Autism genetics: strategies, challenges, and opportunities / Brian J. O'ROAK in Autism Research, 1-1 (February 2008)  

Public ISBD [article]  inAutism Research > 1-1 (February 2008) . - p.4-17 Titre : Autism genetics: strategies, challenges, and opportunities Type de document : Texte imprimé et/ou numérique Auteurs : Brian J. O'ROAK, Auteur ; Matthew W. STATE, Auteur Année de publication : 2008 Article en page(s) : p.4-17 Langues : Anglais (eng) Mots-clés : autism genetics linkage association gene-discovery Index. décimale : PER Périodiques Résumé : Although genes have long been appreciated to play a critical role in determining the risk for pervasive developmental disorders, the specific transcripts contributing to autism spectrum disorders (ASD) have been quite difficult to characterize. However, recent findings are now providing the first insights into the molecular mechanisms underlying these syndromes and have begun to shed light on the allelic architecture of ASD. In this article, we address what is known about the relative contributions of various types of genetic variation to ASD, consider the obstacles facing gene discovery in this complex disorder, and evaluate the common methodologies employed to address these issues, including linkage, molecular and array-based cytogenetics, and association strategies. We review the current literature, highlighting recent findings implicating both rare mutations and common genetic polymorphisms in the etiology of autism. Finally, we describe key advances in genomic technologies that are transforming all areas of human genetics and consider both the opportunities and challenges for autism research posed by these rapid changes. En ligne : http://dx.doi.org/10.1002/aur.3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=929 [article] Autism genetics: strategies, challenges, and opportunities [Texte imprimé et/ou numérique] / Brian J. O'ROAK, Auteur ; Matthew W. STATE, Auteur . - 2008 . - p.4-17. Langues : Anglais (eng) in Autism Research > 1-1 (February 2008) . - p.4-17 Mots-clés : autism genetics linkage association gene-discovery Index. décimale : PER Périodiques Résumé : Although genes have long been appreciated to play a critical role in determining the risk for pervasive developmental disorders, the specific transcripts contributing to autism spectrum disorders (ASD) have been quite difficult to characterize. However, recent findings are now providing the first insights into the molecular mechanisms underlying these syndromes and have begun to shed light on the allelic architecture of ASD. In this article, we address what is known about the relative contributions of various types of genetic variation to ASD, consider the obstacles facing gene discovery in this complex disorder, and evaluate the common methodologies employed to address these issues, including linkage, molecular and array-based cytogenetics, and association strategies. We review the current literature, highlighting recent findings implicating both rare mutations and common genetic polymorphisms in the etiology of autism. Finally, we describe key advances in genomic technologies that are transforming all areas of human genetics and consider both the opportunities and challenges for autism research posed by these rapid changes. En ligne : http://dx.doi.org/10.1002/aur.3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=929

Detailed phenotyping of Tbr1-2A-CreER knock-in mice demonstrates significant impacts on TBR1 protein levels and axon development / Grace K. O'BRIEN ; Kevin M. WRIGHT ; Brian J. O'ROAK in Autism Research, 18-5 (May 2025)  

Public ISBD [article]  inAutism Research > 18-5 (May 2025) . - p.922-932 Titre : Detailed phenotyping of Tbr1-2A-CreER knock-in mice demonstrates significant impacts on TBR1 protein levels and axon development Type de document : Texte imprimé et/ou numérique Auteurs : Grace K. O'BRIEN, Auteur ; Kevin M. WRIGHT, Auteur ; Brian J. O'ROAK, Auteur Article en page(s) : p.922-932 Langues : Anglais (eng) Mots-clés : anterior commissure  axon  cortex  mice  TBR1  transcription factor Index. décimale : PER Périodiques Résumé : Abstract Cre recombinase knock-in mouse lines have served as invaluable genetic tools for understanding key developmental processes altered in autism. However, insertion of exogenous DNA into the genome can have unintended effects on local gene regulation or protein function that must be carefully considered. Here, we analyze a recently generated Tbr1-2A-CreER knock-in mouse line, where a 2A-CreER cassette was inserted in-frame before the stop codon of the transcription factor gene Tbr1. Heterozygous TBR1 mutations in humans and mice are known to cause autism or autism-like behavioral phenotypes accompanied by structural brain malformations, most frequently a reduction of the anterior commissure (AC). Thus, it is critical for modified versions of Tbr1 to exhibit true wild-type-like activity. We evaluated the Tbr1-2A-CreER allele for its potential impact on Tbr1 function and complementation to Tbr1 loss-of-function alleles. In mice with one copy of the Tbr1-2A-CreER allele, we identified reduction of TBR1 protein in early postnatal cortex along with thinning of the AC, suggesting hypersensitivity of this structure to TBR1 dosage. Comparing Tbr1-2A-CreER and Tbr1-null mice to Tbr1-null complementation crosses showed reductions of TBR1 dosage ranging from 20% to 100%. Using six combinatorial genotypes, we found that moderate to severe TBR1 reductions (?44%) were associated with cortical layer 5 expansion, while only the complete absence of TBR1 was associated with reeler-like ?inverted? cortical layering. In total, these results strongly support the conclusion that Tbr1-2A-CreER is a hypomorphic allele. We advise caution when interpreting experiments using this allele, considering the sensitivity of various corticogenic processes to TBR1 dosage and the association of heterozygous TBR1 mutations with complex neurodevelopmental disorders. En ligne : https://doi.org/10.1002/aur.3271 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=558 [article] Detailed phenotyping of Tbr1-2A-CreER knock-in mice demonstrates significant impacts on TBR1 protein levels and axon development [Texte imprimé et/ou numérique] / Grace K. O'BRIEN, Auteur ; Kevin M. WRIGHT, Auteur ; Brian J. O'ROAK, Auteur . - p.922-932. Langues : Anglais (eng) in Autism Research > 18-5 (May 2025) . - p.922-932 Mots-clés : anterior commissure  axon  cortex  mice  TBR1  transcription factor Index. décimale : PER Périodiques Résumé : Abstract Cre recombinase knock-in mouse lines have served as invaluable genetic tools for understanding key developmental processes altered in autism. However, insertion of exogenous DNA into the genome can have unintended effects on local gene regulation or protein function that must be carefully considered. Here, we analyze a recently generated Tbr1-2A-CreER knock-in mouse line, where a 2A-CreER cassette was inserted in-frame before the stop codon of the transcription factor gene Tbr1. Heterozygous TBR1 mutations in humans and mice are known to cause autism or autism-like behavioral phenotypes accompanied by structural brain malformations, most frequently a reduction of the anterior commissure (AC). Thus, it is critical for modified versions of Tbr1 to exhibit true wild-type-like activity. We evaluated the Tbr1-2A-CreER allele for its potential impact on Tbr1 function and complementation to Tbr1 loss-of-function alleles. In mice with one copy of the Tbr1-2A-CreER allele, we identified reduction of TBR1 protein in early postnatal cortex along with thinning of the AC, suggesting hypersensitivity of this structure to TBR1 dosage. Comparing Tbr1-2A-CreER and Tbr1-null mice to Tbr1-null complementation crosses showed reductions of TBR1 dosage ranging from 20% to 100%. Using six combinatorial genotypes, we found that moderate to severe TBR1 reductions (?44%) were associated with cortical layer 5 expansion, while only the complete absence of TBR1 was associated with reeler-like ?inverted? cortical layering. In total, these results strongly support the conclusion that Tbr1-2A-CreER is a hypomorphic allele. We advise caution when interpreting experiments using this allele, considering the sensitivity of various corticogenic processes to TBR1 dosage and the association of heterozygous TBR1 mutations with complex neurodevelopmental disorders. En ligne : https://doi.org/10.1002/aur.3271 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=558

Validation of Autism Diagnosis and Clinical Data in the SPARK Cohort / Eric FOMBONNE in Journal of Autism and Developmental Disorders, 52-8 (August 2022)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 52-8 (August 2022) . - p.3383-3398 Titre : Validation of Autism Diagnosis and Clinical Data in the SPARK Cohort Type de document : Texte imprimé et/ou numérique Auteurs : Eric FOMBONNE, Auteur ; Leigh COPPOLA, Auteur ; Sarah MASTEL, Auteur ; Brian J. O'ROAK, Auteur Article en page(s) : p.3383-3398 Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/diagnosis  Autistic Disorder/diagnosis  Caregivers  Child  Cohort Studies  Databases, Factual  Female  Humans  Male  Adults  Autism  Birth weight  Electronic medical records  Intellectual disability  Language delay  Parental report  Regression  SPARK cohort  Sex differences  Validity Index. décimale : PER Périodiques Résumé : The SPARK cohort was established to facilitate recruitment in studies of large numbers of participants with autism spectrum disorder (ASD). Online registration requires participants to have received a lifetime professional diagnosis by health or school providers although diagnoses are not independently verified. This study was set to examine the validity of self- and caregiver-reported autism diagnoses. Electronic medical records (EMR) of 254 SPARK participants (77.6% male, age 10.7 years) were abstracted. Using two different methods, confirmation of ASD diagnosis in EMRs was obtained in 98.8% of cases. Core clinical features recorded in EMRs were typical of autism samples and showed very good agreement with SPARK cohort data, providing further evidence of the validity of clinical information in the SPARK database. En ligne : http://dx.doi.org/10.1007/s10803-021-05218-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=485 [article] Validation of Autism Diagnosis and Clinical Data in the SPARK Cohort [Texte imprimé et/ou numérique] / Eric FOMBONNE, Auteur ; Leigh COPPOLA, Auteur ; Sarah MASTEL, Auteur ; Brian J. O'ROAK, Auteur . - p.3383-3398. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 52-8 (August 2022) . - p.3383-3398 Mots-clés : Autism Spectrum Disorder/diagnosis  Autistic Disorder/diagnosis  Caregivers  Child  Cohort Studies  Databases, Factual  Female  Humans  Male  Adults  Autism  Birth weight  Electronic medical records  Intellectual disability  Language delay  Parental report  Regression  SPARK cohort  Sex differences  Validity Index. décimale : PER Périodiques Résumé : The SPARK cohort was established to facilitate recruitment in studies of large numbers of participants with autism spectrum disorder (ASD). Online registration requires participants to have received a lifetime professional diagnosis by health or school providers although diagnoses are not independently verified. This study was set to examine the validity of self- and caregiver-reported autism diagnoses. Electronic medical records (EMR) of 254 SPARK participants (77.6% male, age 10.7 years) were abstracted. Using two different methods, confirmation of ASD diagnosis in EMRs was obtained in 98.8% of cases. Core clinical features recorded in EMRs were typical of autism samples and showed very good agreement with SPARK cohort data, providing further evidence of the validity of clinical information in the SPARK database. En ligne : http://dx.doi.org/10.1007/s10803-021-05218-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=485

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