Deep Screening for X Chromosome Parent-of-Origin Effects on Neurobehavioral and Neuroanatomical Phenotypes in 47,XXY Klinefelter Syndrome
Background: X chromosome parent of origin (POX) has been proposed as a source of phenotypic variation within sex chromosome aneuploidies such as Klinefelter syndrome (XXY/KS) and between XX and XY individuals. However, previous studies have yielded conflicting results regarding the presence and natu...
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Elsevier
2024-11-01
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| Series: | Biological Psychiatry Global Open Science |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2667174324001046 |
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| author | Isabella G. Larsen Rachel Gore Moses Bryce A. Seifert Siyuan Liu Samuel Li Andrew J. Oler Elizabeth Levitis Lukas Schaffer Rylee Duncan Colleen Jodarski Michael Kamen Jia Yan François M. Lalonde Rajarshi Ghosh Erin Torres Liv S. Clasen Jonathan Blumenthal Morgan Similuk Armin Raznahan Magdalena A. Walkiewicz |
| author_facet | Isabella G. Larsen Rachel Gore Moses Bryce A. Seifert Siyuan Liu Samuel Li Andrew J. Oler Elizabeth Levitis Lukas Schaffer Rylee Duncan Colleen Jodarski Michael Kamen Jia Yan François M. Lalonde Rajarshi Ghosh Erin Torres Liv S. Clasen Jonathan Blumenthal Morgan Similuk Armin Raznahan Magdalena A. Walkiewicz |
| author_sort | Isabella G. Larsen |
| collection | DOAJ |
| description | Background: X chromosome parent of origin (POX) has been proposed as a source of phenotypic variation within sex chromosome aneuploidies such as Klinefelter syndrome (XXY/KS) and between XX and XY individuals. However, previous studies have yielded conflicting results regarding the presence and nature of POX effects, which we sought to clarify in an expanded sample with deeper neurobehavioral phenotyping. Methods: A cohort of 58 individuals with XXY/KS underwent duo or trio genome sequencing with parents (n = 151), measurement of 66 neurobehavioral phenotypes by standardized research assessments, and measurement of over 1000 anatomical phenotypes by structural magnetic resonance imaging. We developed a novel algorithm, the uniparental disomy visualization for variant call format files, to determine proband POX and then systematically tested for POX associations with all neurobehavioral and neuroanatomical outcomes. Results: The uniparental disomy visualization for variant call format files algorithm showed maternal POX in 35 of 58 cases (60.3%). There were no statistically significant POX effects on any of the 66 subscale measures of cognition, psychopathology, or behavior. Neuroimaging analysis identified 2 regions in the right hemisphere with significantly higher surface area (mean effect size = 1.20) among individuals with paternal versus maternal POX (q = .021). Conclusions: Using deeper phenotyping in an expanded sample, we did not find evidence for substantial POX effects on neurobehavioral variability, except for localized unilateral modulations of surface area in the absence of co-occurring behavioral associations. These findings help to clarify previous inconsistencies in POX research and direct attention toward other sources of clinical variability in sex chromosome aneuploidies. |
| format | Article |
| id | doaj-art-75f5e7341ed143c69b2d4c7abea3e6f4 |
| institution | OA Journals |
| issn | 2667-1743 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Elsevier |
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| series | Biological Psychiatry Global Open Science |
| spelling | doaj-art-75f5e7341ed143c69b2d4c7abea3e6f42025-08-20T01:47:51ZengElsevierBiological Psychiatry Global Open Science2667-17432024-11-014610039110.1016/j.bpsgos.2024.100391Deep Screening for X Chromosome Parent-of-Origin Effects on Neurobehavioral and Neuroanatomical Phenotypes in 47,XXY Klinefelter SyndromeIsabella G. Larsen0Rachel Gore Moses1Bryce A. Seifert2Siyuan Liu3Samuel Li4Andrew J. Oler5Elizabeth Levitis6Lukas Schaffer7Rylee Duncan8Colleen Jodarski9Michael Kamen10Jia Yan11François M. Lalonde12Rajarshi Ghosh13Erin Torres14Liv S. Clasen15Jonathan Blumenthal16Morgan Similuk17Armin Raznahan18Magdalena A. Walkiewicz19Section on Developmental Neurogenomics, National Institute of Mental Health, National Institutes of Health, Bethesda, MarylandCentralized Sequencing Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; Address correspondence to Rachel Gore Moses, Sc.M., C.G.C.Centralized Sequencing Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandSection on Developmental Neurogenomics, National Institute of Mental Health, National Institutes of Health, Bethesda, MarylandBioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandBioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandSection on Developmental Neurogenomics, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; Center for Medical Image Computing, Department of Computer Science, University College London, London, United KingdomInstitute for Behavioral Genetics, University of Colorado Boulder, Boulder, Colorado; Department of Psychology and Neuroscience, University of Colorado Boulder, Boulder, ColoradoDepartment of Psychology, Ohio State University, Columbus, OhioCentralized Sequencing Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandCentralized Sequencing Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandSection on Developmental Neurogenomics, National Institute of Mental Health, National Institutes of Health, Bethesda, MarylandSection on Developmental Neurogenomics, National Institute of Mental Health, National Institutes of Health, Bethesda, MarylandCentralized Sequencing Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandSection on Developmental Neurogenomics, National Institute of Mental Health, National Institutes of Health, Bethesda, MarylandSection on Developmental Neurogenomics, National Institute of Mental Health, National Institutes of Health, Bethesda, MarylandSection on Developmental Neurogenomics, National Institute of Mental Health, National Institutes of Health, Bethesda, MarylandCentralized Sequencing Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandSection on Developmental Neurogenomics, National Institute of Mental Health, National Institutes of Health, Bethesda, MarylandCentralized Sequencing Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MarylandBackground: X chromosome parent of origin (POX) has been proposed as a source of phenotypic variation within sex chromosome aneuploidies such as Klinefelter syndrome (XXY/KS) and between XX and XY individuals. However, previous studies have yielded conflicting results regarding the presence and nature of POX effects, which we sought to clarify in an expanded sample with deeper neurobehavioral phenotyping. Methods: A cohort of 58 individuals with XXY/KS underwent duo or trio genome sequencing with parents (n = 151), measurement of 66 neurobehavioral phenotypes by standardized research assessments, and measurement of over 1000 anatomical phenotypes by structural magnetic resonance imaging. We developed a novel algorithm, the uniparental disomy visualization for variant call format files, to determine proband POX and then systematically tested for POX associations with all neurobehavioral and neuroanatomical outcomes. Results: The uniparental disomy visualization for variant call format files algorithm showed maternal POX in 35 of 58 cases (60.3%). There were no statistically significant POX effects on any of the 66 subscale measures of cognition, psychopathology, or behavior. Neuroimaging analysis identified 2 regions in the right hemisphere with significantly higher surface area (mean effect size = 1.20) among individuals with paternal versus maternal POX (q = .021). Conclusions: Using deeper phenotyping in an expanded sample, we did not find evidence for substantial POX effects on neurobehavioral variability, except for localized unilateral modulations of surface area in the absence of co-occurring behavioral associations. These findings help to clarify previous inconsistencies in POX research and direct attention toward other sources of clinical variability in sex chromosome aneuploidies.http://www.sciencedirect.com/science/article/pii/S266717432400104647,XXYKlinefelter syndromeNeuroanatomyNeurodevelopmentX chromosome parent of origin |
| spellingShingle | Isabella G. Larsen Rachel Gore Moses Bryce A. Seifert Siyuan Liu Samuel Li Andrew J. Oler Elizabeth Levitis Lukas Schaffer Rylee Duncan Colleen Jodarski Michael Kamen Jia Yan François M. Lalonde Rajarshi Ghosh Erin Torres Liv S. Clasen Jonathan Blumenthal Morgan Similuk Armin Raznahan Magdalena A. Walkiewicz Deep Screening for X Chromosome Parent-of-Origin Effects on Neurobehavioral and Neuroanatomical Phenotypes in 47,XXY Klinefelter Syndrome Biological Psychiatry Global Open Science 47,XXY Klinefelter syndrome Neuroanatomy Neurodevelopment X chromosome parent of origin |
| title | Deep Screening for X Chromosome Parent-of-Origin Effects on Neurobehavioral and Neuroanatomical Phenotypes in 47,XXY Klinefelter Syndrome |
| title_full | Deep Screening for X Chromosome Parent-of-Origin Effects on Neurobehavioral and Neuroanatomical Phenotypes in 47,XXY Klinefelter Syndrome |
| title_fullStr | Deep Screening for X Chromosome Parent-of-Origin Effects on Neurobehavioral and Neuroanatomical Phenotypes in 47,XXY Klinefelter Syndrome |
| title_full_unstemmed | Deep Screening for X Chromosome Parent-of-Origin Effects on Neurobehavioral and Neuroanatomical Phenotypes in 47,XXY Klinefelter Syndrome |
| title_short | Deep Screening for X Chromosome Parent-of-Origin Effects on Neurobehavioral and Neuroanatomical Phenotypes in 47,XXY Klinefelter Syndrome |
| title_sort | deep screening for x chromosome parent of origin effects on neurobehavioral and neuroanatomical phenotypes in 47 xxy klinefelter syndrome |
| topic | 47,XXY Klinefelter syndrome Neuroanatomy Neurodevelopment X chromosome parent of origin |
| url | http://www.sciencedirect.com/science/article/pii/S2667174324001046 |
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