X- vs. Y-chromosome dosage effects on human cognition: a deep phenotypic comparison of 47,XXY and 47,XYY syndromes

Sex chromosome aneuploidies are associated with a wide range of neurodevelopmental outcomes, and notably, confer risk for cognitive impairments with varying degrees of severity. Yet, to date, few studies have compared multiple cognitive outcomes between different sex chromosome aneuploidy karyotypes, and it remains unclear how cognitive variation is linked to other elements of functioning. Leveraging high-dimensional data from a large battery of standardized neurocognitive tasks, we systematically characterize cognition across domains among 167 individuals with sex chromosome aneuploidy (n = 102 XXY/Klinefelter syndrome, n = 65 XYY) aged 5-25 years. These profiles of cognition are then compared between sex chromosome aneuploidy groups and related to measures of adaptive functioning, caregiver strain, and psychopathology. Age-normed scores and z-scores describe the cognitive performance across fifteen scales within XXY/Klinefelter syndrome and XYY syndrome relative to instrument-provided population norms. These profiles are compared between groups, revealing an overall intensification of impairment among the XYY group versus the XXY/Klinefelter syndrome group. The relationships between cognitive scores and adaptive functioning are found to be largely congruent between groups, while we find heterogeneity in the relative coupling of cognitive scores and psychopathology. This multidimensional characterization and comparison of cognitive abilities in XXY/Klinefelter syndrome and XYY syndrome contributes to our understanding of X- versus Y-chromosome dosage effects on neurodevelopment, with the potential to inform karyotype-specific targeting of assessment and intervention that may have unique impacts on functioning.