Patterns of psychopathology and cognition in sex chromosome aneuploidy

Srishti Rau; Ethan T Whitman; Kimberly Schauder; Nikhita Gogate; Nancy Raitano Lee; Lauren Kenworthy; Armin Raznahan

doi:10.1186/s11689-021-09407-9

Patterns of psychopathology and cognition in sex chromosome aneuploidy

J Neurodev Disord. 2021 Dec 15;13(1):61. doi: 10.1186/s11689-021-09407-9.

Authors

Srishti Rau^{1

2}, Ethan T Whitman³, Kimberly Schauder^{4

3}, Nikhita Gogate⁵, Nancy Raitano Lee⁶, Lauren Kenworthy^{4

3}, Armin Raznahan³

Affiliations

¹ Center for Autism Spectrum Disorders and Division of Neuropsychology, Children's National Health System, Washington DC, USA. srrau@childrensnational.org.
² Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD, USA. srrau@childrensnational.org.
³ Section on Developmental Neurogenomics, Human Genetics Branch, National Institute of Mental Health, Bethesda, MD, USA.
⁴ Center for Autism Spectrum Disorders and Division of Neuropsychology, Children's National Health System, Washington DC, USA.
⁵ The Department of Biochemistry & Molecular Medicine, The George Washington University Medical Center, Washington DC, USA.
⁶ Department of Psychology, Drexel University, Philadelphia, PA, USA.

Abstract

Background: Sex chromosome aneuploidies (SCAs) are a collectively common family of genetic disorders that increase the risk for neuropsychiatric and cognitive impairment. Beyond being important medical disorders in their own right, SCAs also offer a unique naturally occurring model for studying X- and Y-chromosome influences on the human brain. However, it remains unclear if (i) different SCAs are associated with different profiles of psychopathology and (ii) the notable interindividual variation in psychopathology is related to co-occurring variation in cognitive ability.

Methods: We examined scores for 11 dimensions of psychopathology [Child/Adult Behavior Checklist (CBCL)] and general cognitive ability [full-scale IQ (FSIQ) from Wechsler tests] in 110 youth with varying SCAs (XXY = 41, XYY = 22, XXX = 27, XXYY = 20) and 131 typically developing controls (XX = 59, XY = 72).

Results: All SCAs were associated with elevated CBCL scores across several dimensions of psychopathology (two-sample t tests comparing the euploidic and aneuploidic groups [all |T| > 9, and p < 0.001]). Social and attentional functioning were particularly sensitive to the carriage of a supernumerary Y-chromosome. In particular, the XYY group evidenced significantly more social problems than both extra-X groups (Cohen's d effect size > 0.5, Bonferroni corrected p < .05). There was marked variability in CBCL scores within each SCA group, which generally correlated negatively with IQ, but most strongly so for social and attentional difficulties (standardized β, - 0.3). These correlations showed subtle differences as a function of the SCA group and CBCL scale.

Conclusions: There is domain-specific variation in psychopathology across SCA groups and domain-specific correlation between psychopathology and IQ within SCAs. These findings (i) help to tailor clinical assessment of this common and impactful family of genetic disorders and (ii) suggest that dosage abnormalities of X- and Y-linked genes impart somewhat distinct profiles of neuropsychiatric risk.

Keywords: Cognition; Neurogenetic conditions; Psychopathology; Sex chromosome aneuploidy; Sex chromosomes.

Publication types

Research Support, N.I.H., Intramural

MeSH terms

Adolescent
Adult
Aneuploidy*
Child
Cognition
Humans
Mental Disorders*
Sex Chromosome Aberrations
Sex Chromosomes / genetics