Age-related Differences in Psychopathology Within Sex Chromosome Trisomies

Overview

Journal medRxiv

Date 2024 Nov 28

PMID 39606422

Authors

Melissa R Roybal

Siyuan Liu

Isabella G Larsen

Anastasia Wass

Lukas Schaffer

Tiffany Ajumobi

Ethan T Whitman

Allysa Warling

Liv Clasen

Jonathan Blumenthal

Srishti Rau

Armin Raznahan

Affiliations

Soon will be listed here.

Abstract

Sex chromosome trisomies (SCTs) are a group of genetic disorders characterized by presence of a supernumerary sex chromosome, resulting in karyotypes other than XX or XY. These include XXX (Trisomy X), XXY (Klinefelter syndrome), and XYY (Jacobs syndrome). Sex chromosome trisomies have been linked to increased risk for psychopathology; however, this relationship warrants additional research. Specifically, little is known regarding potential age-related variation in risk for psychopathology and how this may differ across karyotypes and subdomains of psychopathology, which has relevance for psychoeducation, personalized care, and mechanistic research. Thus, we used the Child Behavior Checklist (CBCL) to estimate age-related variation in psychopathology in a large cross-sectional sample of individuals with SCTs (n = 201) and euploidic controls (n = 304) spanning the age range of 5-18 years. We found that elevations of psychopathology in SCT were significantly associated with age in a manner that varied as a combined function of the karyotype and CBCL scale being considered. Post hoc tests revealed there is a uniquely pronounced age-associated increase in severity of social problems in XYY, alongside a lack of statistical evidence for age-related variation in the severity of psychopathology for other CBCL domains and SCT karyotypes. Our findings are relevant for advancing the personalization of clinical assessment and monitoring in SCTs. They also highlight potential windows of dynamic risk emergence for closer clinical and biological study, as well as opportunities to provide intervention to mitigate future risk.

References

Ross J, Roeltgen D, Kushner H, Zinn A, Reiss A, Bardsley M . Behavioral and social phenotypes in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome. Pediatrics. 2012; 129(4):769-78. PMC: 3356148. DOI: 10.1542/peds.2011-0719. View

Blok E, de Mol C, van der Ende J, Hillegers M, Althoff R, Shaw P . Stability and Change of Psychopathology Symptoms Throughout Childhood and Adolescence. Child Psychiatry Hum Dev. 2021; 53(6):1330-1339. PMC: 9560913. DOI: 10.1007/s10578-021-01212-8. View

Yeung J, DeYoung T, Spring S, de Guzman A, Elder M, Beauchamp A . Sex chromosomes and hormones independently influence healthy brain development but act similarly after cranial radiation. Proc Natl Acad Sci U S A. 2024; 121(36):e2404042121. PMC: 11388377. DOI: 10.1073/pnas.2404042121. View

Liu S, Seidlitz J, Blumenthal J, Clasen L, Raznahan A . Integrative structural, functional, and transcriptomic analyses of sex-biased brain organization in humans. Proc Natl Acad Sci U S A. 2020; 117(31):18788-18798. PMC: 7414084. DOI: 10.1073/pnas.1919091117. View

Freilinger P, Kliegel D, Hanig S, Oehl-Jaschkowitz B, Henn W, Meyer J . Behavioral and psychological features in girls and women with triple-X syndrome. Am J Med Genet A. 2018; 176(11):2284-2291. DOI: 10.1002/ajmg.a.40477. View

Berg I, Lucas C, McGuire R . Measurement of behaviour difficulties in children using standard scales administered to mothers by computer: Reliability and validity. Eur Child Adolesc Psychiatry. 2018; 1(1):14-23. DOI: 10.1007/BF02084430. View

Warling A, Liu S, Wilson K, Whitman E, Lalonde F, Clasen L . Sex chromosome aneuploidy alters the relationship between neuroanatomy and cognition. Am J Med Genet C Semin Med Genet. 2020; 184(2):493-505. PMC: 7497743. DOI: 10.1002/ajmg.c.31795. View

Kieling C, Buchweitz C, Caye A, Silvani J, Ameis S, Brunoni A . Worldwide Prevalence and Disability From Mental Disorders Across Childhood and Adolescence: Evidence From the Global Burden of Disease Study. JAMA Psychiatry. 2024; 81(4):347-356. PMC: 10831630. DOI: 10.1001/jamapsychiatry.2023.5051. View

Rau S, Whitman E, Schauder K, Gogate N, Lee N, Kenworthy L . Patterns of psychopathology and cognition in sex chromosome aneuploidy. J Neurodev Disord. 2021; 13(1):61. PMC: 8903493. DOI: 10.1186/s11689-021-09407-9. View

10.

Harris P, Taylor R, Minor B, Elliott V, Fernandez M, ONeal L . The REDCap consortium: Building an international community of software platform partners. J Biomed Inform. 2019; 95:103208. PMC: 7254481. DOI: 10.1016/j.jbi.2019.103208. View

11.

Tartaglia N, Ayari N, Hutaff-Lee C, Boada R . Attention-deficit hyperactivity disorder symptoms in children and adolescents with sex chromosome aneuploidy: XXY, XXX, XYY, and XXYY. J Dev Behav Pediatr. 2012; 33(4):309-18. PMC: 3348431. DOI: 10.1097/DBP.0b013e31824501c8. View

12.

Xenophontos A, Seidlitz J, Liu S, Clasen L, Blumenthal J, Giedd J . Altered Sex Chromosome Dosage Induces Coordinated Shifts in Cortical Anatomy and Anatomical Covariance. Cereb Cortex. 2019; 30(4):2215-2228. PMC: 7175004. DOI: 10.1093/cercor/bhz235. View

13.

Tartaglia N, Howell S, Sutherland A, Wilson R, Wilson L . A review of trisomy X (47,XXX). Orphanet J Rare Dis. 2010; 5:8. PMC: 2883963. DOI: 10.1186/1750-1172-5-8. View

14.

Ross J, Zeger M, Kushner H, Zinn A, Roeltgen D . An extra X or Y chromosome: contrasting the cognitive and motor phenotypes in childhood in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome. Dev Disabil Res Rev. 2009; 15(4):309-17. PMC: 2876236. DOI: 10.1002/ddrr.85. View

15.

Harris P, Taylor R, Thielke R, Payne J, Gonzalez N, Conde J . Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2008; 42(2):377-81. PMC: 2700030. DOI: 10.1016/j.jbi.2008.08.010. View

16.

Bandelow B, Michaelis S . Epidemiology of anxiety disorders in the 21st century. Dialogues Clin Neurosci. 2015; 17(3):327-35. PMC: 4610617. View

17.

van Rijn S . A review of neurocognitive functioning and risk for psychopathology in sex chromosome trisomy (47,XXY, 47,XXX, 47, XYY). Curr Opin Psychiatry. 2019; 32(2):79-84. PMC: 6687415. DOI: 10.1097/YCO.0000000000000471. View

18.

Raznahan A, Lee N, Greenstein D, Wallace G, Blumenthal J, Clasen L . Globally Divergent but Locally Convergent X- and Y-Chromosome Influences on Cortical Development. Cereb Cortex. 2014; 26(1):70-9. PMC: 4701121. DOI: 10.1093/cercor/bhu174. View

19.

Kuiper K, Swaab H, Tartaglia N, van Rijn S . Early developmental impact of sex chromosome trisomies on attention deficit-hyperactivity disorder symptomology in young children. Am J Med Genet A. 2021; 185(12):3664-3674. PMC: 9292447. DOI: 10.1002/ajmg.a.62418. View

20.

Tartaglia N, Cordeiro L, Howell S, Wilson R, Janusz J . The spectrum of the behavioral phenotype in boys and adolescents 47,XXY (Klinefelter syndrome). Pediatr Endocrinol Rev. 2011; 8 Suppl 1:151-9. PMC: 3740580. View