Deep phenotypic analysis of psychiatric features in genetically defined cohorts: application to XYY syndrome / Armin RAZNAHAN in Journal of Neurodevelopmental Disorders, 15 (2023)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 15 (2023) Titre : Deep phenotypic analysis of psychiatric features in genetically defined cohorts: application to XYY syndrome Type de document : texte imprimé Auteurs : Armin RAZNAHAN, Auteur ; Srishti RAU, Auteur ; Luke SCHAFFER, Auteur ; Siyuan LIU, Auteur ; Ari M. FISH, Auteur ; Catherine MANKIW, Auteur ; Anastasia XENOPHONTOS, Auteur ; Liv S. CLASEN, Auteur ; Lisa JOSEPH, Auteur ; Audrey THURM, Auteur ; Jonathan D. BLUMENTHAL, Auteur ; Dani S. BASSETT, Auteur ; Erin N. TORRES, Auteur Langues : Anglais (eng) Mots-clés : Humans  Male  XYY Karyotype  Sex Chromosome Disorders/diagnosis  Cognition  Phenotype  Adaptive function  Behavioral phenotyping  Deep phenotyping  Neurogenetics  Sex chromosomes  Symptom networks Index. décimale : PER Périodiques Résumé : BACKGROUND: Recurrent gene dosage disorders impart substantial risk for psychopathology. Yet, understanding that risk is hampered by complex presentations that challenge classical diagnostic systems. Here, we present a suite of generalizable analytic approaches for parsing this clinical complexity, which we illustrate through application to XYY syndrome. METHOD: We gathered high-dimensional measures of psychopathology in 64 XYY individuals and 60 XY controls, plus additional interviewer-based diagnostic data in the XYY group. We provide the first comprehensive diagnostic description of psychiatric morbidity in XYY syndrome and show how diagnostic morbidity relates to functioning, subthreshold symptoms, and ascertainment bias. We then map behavioral vulnerabilities and resilience across 67 behavioral dimensions before borrowing techniques from network science to resolve the mesoscale architecture of these dimensions and links to observable functional outcomes. RESULTS: Carriage of an extra Y-chromosome increases risk for diverse psychiatric diagnoses, with clinically impactful subthreshold symptomatology. Highest rates are seen for neurodevelopmental and affective disorders. A lower bound of < 25% of carriers are free of any diagnosis. Dimensional analysis of 67 scales details the profile of psychopathology in XYY, which survives control for ascertainment bias, specifies attentional and social domains as the most impacted, and refutes stigmatizing historical associations between XYY and violence. Network modeling compresses all measured symptom scales into 8 modules with dissociable links to cognitive ability, adaptive function, and caregiver strain. Hub modules offer efficient proxies for the full symptom network. CONCLUSIONS: This study parses the complex behavioral phenotype of XYY syndrome by applying new and generalizable analytic approaches for analysis of deep-phenotypic psychiatric data in neurogenetic disorders. En ligne : https://dx.doi.org/10.1186/s11689-023-09476-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Deep phenotypic analysis of psychiatric features in genetically defined cohorts: application to XYY syndrome [texte imprimé] / Armin RAZNAHAN, Auteur ; Srishti RAU, Auteur ; Luke SCHAFFER, Auteur ; Siyuan LIU, Auteur ; Ari M. FISH, Auteur ; Catherine MANKIW, Auteur ; Anastasia XENOPHONTOS, Auteur ; Liv S. CLASEN, Auteur ; Lisa JOSEPH, Auteur ; Audrey THURM, Auteur ; Jonathan D. BLUMENTHAL, Auteur ; Dani S. BASSETT, Auteur ; Erin N. TORRES, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 15 (2023) Mots-clés : Humans  Male  XYY Karyotype  Sex Chromosome Disorders/diagnosis  Cognition  Phenotype  Adaptive function  Behavioral phenotyping  Deep phenotyping  Neurogenetics  Sex chromosomes  Symptom networks Index. décimale : PER Périodiques Résumé : BACKGROUND: Recurrent gene dosage disorders impart substantial risk for psychopathology. Yet, understanding that risk is hampered by complex presentations that challenge classical diagnostic systems. Here, we present a suite of generalizable analytic approaches for parsing this clinical complexity, which we illustrate through application to XYY syndrome. METHOD: We gathered high-dimensional measures of psychopathology in 64 XYY individuals and 60 XY controls, plus additional interviewer-based diagnostic data in the XYY group. We provide the first comprehensive diagnostic description of psychiatric morbidity in XYY syndrome and show how diagnostic morbidity relates to functioning, subthreshold symptoms, and ascertainment bias. We then map behavioral vulnerabilities and resilience across 67 behavioral dimensions before borrowing techniques from network science to resolve the mesoscale architecture of these dimensions and links to observable functional outcomes. RESULTS: Carriage of an extra Y-chromosome increases risk for diverse psychiatric diagnoses, with clinically impactful subthreshold symptomatology. Highest rates are seen for neurodevelopmental and affective disorders. A lower bound of < 25% of carriers are free of any diagnosis. Dimensional analysis of 67 scales details the profile of psychopathology in XYY, which survives control for ascertainment bias, specifies attentional and social domains as the most impacted, and refutes stigmatizing historical associations between XYY and violence. Network modeling compresses all measured symptom scales into 8 modules with dissociable links to cognitive ability, adaptive function, and caregiver strain. Hub modules offer efficient proxies for the full symptom network. CONCLUSIONS: This study parses the complex behavioral phenotype of XYY syndrome by applying new and generalizable analytic approaches for analysis of deep-phenotypic psychiatric data in neurogenetic disorders. En ligne : https://dx.doi.org/10.1186/s11689-023-09476-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

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

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