Effect of sex chromosome number variation on attention-deficit/hyperactivity disorder symptoms, executive function, and processing speed

Aim To study sex differences in attention-deficit/hyperactivity disorder (ADHD) symptoms, we explored whether X chromosome absence or excess is independently associated with deficits in attention and hyperactivity, executive function, and processing speed. Method We assessed 116 children (ages 3y 10mo–11y 11mo, mean 8y 5mo, SD 1y 11mo) with a variable number of sex chromosomes: 36 females with Turner syndrome (45, X0), 20 males with Klinefelter syndrome (47, XXY), 37 typically developing females (XX), and 23 typically developing males (XY). Results X chromosome absence was associated with increased attention problems, hyperactivity, and deficits in inhibitory control, compared with female children with XX (all p<0.003). Conversely, X chromosome excess was associated with weakness in working memory (p=0.018) and approached significance for attention problems (p=0.071) but not with hyperactivity, or weakness in inhibitory control relative to male children with XY. Using non-parametric effect size to quantify the clinical effect revealed that X chromosome absence affected attention, hyperactivity, executive function, and processing speed (all r>0.4), while X excess affected in-laboratory as well as parent-reported working memory (all r>0.4). Interpretation Our observations provide compelling evidence that the absence or excess of an X chromosome distinctly affects cognition and behaviors associated with ADHD.