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Update on our studies of children with an extra X or Y chromosome

Why do some children have difficulties with learning to talk, understand or read? People often assume this is caused by a child’s environment, but genetic differences between children can also be important. We are trying to understand this better, and one approach is to look at known medical conditions that are associated with language problems.

One thing that increases the risk of having language problems is when a person has an extra copy of an X or Y chromosome. We're trying to find out how the extra chromosome has an impact: in particular we've been testing whether it acts by boosting the impact of other genetic variants that usually have only a slight effect.

Between 2011 and 2017 a total of 143 children helped in our study of  extra X and Y chromosomes (‘trisomies’). We visited children at home or school to assess their language and other skills, and we measured blood flow in the brain while they did a language task. We also looked at information from questionnaires that parents completed, to get a detailed picture of the child’s development.

The detailed results of our study are covered in a series of publications: all of these are Open Access, which means you can download the paper for free from the link. Below we summarise the main findings so far.

We will continue to send updates of our findings to families who took part in our studies, unless you let us know you would prefer us not to do so. If you would like to be removed from our mailing list, please email nuala.simpson@psy.ox.ac.uk.

If you would like to have the opportunity to take part in future studies on this topic, please complete this form xxxx.

Language development

Bishop et al (2018): Language phenotypes in children with sex chromosome trisomies, Wellcome Open Research. https://wellcomeopenresearch.org/articles/3-143

We found that language problems are common in children with an extra X or Y chromosome, but there were big differences from child to child. Although they generally needed some additional help, severe language problems were uncommon.  We compared children with a trisomy with a group of twin children whose parents were concerned about their language. There were broad similarities in the typical severity and profile of language problems.

We focused mainly on the subset of children whose trisomy was discovered in the course of prenatal screening or investigation for medical conditions. If the child's trisomy was discovered by a geneticist who was investigating neurodevelopmental problems, then the rate of more serious problems was higher.

We also considered whether the three trisomy groups, XXX, XXY and XYY showed different patterns of problems. Variation within each trisomy group was substantial: but there was no effect of trisomy type. However, the numbers of children were relatively small, and it is possible that with a bigger sample we might have been able to see more systematic patterns.

Social anxiety and autism

Wilson, King & Bishop (2019). Autism spectrum disorder and social anxiety in children with sex chromosome trisomies: an observational study. Wellcome Open Research

In this analysis, we focused on psychiatric symptoms reported by parents on a checklist and an online interview. Previously, it had been proposed that an additional X chromosome was associated with social anxiety – i.e. a marked and persistent fear of social situations that inteferes with everyday life. We found that very few children had social anxiety severe enough to merit a psychiatric diagnosis, though those who did all had an extra X chromosome. Milder symptoms of social anxiety occurred at higher rates than normal in all three trisomies. We also considered whether autism was specifically associated with boys with a trisomy, but found this not to be the case: there was an increased risk of autism in girls with XXX, as well as in boys with XXY or XYY. Nevertheless, the majority of children did not have either autism or social anxiety.  Just as in the language study, the most striking finding was the wide degree of variation in children with trisomies.

Our study also showed that if a trisomy was discovered during genetic testing for behavioural or school-based problems, then problems were usually more severe than in a child whose trisomy was detected through routine prenatal screening. 

These results are of interest to genetic counsellors who advise families when a trisomy is discovered. On the one hand, there is an increased risk of a range of developmental difficulties, and by being aware of these, we can help ensure children get help early on. On the other hand, for cases identified on prenatal screening, difficulties are often mild.

Genetics: the 'double hit' hypothesis

Newbury et al (2018) Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: testing the double hit hypothesis. Wellcome Open Research https://wellcomeopenresearch.org/articles/3-85/v2

In this paper we tested whether the variability in language seen in children with an extra X or Y chromosome might be explained by genetic variation on other chromosomes. According to this 'double hit' hypothesis, a child's neurodevelopment will be affected by a range of genetic variants: if there are two risk factors that both affect a particular neural pathway, then the impact will be more severe. We therefore looked at variation in genes that affect particular aspects of brain development that are likely to be influenced by an X or Y trisomy. We did not find any support for the double hit hypothesis.

There are so many genes we could potentially look at, that we can't conclude the 'double hit' idea is wrong. But it is important that we have a systematic plan for studying different genes, rather than just looking at everything, because in a small sample like this, it would be very easy to find 'false positive' results – associations that were just due to random variation.  We have two further analyses under way and hope to report on these during 2019.

Brain asymmetry

Wilson, A. C., & Bishop, D. V. M. (2018). Resounding failure to replicate links between developmental language disorder and cerebral lateralisation. PeerJ, 6, e4217. doi:10.7717/peerj.4217. https://peerj.com/articles/4217/

Wilson, A. C., & Bishop, D. V. M. (2018). Sex chromosome trisomies are not associated with atypical lateralisation for language. Developmental Medicine and Child Neurology, 60(11), 1132-1139. doi:10.1111/dmcn.13929. https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.13929

We've known for many years that the left side of the brain is much more involved than the right side when we talk. This is term 'language laterality', and it is true for about 95% of people. However, there are people who have different types of brain organisation: either their language is controlled by the right side, or they use both sides equally. It's rather like handedness: most people are right-handed but some are not.

It's long been suggested that developmental language disorders may be related to atypical language laterality. Indeed, it's been argued that an extra X chromosome may interfere with the brain developing a dominant side for language.

We did not find any support for this idea. We were able to measure blood flow in the two sides of the brain while children told us about a story they had seen in a video. As we expected, in most cases, the blood flow was greater to the left than the right side. However, the child's pattern of laterality (left-brained, right-brained, or symmetric) was unrelated to their language skills. Also, the proportions of children with different laterality types was very similar in those with an extra X or Y chromosome to that seen in other children.