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.
Keywords: 47,XXY; Klinefelter syndrome; Neuroanatomy; Neurodevelopment; X chromosome parent of origin.
We investigated whether the parental origin of the extra X chromosome (POX) in Klinefelter syndrome (XXY/KS) affects cognitive, behavioral, and structural brain traits. Our study included 58 people with XXY/KS and used a new method to determine whether the extra X came from the mother (POXm) or father (POXp). Despite previous mixed results, our study found no significant differences in cognitive or behavioral traits based on POX. Imaging revealed some differences in surface area in 2 brain regions, but these findings were limited and require further research. Overall, our study suggests that POX has minimal impact on XXY/KS characteristics.