Annual Research Review: The transdiagnostic revolution in neurodevelopmental disorders / Duncan E. ASTLE in Journal of Child Psychology and Psychiatry, 63-4 (April 2022)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 63-4 (April 2022) . - p.397-417 Titre : Annual Research Review: The transdiagnostic revolution in neurodevelopmental disorders Type de document : Texte imprimé et/ou numérique Auteurs : Duncan E. ASTLE, Auteur ; Joni HOLMES, Auteur ; Rogier. KIEVIT, Auteur ; Susan E. GATHERCOLE, Auteur Article en page(s) : p.397-417 Langues : Anglais (eng) Mots-clés : Adhd  Autism  Developmental Language Disorder  Neurodevelopmental disorders  learning difficulties  working memory Index. décimale : PER Périodiques Résumé : Practitioners frequently use diagnostic criteria to identify children with neurodevelopmental disorders and to guide intervention decisions. These criteria also provide the organising framework for much of the research focussing on these disorders. Study design, recruitment, analysis and theory are largely built on the assumption that diagnostic criteria reflect an underlying reality. However, there is growing concern that this assumption may not be a valid and that an alternative transdiagnostic approach may better serve our understanding of this large heterogeneous population of young people. This review draws on important developments over the past decade that have set the stage for much-needed breakthroughs in understanding neurodevelopmental disorders. We evaluate contemporary approaches to study design and recruitment, review the use of data-driven methods to characterise cognition, behaviour and neurobiology, and consider what alternative transdiagnostic models could mean for children and families. This review concludes that an overreliance on ill-fitting diagnostic criteria is impeding progress towards identifying the barriers that children encounter, understanding underpinning mechanisms and finding the best route to supporting them. En ligne : http://dx.doi.org/10.1111/jcpp.13481 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=475 [article] Annual Research Review: The transdiagnostic revolution in neurodevelopmental disorders [Texte imprimé et/ou numérique] / Duncan E. ASTLE, Auteur ; Joni HOLMES, Auteur ; Rogier. KIEVIT, Auteur ; Susan E. GATHERCOLE, Auteur . - p.397-417. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 63-4 (April 2022) . - p.397-417 Mots-clés : Adhd  Autism  Developmental Language Disorder  Neurodevelopmental disorders  learning difficulties  working memory Index. décimale : PER Périodiques Résumé : Practitioners frequently use diagnostic criteria to identify children with neurodevelopmental disorders and to guide intervention decisions. These criteria also provide the organising framework for much of the research focussing on these disorders. Study design, recruitment, analysis and theory are largely built on the assumption that diagnostic criteria reflect an underlying reality. However, there is growing concern that this assumption may not be a valid and that an alternative transdiagnostic approach may better serve our understanding of this large heterogeneous population of young people. This review draws on important developments over the past decade that have set the stage for much-needed breakthroughs in understanding neurodevelopmental disorders. We evaluate contemporary approaches to study design and recruitment, review the use of data-driven methods to characterise cognition, behaviour and neurobiology, and consider what alternative transdiagnostic models could mean for children and families. This review concludes that an overreliance on ill-fitting diagnostic criteria is impeding progress towards identifying the barriers that children encounter, understanding underpinning mechanisms and finding the best route to supporting them. En ligne : http://dx.doi.org/10.1111/jcpp.13481 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=475

Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study / Diandra BRKI? in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) Titre : Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study Type de document : Texte imprimé et/ou numérique Auteurs : Diandra BRKI?, Auteur ; Elise NG-CORDELL, Auteur ; Sinéad O'BRIEN, Auteur ; Gaia SCERIF, Auteur ; Duncan E. ASTLE, Auteur ; Kate BAKER, Auteur Langues : Anglais (eng) Mots-clés : Anxiety  Autism dimensions  Genetics  Hyperactivity  Intellectual disability Index. décimale : PER Périodiques Résumé : BACKGROUND: The relationships between specific genetic aetiology and phenotype in neurodevelopmental disorders are complex and hotly contested. Genes associated with intellectual disability (ID) can be grouped into networks according to gene function. This study explored whether individuals with ID show differences in autism spectrum characteristics (ASC), depending on the functional network membership of their rare, pathogenic de novo genetic variants. METHODS: Children and young people with ID of known genetic origin were allocated to two broad functional network groups: synaptic physiology (n?=?29) or chromatin regulation (n?=?23). We applied principle components analysis to the Social Responsiveness Scale to map the structure of ASC in this population and identified three components-Inflexibility, Social Understanding and Social Motivation. We then used Akaike information criterion to test the best fitting models for predicting ASC components, including demographic factors (age, gender), non-ASC behavioural factors (global adaptive function, anxiety, hyperactivity, inattention), and gene functional networks. RESULTS: We found that, when other factors are accounted for, the chromatin regulation group showed higher levels of Inflexibility. We also observed contrasting predictors of ASC within each network group. Within the chromatin regulation group, Social Understanding was associated with inattention, and Social Motivation was predicted by hyperactivity. Within the synaptic group, Social Understanding was associated with hyperactivity, and Social Motivation was linked to anxiety. LIMITATIONS: Functional network definitions were manually curated based on multiple sources of evidence, but a data-driven approach to classification may be more robust. Sample sizes for rare genetic diagnoses remain small, mitigated by our network-based approach to group comparisons. This is a cross-sectional study across a wide age range, and longitudinal data within focused age groups will be informative of developmental trajectories across network groups. CONCLUSION: We report that gene functional networks can predict Inflexibility, but not other ASC dimensions. Contrasting behavioural associations within each group suggest network-specific developmental pathways from genomic variation to autism. Simple classification of neurodevelopmental disorder genes as high risk or low risk for autism is unlikely to be valid or useful. En ligne : http://dx.doi.org/10.1186/s13229-020-00403-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=438 [article] Gene functional networks and autism spectrum characteristics in young people with intellectual disability: a dimensional phenotyping study [Texte imprimé et/ou numérique] / Diandra BRKI?, Auteur ; Elise NG-CORDELL, Auteur ; Sinéad O'BRIEN, Auteur ; Gaia SCERIF, Auteur ; Duncan E. ASTLE, Auteur ; Kate BAKER, Auteur. Langues : Anglais (eng) in Molecular Autism > 11 (2020) Mots-clés : Anxiety  Autism dimensions  Genetics  Hyperactivity  Intellectual disability Index. décimale : PER Périodiques Résumé : BACKGROUND: The relationships between specific genetic aetiology and phenotype in neurodevelopmental disorders are complex and hotly contested. Genes associated with intellectual disability (ID) can be grouped into networks according to gene function. This study explored whether individuals with ID show differences in autism spectrum characteristics (ASC), depending on the functional network membership of their rare, pathogenic de novo genetic variants. METHODS: Children and young people with ID of known genetic origin were allocated to two broad functional network groups: synaptic physiology (n?=?29) or chromatin regulation (n?=?23). We applied principle components analysis to the Social Responsiveness Scale to map the structure of ASC in this population and identified three components-Inflexibility, Social Understanding and Social Motivation. We then used Akaike information criterion to test the best fitting models for predicting ASC components, including demographic factors (age, gender), non-ASC behavioural factors (global adaptive function, anxiety, hyperactivity, inattention), and gene functional networks. RESULTS: We found that, when other factors are accounted for, the chromatin regulation group showed higher levels of Inflexibility. We also observed contrasting predictors of ASC within each network group. Within the chromatin regulation group, Social Understanding was associated with inattention, and Social Motivation was predicted by hyperactivity. Within the synaptic group, Social Understanding was associated with hyperactivity, and Social Motivation was linked to anxiety. LIMITATIONS: Functional network definitions were manually curated based on multiple sources of evidence, but a data-driven approach to classification may be more robust. Sample sizes for rare genetic diagnoses remain small, mitigated by our network-based approach to group comparisons. This is a cross-sectional study across a wide age range, and longitudinal data within focused age groups will be informative of developmental trajectories across network groups. CONCLUSION: We report that gene functional networks can predict Inflexibility, but not other ASC dimensions. Contrasting behavioural associations within each group suggest network-specific developmental pathways from genomic variation to autism. Simple classification of neurodevelopmental disorder genes as high risk or low risk for autism is unlikely to be valid or useful. En ligne : http://dx.doi.org/10.1186/s13229-020-00403-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=438

Psychopathology and cognitive performance in individuals with membrane-associated guanylate kinase mutations: a functional network phenotyping study / K. BAKER in Journal of Neurodevelopmental Disorders, 7-1 (December 2015)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.8 Titre : Psychopathology and cognitive performance in individuals with membrane-associated guanylate kinase mutations: a functional network phenotyping study Type de document : Texte imprimé et/ou numérique Auteurs : K. BAKER, Auteur ; G. SCERIF, Auteur ; Duncan E. ASTLE, Auteur ; P. C. FLETCHER, Auteur ; F. L. RAYMOND, Auteur Article en page(s) : p.8 Langues : Anglais (eng) Mots-clés : Cognition  Dlg3  Genetics  Intellectual disability  Maguk  Psychiatric disorders Index. décimale : PER Périodiques Résumé : BACKGROUND: Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual disability (ID) and have recently been associated with neuropsychiatric risk in the non-ID population. However, it is not known whether risk for psychiatric symptoms amongst individuals with ID due to MAGUK gene mutations is higher than expected for the degree of general intellectual impairment, nor whether specific cognitive differences are associated with disruption to this gene functional network. METHODS: This study addresses these two questions via behavioural questionnaires and cognitive testing, applying quantitative methods previously validated in populations with ID. We compared males with X-linked ID caused by mutations in three MAGUK genes (PAK3, DLG3, OPHN1; n = 9) to males with ID caused by mutations in other X chromosome genes (n = 17). Non-parametric and parametric analyses were applied as appropriate to data. RESULTS: Groups did not differ in age, global cognitive impairment, adaptive function or epilepsy prevalence. However, individuals with MAGUK gene mutations demonstrated significantly higher psychopathology risks, comprising elevated total problem behaviours, prominent hyperactivity and elevated scores on an autism screening checklist. Despite these overt difficulties, individuals in the MAGUK group performed more accurately than expected for age and intelligence quotient (IQ) on computerised tests of visual attention, convergent with mouse models of MAGUK loss-of-function. CONCLUSIONS: Our findings support a role for MAGUK genes in influencing cognitive parameters relevant to psychiatric risk. In addition to establishing clear patterns of impairment for this group, our findings highlight the importance of careful phenotyping after genetic diagnosis, showing that gene functional network disruptions can be associated with specific psychopathological risks and cognitive differences within the context of ID. En ligne : http://dx.doi.org/10.1186/s11689-015-9105-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=347 [article] Psychopathology and cognitive performance in individuals with membrane-associated guanylate kinase mutations: a functional network phenotyping study [Texte imprimé et/ou numérique] / K. BAKER, Auteur ; G. SCERIF, Auteur ; Duncan E. ASTLE, Auteur ; P. C. FLETCHER, Auteur ; F. L. RAYMOND, Auteur . - p.8. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.8 Mots-clés : Cognition  Dlg3  Genetics  Intellectual disability  Maguk  Psychiatric disorders Index. décimale : PER Périodiques Résumé : BACKGROUND: Rare pathogenic variants in membrane-associated guanylate kinase (MAGUK) genes cause intellectual disability (ID) and have recently been associated with neuropsychiatric risk in the non-ID population. However, it is not known whether risk for psychiatric symptoms amongst individuals with ID due to MAGUK gene mutations is higher than expected for the degree of general intellectual impairment, nor whether specific cognitive differences are associated with disruption to this gene functional network. METHODS: This study addresses these two questions via behavioural questionnaires and cognitive testing, applying quantitative methods previously validated in populations with ID. We compared males with X-linked ID caused by mutations in three MAGUK genes (PAK3, DLG3, OPHN1; n = 9) to males with ID caused by mutations in other X chromosome genes (n = 17). Non-parametric and parametric analyses were applied as appropriate to data. RESULTS: Groups did not differ in age, global cognitive impairment, adaptive function or epilepsy prevalence. However, individuals with MAGUK gene mutations demonstrated significantly higher psychopathology risks, comprising elevated total problem behaviours, prominent hyperactivity and elevated scores on an autism screening checklist. Despite these overt difficulties, individuals in the MAGUK group performed more accurately than expected for age and intelligence quotient (IQ) on computerised tests of visual attention, convergent with mouse models of MAGUK loss-of-function. CONCLUSIONS: Our findings support a role for MAGUK genes in influencing cognitive parameters relevant to psychiatric risk. In addition to establishing clear patterns of impairment for this group, our findings highlight the importance of careful phenotyping after genetic diagnosis, showing that gene functional network disruptions can be associated with specific psychopathological risks and cognitive differences within the context of ID. En ligne : http://dx.doi.org/10.1186/s11689-015-9105-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=347

STXBP1-associated neurodevelopmental disorder: a comparative study of behavioural characteristics / S. O'BRIEN in Journal of Neurodevelopmental Disorders, 11-1 (December 2019)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 11-1 (December 2019) . - 17 p. Titre : STXBP1-associated neurodevelopmental disorder: a comparative study of behavioural characteristics Type de document : Texte imprimé et/ou numérique Auteurs : S. O'BRIEN, Auteur ; E. NG-CORDELL, Auteur ; Duncan E. ASTLE, Auteur ; G. SCERIF, Auteur ; K. BAKER, Auteur Article en page(s) : 17 p. Langues : Anglais (eng) Mots-clés : Epilepsy  Intellectual disability  Language  Stxbp1  Social Index. décimale : PER Périodiques Résumé : BACKGROUND: De novo loss of function mutations in STXBP1 are a relatively common cause of epilepsy and intellectual disability (ID). However, little is known about the types and severities of behavioural features associated with this genetic diagnosis. METHODS: To address this, we collected systematic phenotyping data encompassing neurological, developmental, and behavioural characteristics. Participants were 14 individuals with STXBP1-associated neurodevelopmental disorder, ascertained from clinical genetics and neurology services UK-wide. Data was collected via standardised questionnaires administered to parents at home, supplemented by researcher observations. To isolate discriminating phenotypes, the STXBP1 group was compared to 33 individuals with pathogenic mutations in other ID-associated genes (ID group). To account for the potential impact of global cognitive impairment, a secondary comparison was made to an ability-matched subset of the ID group (low-ability ID group). RESULTS: The STXBP1 group demonstrated impairments across all assessed domains. In comparison to the ID group, the STXBP1 group had more severe global adaptive impairments, fine motor difficulties, and hyperactivity. In comparison to the low-ability ID group, severity of receptive language and social impairments discriminated the STXBP1 group. A striking feature of the STXBP1 group, with reference to both comparison groups, was preservation of social motivation. CONCLUSIONS: De novo mutations in STXBP1 are associated with complex and variable neurodevelopmental impairments. Consistent features, which discriminate this disorder from other monogenic causes of ID, are severe language impairment and difficulties managing social interactions, despite strong social motivation. Future work could explore the physiological mechanisms linking motor, speech, and social development in this disorder. Understanding the developmental emergence of behavioural characteristics can help to focus clinical assessment and management after genetic diagnosis, with the long-term aim of improving outcomes for patients and families. En ligne : https://dx.doi.org/10.1186/s11689-019-9278-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=409 [article] STXBP1-associated neurodevelopmental disorder: a comparative study of behavioural characteristics [Texte imprimé et/ou numérique] / S. O'BRIEN, Auteur ; E. NG-CORDELL, Auteur ; Duncan E. ASTLE, Auteur ; G. SCERIF, Auteur ; K. BAKER, Auteur . - 17 p. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 11-1 (December 2019) . - 17 p. Mots-clés : Epilepsy  Intellectual disability  Language  Stxbp1  Social Index. décimale : PER Périodiques Résumé : BACKGROUND: De novo loss of function mutations in STXBP1 are a relatively common cause of epilepsy and intellectual disability (ID). However, little is known about the types and severities of behavioural features associated with this genetic diagnosis. METHODS: To address this, we collected systematic phenotyping data encompassing neurological, developmental, and behavioural characteristics. Participants were 14 individuals with STXBP1-associated neurodevelopmental disorder, ascertained from clinical genetics and neurology services UK-wide. Data was collected via standardised questionnaires administered to parents at home, supplemented by researcher observations. To isolate discriminating phenotypes, the STXBP1 group was compared to 33 individuals with pathogenic mutations in other ID-associated genes (ID group). To account for the potential impact of global cognitive impairment, a secondary comparison was made to an ability-matched subset of the ID group (low-ability ID group). RESULTS: The STXBP1 group demonstrated impairments across all assessed domains. In comparison to the ID group, the STXBP1 group had more severe global adaptive impairments, fine motor difficulties, and hyperactivity. In comparison to the low-ability ID group, severity of receptive language and social impairments discriminated the STXBP1 group. A striking feature of the STXBP1 group, with reference to both comparison groups, was preservation of social motivation. CONCLUSIONS: De novo mutations in STXBP1 are associated with complex and variable neurodevelopmental impairments. Consistent features, which discriminate this disorder from other monogenic causes of ID, are severe language impairment and difficulties managing social interactions, despite strong social motivation. Future work could explore the physiological mechanisms linking motor, speech, and social development in this disorder. Understanding the developmental emergence of behavioural characteristics can help to focus clinical assessment and management after genetic diagnosis, with the long-term aim of improving outcomes for patients and families. En ligne : https://dx.doi.org/10.1186/s11689-019-9278-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=409

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