ; Idan MENASHE, Auteur Langues : Anglais (eng) Mots-clés : Humans  Autism Spectrum Disorder/genetics/diagnostic imaging  Female  Male  Ultrasonography, Prenatal  Child  Exome Sequencing  Pregnancy  Cross-Sectional Studies  Child, Preschool  Genetic Variation  Genetic Predisposition to Disease  Autism spectrum disorder  Congenital anomalies  Fetal development  Genetic mutations  Prenatal ultrasound  Ultrasonography fetal anomalies  Whole-exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Recent evidence suggests that certain fetal anomalies detected upon prenatal ultrasound screenings are associated with autism spectrum disorder (ASD). In this cross-sectional study, we aimed to identify genetic variants associated with fetal ultrasound anomalies (UFAs) in children with ASD. METHODS: The study included all children with ASD who are registered in the database of the Azrieli National Center of Autism and Neurodevelopment and for whom both prenatal ultrasound and whole exome sequencing (WES) data were available. We applied our in-house integrative bioinformatics pipeline, AutScore, to these WES data to prioritize rare, gene-disrupting variants (GDVs) probably contributing to ASD susceptibily. Univariate statistics and multivariable regression were used to assess the associations between UFAs and GDVs identified in these children. RESULTS: The study sample comprised 126 children, of whom 43 (34.1%) had at least one UFA detected in the prenatal ultrasound scan. A total of 87 candidate ASD genetic variants were detected in 60 children, with 24 (40%) children carrying multiple variants. Children with UFAs were more likely to have loss-of-function (LoF) mutations (aOR = 2.55, 95%CI: 1.13-5.80). This association was particularly noticeable when children with structural anomalies or children with UFAs in their head and brain scans were compared to children without UFAs (any mutation: aOR = 8.28, 95%CI: 2.29-30.01; LoF: aOR = 5.72, 95%CI: 2.08-15.71 and any mutation: aOR = 6.39, 95%CI: 1.34-30.47; LoF: aOR = 4.50, 95%CI: 1.32-15.35, respectively). GDVs associated with UFAs were enriched in genes highly expressed across all tissues (aOR = 2.76, 95%CI: 1.14-6.68). There was a weak, but significant, correlation between the number of mutations and the number of abnormalities detected in the same children (r = 0.21, P = 0.016). CONCLUSIONS: The results provide valuable insights into the potential genetic basis of prenatal organogenesis abnormalities associated with ASD and shed light on the complex interplay between genetic factors and fetal development. En ligne : https://dx.doi.org/10.1186/s11689-024-09573-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] Association between rare, genetic variants linked to autism and ultrasonography fetal anomalies in children with autism spectrum disorder [texte imprimé] / Ohad REGEV, Auteur ; Apurba SHIL, Auteur ; Tal BRONSHTEIN, Auteur ; Amnon HADAR, Auteur ; Gal MEIRI, Auteur ; Dikla ZIGDON, Auteur ; Analya MICHAELOVSKI, Auteur ; Reli HERSHKOVITZ, Auteur ; Idan MENASHE, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Autism Spectrum Disorder/genetics/diagnostic imaging  Female  Male  Ultrasonography, Prenatal  Child  Exome Sequencing  Pregnancy  Cross-Sectional Studies  Child, Preschool  Genetic Variation  Genetic Predisposition to Disease  Autism spectrum disorder  Congenital anomalies  Fetal development  Genetic mutations  Prenatal ultrasound  Ultrasonography fetal anomalies  Whole-exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Recent evidence suggests that certain fetal anomalies detected upon prenatal ultrasound screenings are associated with autism spectrum disorder (ASD). In this cross-sectional study, we aimed to identify genetic variants associated with fetal ultrasound anomalies (UFAs) in children with ASD. METHODS: The study included all children with ASD who are registered in the database of the Azrieli National Center of Autism and Neurodevelopment and for whom both prenatal ultrasound and whole exome sequencing (WES) data were available. We applied our in-house integrative bioinformatics pipeline, AutScore, to these WES data to prioritize rare, gene-disrupting variants (GDVs) probably contributing to ASD susceptibily. Univariate statistics and multivariable regression were used to assess the associations between UFAs and GDVs identified in these children. RESULTS: The study sample comprised 126 children, of whom 43 (34.1%) had at least one UFA detected in the prenatal ultrasound scan. A total of 87 candidate ASD genetic variants were detected in 60 children, with 24 (40%) children carrying multiple variants. Children with UFAs were more likely to have loss-of-function (LoF) mutations (aOR = 2.55, 95%CI: 1.13-5.80). This association was particularly noticeable when children with structural anomalies or children with UFAs in their head and brain scans were compared to children without UFAs (any mutation: aOR = 8.28, 95%CI: 2.29-30.01; LoF: aOR = 5.72, 95%CI: 2.08-15.71 and any mutation: aOR = 6.39, 95%CI: 1.34-30.47; LoF: aOR = 4.50, 95%CI: 1.32-15.35, respectively). GDVs associated with UFAs were enriched in genes highly expressed across all tissues (aOR = 2.76, 95%CI: 1.14-6.68). There was a weak, but significant, correlation between the number of mutations and the number of abnormalities detected in the same children (r = 0.21, P = 0.016). CONCLUSIONS: The results provide valuable insights into the potential genetic basis of prenatal organogenesis abnormalities associated with ASD and shed light on the complex interplay between genetic factors and fetal development. En ligne : https://dx.doi.org/10.1186/s11689-024-09573-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings / Kei OHASHI in Journal of Autism and Developmental Disorders, 51-12 (December 2021)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 51-12 (December 2021) . - p.4655-4662 Titre : Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings Type de document : texte imprimé Auteurs : Kei OHASHI, Auteur ; Satomi FUKUHARA, Auteur ; Taishi MIYACHI, Auteur ; Tomoko ASAI, Auteur ; Masayuki IMAEDA, Auteur ; Masahide GOTO, Auteur ; Yoshie KUROKAWA, Auteur ; Tatsuya ANZAI, Auteur ; Yoshinori TSURUSAKI, Auteur ; Noriko MIYAKE, Auteur ; Naomichi MATSUMOTO, Auteur ; Takanori YAMAGATA, Auteur ; Shinji SAITOH, Auteur Article en page(s) : p.4655-4662 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/diagnosis/genetics  Comparative Genomic Hybridization  DNA Copy Number Variations  Genetic Predisposition to Disease  Genetic Testing  Genomics  Humans  Autism spectrum disorder  Genetic analysis  Microarray comparative genomic hybridization  Whole-exome sequencing Index. décimale : PER Périodiques Résumé : Although genetic factors are involved in the etiology of autism spectrum disorder (ASD), the significance of genetic analysis in clinical settings is unclear. Forty-nine subjects diagnosed with non-syndromic ASD were analyzed by microarray comparative genomic hybridization (CGH) analysis, whole-exome sequencing (WES) analysis, and panel sequencing analysis for 52 common causative genes of ASD to detect inherited rare variants. Genetic analysis by microarray CGH and WES analyses showed conclusive results in about 10% of patients, however, many inherited variants detected by panel sequencing analysis were difficult to interpret and apply in clinical practice in the majority of patients. Further improvement of interpretation of many variants detected would be necessary for combined genetic tests to be used in clinical settings. En ligne : http://dx.doi.org/10.1007/s10803-021-04910-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=454 [article] Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings [texte imprimé] / Kei OHASHI, Auteur ; Satomi FUKUHARA, Auteur ; Taishi MIYACHI, Auteur ; Tomoko ASAI, Auteur ; Masayuki IMAEDA, Auteur ; Masahide GOTO, Auteur ; Yoshie KUROKAWA, Auteur ; Tatsuya ANZAI, Auteur ; Yoshinori TSURUSAKI, Auteur ; Noriko MIYAKE, Auteur ; Naomichi MATSUMOTO, Auteur ; Takanori YAMAGATA, Auteur ; Shinji SAITOH, Auteur . - p.4655-4662. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 51-12 (December 2021) . - p.4655-4662 Mots-clés : Autism Spectrum Disorder/diagnosis/genetics  Comparative Genomic Hybridization  DNA Copy Number Variations  Genetic Predisposition to Disease  Genetic Testing  Genomics  Humans  Autism spectrum disorder  Genetic analysis  Microarray comparative genomic hybridization  Whole-exome sequencing Index. décimale : PER Périodiques Résumé : Although genetic factors are involved in the etiology of autism spectrum disorder (ASD), the significance of genetic analysis in clinical settings is unclear. Forty-nine subjects diagnosed with non-syndromic ASD were analyzed by microarray comparative genomic hybridization (CGH) analysis, whole-exome sequencing (WES) analysis, and panel sequencing analysis for 52 common causative genes of ASD to detect inherited rare variants. Genetic analysis by microarray CGH and WES analyses showed conclusive results in about 10% of patients, however, many inherited variants detected by panel sequencing analysis were difficult to interpret and apply in clinical practice in the majority of patients. Further improvement of interpretation of many variants detected would be necessary for combined genetic tests to be used in clinical settings. En ligne : http://dx.doi.org/10.1007/s10803-021-04910-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=454

Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation / MatthewJ GAZZELLONE in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.36 Titre : Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation Type de document : texte imprimé Auteurs : MatthewJ GAZZELLONE, Auteur ; Mehdi ZARREI, Auteur ; Christie L. BURTON, Auteur ; Susan WALKER, Auteur ; Mohammed UDDIN, Auteur ; S.M. SHAHEEN, Auteur ; Julie COSTE, Auteur ; Rageen RAJENDRAM, Auteur ; Reva J. SCHACHTER, Auteur ; Marlena COLASANTO, Auteur ; Gregory L. HANNA, Auteur ; David R. ROSENBERG, Auteur ; Noam SORENI, Auteur ; Kate D. FITZGERALD, Auteur ; Christian R. MARSHALL, Auteur ; Janet A. BUCHANAN, Auteur ; Daniele MERICO, Auteur ; Paul D. ARNOLD, Auteur ; Stephen SCHERER, Auteur Article en page(s) : p.36 Langues : Anglais (eng) Mots-clés : Copy number variation  Obsessive-compulsive disorder  Pediatrics  Whole-exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD. METHODS: We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD. RESULTS: We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal p = 1.85 x 10(-03); FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1 and PTPRD), and postsynaptic scaffolding (DLGAP1 and DLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified BTBD9 as a candidate gene for OCD. We also sequenced exomes of ten "CNV positive" trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion in DRD4. CONCLUSIONS: Our findings suggest that rare CNVs may contribute to the etiology of OCD. En ligne : http://dx.doi.org/10.1186/s11689-016-9170-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349 [article] Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation [texte imprimé] / MatthewJ GAZZELLONE, Auteur ; Mehdi ZARREI, Auteur ; Christie L. BURTON, Auteur ; Susan WALKER, Auteur ; Mohammed UDDIN, Auteur ; S.M. SHAHEEN, Auteur ; Julie COSTE, Auteur ; Rageen RAJENDRAM, Auteur ; Reva J. SCHACHTER, Auteur ; Marlena COLASANTO, Auteur ; Gregory L. HANNA, Auteur ; David R. ROSENBERG, Auteur ; Noam SORENI, Auteur ; Kate D. FITZGERALD, Auteur ; Christian R. MARSHALL, Auteur ; Janet A. BUCHANAN, Auteur ; Daniele MERICO, Auteur ; Paul D. ARNOLD, Auteur ; Stephen SCHERER, Auteur . - p.36. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.36 Mots-clés : Copy number variation  Obsessive-compulsive disorder  Pediatrics  Whole-exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Obsessive-compulsive disorder (OCD) is a heterogeneous neuropsychiatric condition, thought to have a significant genetic component. When onset occurs in childhood, affected individuals generally exhibit different characteristics from adult-onset OCD, including higher prevalence in males and increased heritability. Since neuropsychiatric conditions are associated with copy number variations (CNVs), we considered their potential role in the etiology of OCD. METHODS: We genotyped 307 unrelated pediatric probands with idiopathic OCD (including 174 that were part of complete parent-child trios) and compared their genotypes with those of 3861 population controls, to identify rare CNVs (<0.5 % frequency) of at least 15 kb in size that might contribute to OCD. RESULTS: We uncovered de novo CNVs in 4/174 probands (2.3 %). Our case cohort was enriched for CNVs in genes that encode targets of the fragile X mental retardation protein (nominal p = 1.85 x 10(-03); FDR=0.09), similar to previous findings in autism and schizophrenia. These results also identified deletions or duplications of exons in genes involved in neuronal migration (ASTN2), synapse formation (NLGN1 and PTPRD), and postsynaptic scaffolding (DLGAP1 and DLGAP2), which may be relevant to the pathogenesis of OCD. Four cases had CNVs involving known genomic disorder loci (1q21.1-21.2, 15q11.2-q13.1, 16p13.11, and 17p12). Further, we identified BTBD9 as a candidate gene for OCD. We also sequenced exomes of ten "CNV positive" trios and identified in one an additional plausibly relevant mutation: a 13 bp exonic deletion in DRD4. CONCLUSIONS: Our findings suggest that rare CNVs may contribute to the etiology of OCD. En ligne : http://dx.doi.org/10.1186/s11689-016-9170-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349