Behavioral signatures related to genetic disorders in autism / Hilgo BRUINING in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Behavioral signatures related to genetic disorders in autism Type de document : texte imprimé Auteurs : Hilgo BRUINING, Auteur ; Marinus EIJKEMANS, Auteur ; Martien KAS, Auteur ; Sarah CURRAN, Auteur ; Jacob VORSTMAN, Auteur ; Patrick BOLTON, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is well recognized to be genetically heterogeneous. It is assumed that the genetic risk factors give rise to a broad spectrum of indistinguishable behavioral presentations. We tested this assumption by analyzing the Autism Diagnostic Interview-Revised (ADI-R) symptom profiles in samples comprising six genetic disorders that carry an increased risk for ASD (22q11.2 deletion, Down's syndrome, Prader-Willi, supernumerary marker chromosome 15, tuberous sclerosis complex and Klinefelter syndrome; total n=322 cases, groups ranging in sample sizes from 21 to 90 cases). We mined the data to test the existence and specificity of ADI-R profiles using a multiclass extension of support vector machine (SVM) learning. We subsequently applied the SVM genetic disorder algorithm on idiopathic ASD profiles from the Autism Genetics Resource Exchange (AGRE). Genetic disorders were associated with behavioral specificity, indicated by the accuracy and certainty of SVM predictions; one-by-one genetic disorder stratifications were highly accurate leading to 63% accuracy of correct genotype prediction when all six genetic disorder groups were analyzed simultaneously. Application of the SVM algorithm to AGRE cases indicated that the algorithm could detect similarity of genetic behavioral signatures in idiopathic ASD subjects. Also, affected sib pairs in the AGRE were behaviorally more similar when they had been allocated to the same genetic disorder group. Our findings provide evidence for genotype-phenotype correlations in relation to autistic symptomatology. SVM algorithms may be used to stratify idiopathic cases of ASD according to behavioral signature patterns associated with genetic disorders. Together, the results suggest a new approach for disentangling the heterogeneity of ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-5-11 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Behavioral signatures related to genetic disorders in autism [texte imprimé] / Hilgo BRUINING, Auteur ; Marinus EIJKEMANS, Auteur ; Martien KAS, Auteur ; Sarah CURRAN, Auteur ; Jacob VORSTMAN, Auteur ; Patrick BOLTON, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is well recognized to be genetically heterogeneous. It is assumed that the genetic risk factors give rise to a broad spectrum of indistinguishable behavioral presentations. We tested this assumption by analyzing the Autism Diagnostic Interview-Revised (ADI-R) symptom profiles in samples comprising six genetic disorders that carry an increased risk for ASD (22q11.2 deletion, Down's syndrome, Prader-Willi, supernumerary marker chromosome 15, tuberous sclerosis complex and Klinefelter syndrome; total n=322 cases, groups ranging in sample sizes from 21 to 90 cases). We mined the data to test the existence and specificity of ADI-R profiles using a multiclass extension of support vector machine (SVM) learning. We subsequently applied the SVM genetic disorder algorithm on idiopathic ASD profiles from the Autism Genetics Resource Exchange (AGRE). Genetic disorders were associated with behavioral specificity, indicated by the accuracy and certainty of SVM predictions; one-by-one genetic disorder stratifications were highly accurate leading to 63% accuracy of correct genotype prediction when all six genetic disorder groups were analyzed simultaneously. Application of the SVM algorithm to AGRE cases indicated that the algorithm could detect similarity of genetic behavioral signatures in idiopathic ASD subjects. Also, affected sib pairs in the AGRE were behaviorally more similar when they had been allocated to the same genetic disorder group. Our findings provide evidence for genotype-phenotype correlations in relation to autistic symptomatology. SVM algorithms may be used to stratify idiopathic cases of ASD according to behavioral signature patterns associated with genetic disorders. Together, the results suggest a new approach for disentangling the heterogeneity of ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-5-11 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice / Remco T. MOLENHUIS in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.6 Titre : Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice Type de document : texte imprimé Auteurs : Remco T. MOLENHUIS, Auteur ; Hilgo BRUINING, Auteur ; Esther REMMELINK, Auteur ; Leonie DE VISSER, Auteur ; Maarten LOOS, Auteur ; J. Peter H. BURBACH, Auteur ; Martien J.H. KAS, Auteur Article en page(s) : p.6 Langues : Anglais (eng) Mots-clés : 3p deletion syndrome  Autism spectrum disorder  Behavior  Cntn4  Developmental trajectories  Hyperreactivity  Mouse model  Negative findings  Reversal learning  Schizophrenia Index. décimale : PER Périodiques Résumé : BACKGROUND: Mouse models offer an essential tool to unravel the impact of genetic mutations on autism-related phenotypes. The behavioral impact of some important candidate gene models for autism spectrum disorder (ASD) has not yet been studied, and existing characterizations mostly describe behavioral phenotypes at adult ages, disregarding the developmental nature of the disorder. In this context, the behavioral influence of CNTN4, one of the strongest suggested ASD candidate genes, is unknown. Here, we used our recently established developmental test battery to characterize the consequences of disruption of contactin 4 (Cntn4) on neurological, sensory, cognitive, and behavioral phenotypes across different developmental stages. METHODS: C57BL/6J mice with heterozygous and homozygous disruption of Cntn4 were studied through an extensive, partially longitudinal, test battery at various developmental stages, including various paradigms testing social and restricted repetitive behaviors. RESULTS: Developmental neurological and cognitive screenings revealed no significant differences between genotypes, and ASD-related behavioral domains were also unchanged in Cntn4-deficient versus wild-type mice. The impact of Cntn4-deficiency was found to be limited to increased startle responsiveness following auditory stimuli of different high amplitudes in heterozygous and homozygous Cntn4-deficient mice and enhanced acquisition in a spatial learning task in homozygous mice. CONCLUSIONS: Disruption of Cntn4 in the C57BL/6J background does not affect specific autism-related phenotypes in developing or adult mice but causes subtle non-disorder specific changes in sensory behavioral responses and cognitive performance. En ligne : http://dx.doi.org/10.1186/s11689-016-9140-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 [article] Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice [texte imprimé] / Remco T. MOLENHUIS, Auteur ; Hilgo BRUINING, Auteur ; Esther REMMELINK, Auteur ; Leonie DE VISSER, Auteur ; Maarten LOOS, Auteur ; J. Peter H. BURBACH, Auteur ; Martien J.H. KAS, Auteur . - p.6. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.6 Mots-clés : 3p deletion syndrome  Autism spectrum disorder  Behavior  Cntn4  Developmental trajectories  Hyperreactivity  Mouse model  Negative findings  Reversal learning  Schizophrenia Index. décimale : PER Périodiques Résumé : BACKGROUND: Mouse models offer an essential tool to unravel the impact of genetic mutations on autism-related phenotypes. The behavioral impact of some important candidate gene models for autism spectrum disorder (ASD) has not yet been studied, and existing characterizations mostly describe behavioral phenotypes at adult ages, disregarding the developmental nature of the disorder. In this context, the behavioral influence of CNTN4, one of the strongest suggested ASD candidate genes, is unknown. Here, we used our recently established developmental test battery to characterize the consequences of disruption of contactin 4 (Cntn4) on neurological, sensory, cognitive, and behavioral phenotypes across different developmental stages. METHODS: C57BL/6J mice with heterozygous and homozygous disruption of Cntn4 were studied through an extensive, partially longitudinal, test battery at various developmental stages, including various paradigms testing social and restricted repetitive behaviors. RESULTS: Developmental neurological and cognitive screenings revealed no significant differences between genotypes, and ASD-related behavioral domains were also unchanged in Cntn4-deficient versus wild-type mice. The impact of Cntn4-deficiency was found to be limited to increased startle responsiveness following auditory stimuli of different high amplitudes in heterozygous and homozygous Cntn4-deficient mice and enhanced acquisition in a spatial learning task in homozygous mice. CONCLUSIONS: Disruption of Cntn4 in the C57BL/6J background does not affect specific autism-related phenotypes in developing or adult mice but causes subtle non-disorder specific changes in sensory behavioral responses and cognitive performance. En ligne : http://dx.doi.org/10.1186/s11689-016-9140-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348

Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice / Remco T. MOLENHUIS in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 63 p. Titre : Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice Type de document : texte imprimé Auteurs : Remco T. MOLENHUIS, Auteur ; Hilgo BRUINING, Auteur ; Myrna J.V. BRANDT, Auteur ; Petra E. VAN SOLDT, Auteur ; Hanifa J. ABU-TOAMIH ATAMNI, Auteur ; J. Peter H. BURBACH, Auteur ; Fuad A. IRAQI, Auteur ; Richard F. MOTT, Auteur ; Martien J.H. KAS, Auteur Article en page(s) : 63 p. Langues : Anglais (eng) Mots-clés : Animals  Autism Spectrum Disorder/*genetics  Genetics, Behavioral/*methods/standards  Genome-Wide Association Study/*methods/standards  Male  Mice  Mice, Inbred C57BL  Multifactorial Inheritance  Quantitative Trait Loci  Reference Standards  *Animal models  *Autism  *Behavioral neuroscience  *Genetic reference population  *Histamine 3 receptor  *Neurodevelopmental disorders  *Quantitative genetics  *Repetitive behavior  Care and Use Committee of Tel Aviv University.Not applicable.The authors declare  that they have no competing interests.Springer Nature remains neutral with regard  to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Animal models for neurodevelopmental disorders (NDD) generally rely on a single genetic mutation on a fixed genetic background. Recent human genetic studies however indicate that a clinical diagnosis with ASDAutism Spectrum Disorder (ASD) is almost always associated with multiple genetic fore- and background changes. The translational value of animal model studies would be greatly enhanced if genetic insults could be studied in a more quantitative framework across genetic backgrounds. Methods: We used the Collaborative Cross (CC), a novel mouse genetic reference population, to investigate the quantitative genetic architecture of mouse behavioral phenotypes commonly used in animal models for NDD. Results: Classical tests of social recognition and grooming phenotypes appeared insufficient for quantitative studies due to genetic dilution and limited heritability. In contrast, digging, locomotor activity, and stereotyped exploratory patterns were characterized by continuous distribution across our CC sample and also mapped to quantitative trait loci containing genes associated with corresponding phenotypes in human populations. Conclusions: These findings show that the CC can move animal model studies beyond comparative single gene-single background designs, and point out which type of behavioral phenotypes are most suitable to quantify the effect of developmental etiologies across multiple genetic backgrounds. En ligne : https://dx.doi.org/10.1186/s13229-018-0252-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 [article] Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice [texte imprimé] / Remco T. MOLENHUIS, Auteur ; Hilgo BRUINING, Auteur ; Myrna J.V. BRANDT, Auteur ; Petra E. VAN SOLDT, Auteur ; Hanifa J. ABU-TOAMIH ATAMNI, Auteur ; J. Peter H. BURBACH, Auteur ; Fuad A. IRAQI, Auteur ; Richard F. MOTT, Auteur ; Martien J.H. KAS, Auteur . - 63 p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 63 p. Mots-clés : Animals  Autism Spectrum Disorder/*genetics  Genetics, Behavioral/*methods/standards  Genome-Wide Association Study/*methods/standards  Male  Mice  Mice, Inbred C57BL  Multifactorial Inheritance  Quantitative Trait Loci  Reference Standards  *Animal models  *Autism  *Behavioral neuroscience  *Genetic reference population  *Histamine 3 receptor  *Neurodevelopmental disorders  *Quantitative genetics  *Repetitive behavior  Care and Use Committee of Tel Aviv University.Not applicable.The authors declare  that they have no competing interests.Springer Nature remains neutral with regard  to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Animal models for neurodevelopmental disorders (NDD) generally rely on a single genetic mutation on a fixed genetic background. Recent human genetic studies however indicate that a clinical diagnosis with ASDAutism Spectrum Disorder (ASD) is almost always associated with multiple genetic fore- and background changes. The translational value of animal model studies would be greatly enhanced if genetic insults could be studied in a more quantitative framework across genetic backgrounds. Methods: We used the Collaborative Cross (CC), a novel mouse genetic reference population, to investigate the quantitative genetic architecture of mouse behavioral phenotypes commonly used in animal models for NDD. Results: Classical tests of social recognition and grooming phenotypes appeared insufficient for quantitative studies due to genetic dilution and limited heritability. In contrast, digging, locomotor activity, and stereotyped exploratory patterns were characterized by continuous distribution across our CC sample and also mapped to quantitative trait loci containing genes associated with corresponding phenotypes in human populations. Conclusions: These findings show that the CC can move animal model studies beyond comparative single gene-single background designs, and point out which type of behavioral phenotypes are most suitable to quantify the effect of developmental etiologies across multiple genetic backgrounds. En ligne : https://dx.doi.org/10.1186/s13229-018-0252-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389

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