Characterization of autism spectrum disorder and neurodevelopmental profiles in youth with XYY syndrome / Lisa JOSEPH in Journal of Neurodevelopmental Disorders, 10-1 (December 2018)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 10-1 (December 2018) . - 30 p. Titre : Characterization of autism spectrum disorder and neurodevelopmental profiles in youth with XYY syndrome Type de document : texte imprimé Auteurs : Lisa JOSEPH, Auteur ; Cristan FARMER, Auteur ; Colby CHLEBOWSKI, Auteur ; Laura HENRY, Auteur ; Ari FISH, Auteur ; Catherine MANKIW, Auteur ; Anastasia XENOPHONTOS, Auteur ; Liv S. CLASEN, Auteur ; Bethany SAULS, Auteur ; Jakob SEIDLITZ, Auteur ; Jonathan D. BLUMENTHAL, Auteur ; Erin TORRES, Auteur ; Audrey THURM, Auteur ; Armin RAZNAHAN, Auteur Année de publication : 2018 Article en page(s) : 30 p. Langues : Anglais (eng) Mots-clés : Adaptive behavior  Autism spectrum disorder symptoms  Cognitive functioning  Learning disabilities  Sex chromosome aneuploidies Index. décimale : PER Périodiques Résumé : BACKGROUND: XYY syndrome is a sex chromosome aneuploidy that occurs in ~ 1/850 male births and is associated with increased risk for neurodevelopmental difficulties. However, the profile of neurodevelopmental impairments, including symptoms of autism spectrum disorder (ASD) in XYY remains poorly understood. This gap in knowledge has persisted in part due to lack of access to patient cohorts with dense and homogeneous phenotypic data. METHODS: We evaluated a single-center cohort of 64 individuals with XYY aged 5-25 years, using a standardized battery of cognitive and behavioral assessments spanning developmental milestones, IQ, adaptive behavior, academic achievement, behavioral problems, and gold-standard diagnostic instruments for ASD. Our goals were to (i) detail the neurodevelopmental profile of XYY with a focus on ASD diagnostic rates and symptom profiles, (ii) screen phenotypes for potential ascertainment bias effects by contrasting pre- vs. postnatally diagnosed XYY subgroups, and (iii) define major modules of phenotypic variation using graph-theoretical analysis. RESULTS: Although there was marked inter-individual variability, the average profile was characterized by some degree of developmental delay, and decreased IQ and adaptive behavior. Impairments were most pronounced for language and socio-communicative functioning. The rate of ASD was 14%, and these individuals exhibited autism symptom profiles resembling those observed in ASD without XYY. Most neurodevelopmental dimensions showed milder impairment among pre- vs. postnatally diagnosed individuals, with clinically meaningful differences in verbal IQ. Feature network analysis revealed three reliably separable modules comprising (i) cognition and academic achievement, (ii) broad domain psychopathology and adaptive behavior, and (iii) ASD-related features. CONCLUSIONS: By adding granularity to our understanding of neurodevelopmental difficulties in XYY, these findings assist targeted clinical assessment of newly identified cases, motivate greater provision of specialized multidisciplinary support, and inform future efforts to integrate behavioral phenotypes in XYY with neurobiology. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls." En ligne : http://dx.doi.org/10.1186/s11689-018-9248-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386 [article] Characterization of autism spectrum disorder and neurodevelopmental profiles in youth with XYY syndrome [texte imprimé] / Lisa JOSEPH, Auteur ; Cristan FARMER, Auteur ; Colby CHLEBOWSKI, Auteur ; Laura HENRY, Auteur ; Ari FISH, Auteur ; Catherine MANKIW, Auteur ; Anastasia XENOPHONTOS, Auteur ; Liv S. CLASEN, Auteur ; Bethany SAULS, Auteur ; Jakob SEIDLITZ, Auteur ; Jonathan D. BLUMENTHAL, Auteur ; Erin TORRES, Auteur ; Audrey THURM, Auteur ; Armin RAZNAHAN, Auteur . - 2018 . - 30 p. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 10-1 (December 2018) . - 30 p. Mots-clés : Adaptive behavior  Autism spectrum disorder symptoms  Cognitive functioning  Learning disabilities  Sex chromosome aneuploidies Index. décimale : PER Périodiques Résumé : BACKGROUND: XYY syndrome is a sex chromosome aneuploidy that occurs in ~ 1/850 male births and is associated with increased risk for neurodevelopmental difficulties. However, the profile of neurodevelopmental impairments, including symptoms of autism spectrum disorder (ASD) in XYY remains poorly understood. This gap in knowledge has persisted in part due to lack of access to patient cohorts with dense and homogeneous phenotypic data. METHODS: We evaluated a single-center cohort of 64 individuals with XYY aged 5-25 years, using a standardized battery of cognitive and behavioral assessments spanning developmental milestones, IQ, adaptive behavior, academic achievement, behavioral problems, and gold-standard diagnostic instruments for ASD. Our goals were to (i) detail the neurodevelopmental profile of XYY with a focus on ASD diagnostic rates and symptom profiles, (ii) screen phenotypes for potential ascertainment bias effects by contrasting pre- vs. postnatally diagnosed XYY subgroups, and (iii) define major modules of phenotypic variation using graph-theoretical analysis. RESULTS: Although there was marked inter-individual variability, the average profile was characterized by some degree of developmental delay, and decreased IQ and adaptive behavior. Impairments were most pronounced for language and socio-communicative functioning. The rate of ASD was 14%, and these individuals exhibited autism symptom profiles resembling those observed in ASD without XYY. Most neurodevelopmental dimensions showed milder impairment among pre- vs. postnatally diagnosed individuals, with clinically meaningful differences in verbal IQ. Feature network analysis revealed three reliably separable modules comprising (i) cognition and academic achievement, (ii) broad domain psychopathology and adaptive behavior, and (iii) ASD-related features. CONCLUSIONS: By adding granularity to our understanding of neurodevelopmental difficulties in XYY, these findings assist targeted clinical assessment of newly identified cases, motivate greater provision of specialized multidisciplinary support, and inform future efforts to integrate behavioral phenotypes in XYY with neurobiology. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls." En ligne : http://dx.doi.org/10.1186/s11689-018-9248-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=386

Modeling familial predictors of proband outcomes in neurogenetic disorders: initial application in XYY syndrome / Kathleen E. WILSON in Journal of Neurodevelopmental Disorders, 13 (2021)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 13 (2021) Titre : Modeling familial predictors of proband outcomes in neurogenetic disorders: initial application in XYY syndrome Type de document : texte imprimé Auteurs : Kathleen E. WILSON, Auteur ; Ari M. FISH, Auteur ; Catherine MANKIW, Auteur ; Anastasia XENOPHONTOS, Auteur ; Allysa WARLING, Auteur ; Ethan WHITMAN, Auteur ; Liv CLASEN, Auteur ; Erin TORRES, Auteur ; Jonathan BLUMENTHAL, Auteur ; Armin RAZNAHAN, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Adult  Autism Spectrum Disorder  Child  Child, Preschool  DNA Copy Number Variations  Family  Humans  Male  Sex Chromosome Disorders  XYY Karyotype  Young Adult  Copy number variants  Modeling penetrance  Neurogenetic disorders  Precision psychiatry  Sex chromosome aneuploidies  Health (NIMH). The authors have no additional competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: Disorders of gene dosage can significantly increase risk for psychopathology, but outcomes vary greatly amongst carriers of any given chromosomal aneuploidy or sub-chromosomal copy number variation (CNV). One potential path to advance precision medicine for neurogenetic disorders is modeling penetrance in probands relative to observed phenotypes in their non-carrier relatives. Here, we seek to advance this general analytic framework by developing new methods in application to XYY syndrome-a sex chromosome aneuploidy that is known to increase risk for psychopathology. METHODS: We analyzed a range of cognitive and behavioral domains in XYY probands and their non-carrier family members (n = 58 families), including general cognitive ability (FSIQ), as well as continuous measures of traits related to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Proband and relative scores were compared using covariance, regression and cluster analysis. Comparisons were made both within and across traits. RESULTS: Proband scores were shifted away from family scores with effect sizes varying between 0.9 and 2.4 across traits. Only FSIQ and vocabulary scores showed a significant positive correlation between probands and their non-carrier relatives across families (R(2) ~ 0.4). Variability in family FSIQ also cross-predicted variability in proband ASD trait severity. Cluster analysis across all trait-relative pairings revealed that variability in parental psychopathology was more weakly coupled to their XYY versus their euploid offspring. CONCLUSIONS: We present a suite of generalizable methods for modeling variable penetrance in aneuploidy and CNV carriers using family data. These methods update estimates of phenotypic penetrance for XYY and suggest that the predictive utility of family data is likely to vary for different traits and different gene dosage disorders. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls." Date of registry: 01 October 1989. En ligne : https://dx.doi.org/10.1186/s11689-021-09360-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Modeling familial predictors of proband outcomes in neurogenetic disorders: initial application in XYY syndrome [texte imprimé] / Kathleen E. WILSON, Auteur ; Ari M. FISH, Auteur ; Catherine MANKIW, Auteur ; Anastasia XENOPHONTOS, Auteur ; Allysa WARLING, Auteur ; Ethan WHITMAN, Auteur ; Liv CLASEN, Auteur ; Erin TORRES, Auteur ; Jonathan BLUMENTHAL, Auteur ; Armin RAZNAHAN, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 13 (2021) Mots-clés : Adolescent  Adult  Autism Spectrum Disorder  Child  Child, Preschool  DNA Copy Number Variations  Family  Humans  Male  Sex Chromosome Disorders  XYY Karyotype  Young Adult  Copy number variants  Modeling penetrance  Neurogenetic disorders  Precision psychiatry  Sex chromosome aneuploidies  Health (NIMH). The authors have no additional competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: Disorders of gene dosage can significantly increase risk for psychopathology, but outcomes vary greatly amongst carriers of any given chromosomal aneuploidy or sub-chromosomal copy number variation (CNV). One potential path to advance precision medicine for neurogenetic disorders is modeling penetrance in probands relative to observed phenotypes in their non-carrier relatives. Here, we seek to advance this general analytic framework by developing new methods in application to XYY syndrome-a sex chromosome aneuploidy that is known to increase risk for psychopathology. METHODS: We analyzed a range of cognitive and behavioral domains in XYY probands and their non-carrier family members (n = 58 families), including general cognitive ability (FSIQ), as well as continuous measures of traits related to autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). Proband and relative scores were compared using covariance, regression and cluster analysis. Comparisons were made both within and across traits. RESULTS: Proband scores were shifted away from family scores with effect sizes varying between 0.9 and 2.4 across traits. Only FSIQ and vocabulary scores showed a significant positive correlation between probands and their non-carrier relatives across families (R(2) ~ 0.4). Variability in family FSIQ also cross-predicted variability in proband ASD trait severity. Cluster analysis across all trait-relative pairings revealed that variability in parental psychopathology was more weakly coupled to their XYY versus their euploid offspring. CONCLUSIONS: We present a suite of generalizable methods for modeling variable penetrance in aneuploidy and CNV carriers using family data. These methods update estimates of phenotypic penetrance for XYY and suggest that the predictive utility of family data is likely to vary for different traits and different gene dosage disorders. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT00001246 , "89-M-0006: Brain Imaging of Childhood Onset Psychiatric Disorders, Endocrine Disorders and Healthy Controls." Date of registry: 01 October 1989. En ligne : https://dx.doi.org/10.1186/s11689-021-09360-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

X- vs. Y-chromosome influences on human behavior: a deep phenotypic comparison of psychopathology in XXY and XYY syndromes / Lukas SCHAFFER in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : X- vs. Y-chromosome influences on human behavior: a deep phenotypic comparison of psychopathology in XXY and XYY syndromes Type de document : texte imprimé Auteurs : Lukas SCHAFFER, Auteur ; Srishti RAU, Auteur ; Isabella G. LARSEN, Auteur ; Liv CLASEN, Auteur ; Allysa WARLING, Auteur ; Ethan T. WHITMAN, Auteur ; Ajay NADIG, Auteur ; Cassidy MCDERMOTT, Auteur ; Anastasia XENOPHONTOS, Auteur ; Kathleen WILSON, Auteur ; Jonathan BLUMENTHAL, Auteur ; Erin TORRES, Auteur ; Armin RAZNAHAN, Auteur Langues : Anglais (eng) Mots-clés : Humans  Male  Female  Klinefelter Syndrome/genetics/diagnosis  Adult  Phenotype  XYY Karyotype/genetics  Adolescent  Chromosomes, Human, Y/genetics  Mental Disorders/genetics/diagnosis  Young Adult  Chromosomes, Human, X/genetics  Child  Middle Aged Index. décimale : PER Périodiques Résumé : BACKGROUND: Do different genetic disorders impart different psychiatric risk profiles? This question has major implications for biological and translational aspects of psychiatry, but has been difficult to tackle given limited access to shared batteries of fine-grained clinical data across genetic disorders. METHODS: Using a new suite of generalizable analytic approaches, we examine gold-standard diagnostic ratings, scores on 66 dimensional measures of psychopathology, and measures of cognition and functioning in two different sex chromosome aneuploidies (SCAs)-Klinefelter (XXY/KS) and XYY syndrome (n = 102 and 64 vs. n = 74 and 60 matched XY controls, total n = 300). We focus on SCAs for their high collective prevalence, informativeness regarding differential X- vs. Y-chromosome effects, and potential relevance for normative sex differences. RESULTS: We show that XXY/KS elevates rates for most psychiatric diagnoses as previously reported for XYY, but disproportionately so for anxiety disorders. Fine-mapping across all 66 traits provides a detailed profile of psychopathology in XXY/KS which is strongly correlated with that of XYY (r = .75 across traits) and robust to ascertainment biases, but reveals: (i) a greater penetrance of XYY than KS/XXY for most traits except mood/anxiety problems, and (ii) a disproportionate impact of XYY vs. XXY/KS on social problems. XXY/KS and XYY showed a similar coupling of psychopathology with adaptive function and caregiver strain, but not IQ. CONCLUSIONS: This work provides new tools for deep-phenotypic comparisons of genetic disorders in psychiatry and uses these to detail unique and shared effects of the X- and Y-chromosome on human behavior. En ligne : https://dx.doi.org/10.1186/s11689-024-09574-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576 [article] X- vs. Y-chromosome influences on human behavior: a deep phenotypic comparison of psychopathology in XXY and XYY syndromes [texte imprimé] / Lukas SCHAFFER, Auteur ; Srishti RAU, Auteur ; Isabella G. LARSEN, Auteur ; Liv CLASEN, Auteur ; Allysa WARLING, Auteur ; Ethan T. WHITMAN, Auteur ; Ajay NADIG, Auteur ; Cassidy MCDERMOTT, Auteur ; Anastasia XENOPHONTOS, Auteur ; Kathleen WILSON, Auteur ; Jonathan BLUMENTHAL, Auteur ; Erin TORRES, Auteur ; Armin RAZNAHAN, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Male  Female  Klinefelter Syndrome/genetics/diagnosis  Adult  Phenotype  XYY Karyotype/genetics  Adolescent  Chromosomes, Human, Y/genetics  Mental Disorders/genetics/diagnosis  Young Adult  Chromosomes, Human, X/genetics  Child  Middle Aged Index. décimale : PER Périodiques Résumé : BACKGROUND: Do different genetic disorders impart different psychiatric risk profiles? This question has major implications for biological and translational aspects of psychiatry, but has been difficult to tackle given limited access to shared batteries of fine-grained clinical data across genetic disorders. METHODS: Using a new suite of generalizable analytic approaches, we examine gold-standard diagnostic ratings, scores on 66 dimensional measures of psychopathology, and measures of cognition and functioning in two different sex chromosome aneuploidies (SCAs)-Klinefelter (XXY/KS) and XYY syndrome (n = 102 and 64 vs. n = 74 and 60 matched XY controls, total n = 300). We focus on SCAs for their high collective prevalence, informativeness regarding differential X- vs. Y-chromosome effects, and potential relevance for normative sex differences. RESULTS: We show that XXY/KS elevates rates for most psychiatric diagnoses as previously reported for XYY, but disproportionately so for anxiety disorders. Fine-mapping across all 66 traits provides a detailed profile of psychopathology in XXY/KS which is strongly correlated with that of XYY (r = .75 across traits) and robust to ascertainment biases, but reveals: (i) a greater penetrance of XYY than KS/XXY for most traits except mood/anxiety problems, and (ii) a disproportionate impact of XYY vs. XXY/KS on social problems. XXY/KS and XYY showed a similar coupling of psychopathology with adaptive function and caregiver strain, but not IQ. CONCLUSIONS: This work provides new tools for deep-phenotypic comparisons of genetic disorders in psychiatry and uses these to detail unique and shared effects of the X- and Y-chromosome on human behavior. En ligne : https://dx.doi.org/10.1186/s11689-024-09574-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=576

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