Journal of Child Psychology and Psychiatry 53:10 (2012), pp 1082–1083 doi:10.1111/j.1469-7610.2012.02610.x Commentary: Unravelling the effects of additional sex chromosomes on cognition and communication – reflections on Lee et al. (2012) Dorothy V.M. Bishop Department of Experimental Psychology, University of Oxford, Oxford, UK Most people have 23 pairs of chromosomes; one set from the mother and one from the father. However, nondisjunction errors during meiosis can lead to a case of trisomy, where there are three rather than two chromosomes. Although such events are not uncommon, they are usually lethal, and account for a high proportion of spontaneous abortions. The most common trisomy compatible with survival to birth involves chromosome 21, one of the smallest chromosomes. This is associated with serious developmental abnormalities affecting a range of organs (Down syndrome). In comparison, the effects of a sex chromosome trisomy are relatively mild. Most children with XXX, XXY or XYY constitutions attend regular school and, apart from a tendency to be somewhat taller than average, appear physically normal. The reason for this can be found in the peculiar nature of the sex chromosomes. The Y chromosome is very small and is thought to contain fewer than 100 genes, com- pared with over 1000 on the X chromosome. All else being equal, females should have considerably more gene product than males. However, in normal XX females, most of one X-chromosome is inactivated. A process of methylation causes the DNA to be packed in a tight ball, preventing gene expression. This process of ‘dosage compensation’ has the effect of reducing the difference between males and females in amount of gene product. X-inactivation is not complete; there are regions on the tips of the sex chromosomes that remain active and behave just like autosomes; these are referred to as the pseudoautosomal region. In addition, there are areas of the X-chromosome outside the pseudoaut- osomal region that escape inactivation, where both copies of a gene are expressed. There appears to be quite substantial individual variation in the number and location of genes that escape inactivation. If we put these pieces of information together, we start to see why the impact of an additional sex chromosome is relatively mild. For boys with XYY constitution, the additional Y chromosome contains relatively few genes. For girls or boys with an extra X, only one X chromosome is completely activated, and so a minority of X-linked genes are expressed in extra dose. The author has declared that she has no competing or poten- tial conﬂicts of interest. Nevertheless, there are cognitive impacts of an extra sex chromosome, as discussed in the article by Lee et al. (2012), with intriguing differences between those with an extra X or Y. There is surprisingly little research on sex chromosome trisomies: The expla- nation is largely due to the mild impact of the tri- somy, which means that many people who have a sex chromosome trisomy would not be aware of their status. Most of the information we have about prev- alence and consequences of sex chromosome triso- mies comes from a set of studies carried out in the 1960–1970s in which newborn babies underwent chromosome screening. Such studies are unlikely to be repeated now for two reasons. First, they are highly labour-intensive: given that, for instance, XXX chromosome constitution is found in around 1 in 1,000 girls, this means we would have to screen 10,000 cases to get a sample of just 10 affected cases. Research is also limited by ethical concerns. The studies done in the 1960s proved problematic as the researchers started to realise that telling parents that their newborn child had a sex chromosome tri- somy was bound to cause anxiety and distress, especially since information about its likely impact was so uncertain. Findings from the newborn screening studies were summarized in a systematic review by Leggett, Jacobs, Nation, Scerif, and Bishop (2010), who noted a reduction in IQ in XXX, XXY and XYY groups, with both groups of males showing evidence of disproportionate verbal impairments. Such deﬁcits are assumed to be caused by the excess proteins that arise from supernumerary X- or Y- linked genes that escape inactivation. The report by Lee et al. makes a unique contribu- tion by extending the study of the impact of super- numerary sex chromosomes to include rare cases of children with four or ﬁve sex chromosomes. They demonstrate a clear ‘dosage’ effect, whereby the more chromosomes, the greater the negative impact on IQ and development. Each additional X- or Y- chromosome was associated with a decrease in IQ of around 1 SD. Intriguingly, they also found that additional X chromosomes had a greater effect on structural language skills, whereas additional Y chromosomes had disproportionate effect on prag- matic problems and autistic features. It should be noted, however, that those with extra X chromo- somes included both girls and boys, whereas the extra-Y chromosome group were all male. Bishop 2012 The Authors. Journal of Child Psychology and Psychiatry 2012 Association for Child and Adolescent Mental Health. Published by Blackwell Publishing, 9600 Garsington Road, Oxford OX4 2DQ, UK and 350 Main St, Malden, MA 02148, USA