Abstract
Sex chromosome trisomies (SCTs) (XXX, XXY, and XYY karyotypes) are associated with an elevated risk of neurodevelopmental disorders. The range of severity of the phenotype is substantial. We considered whether this variable outcome was related to the presence of copy number variants (CNVs)-stretches of duplicated or deleted DNA. A sample of 125 children with an SCT were compared with 181 children of normal karyotype who had been given the same assessments. First, we compared the groups on measures of overall CNV burden: number of CNVs, total span of CNVs, and likely functional impact (probability of loss-of-function intolerance, pLI, summed over CNVs). Differences between groups were small relative to within-group variance and not statistically significant on overall test. Next, we considered whether a measure of general neurodevelopmental impairment was predicted by pLI summed score, SCT versus comparison group, or the interaction between them. There was a substantial effect of SCT/comparison status but the pLI score was not predictive of outcomes in either group. We conclude that variable presence of CNVs is not a likely explanation for the wide phenotypic variation in children with SCTs. We discuss methodological challenges of testing whether CNVs are implicated in causing neurodevelopmental problems.
Highlights
Children who carry an extra X or Y chromosome do not have any gross physical or mental abnormalities; there is a pronounced increase in the risk of language disorders and autism (Bishop et al, 2011)
A notable feature of sex chromosome trisomies (SCT) is the variability of the cognitive phenotype, which is substantial in all three forms of SCT: trisomy X (47, XXX), Klinefelter syndrome (47, XXY), and XYY karyotype known as Jacobs syndrome (47, XYY) (Bishop et al, 2011, 2019; Wilson, King & Bishop, 2019)
Simpson, Thompson and Bishop (2018) tested the “double hit” hypothesis, which maintains that the presence of an extra dose of neuroligin associated with overexpression of NLGN4 on X and Y chromosomes could amplify the impact of genetic variants that normally create only a minor risk for neurodevelopmental abnormalities
Summary
Children who carry an extra X or Y chromosome do not have any gross physical or mental abnormalities; there is a pronounced increase in the risk of language disorders and autism (Bishop et al, 2011). The epistasis hypothesis predicts that the risk of neurodevelopmental disorder associated with a CNV will be increased when there is a trisomy, because of interactions between CNVs and the overexpression of genes on the sex chromosomes This relates to the idea of a two-hit model (Veltman & Brunner, 2010), whereby the effect of a microdeletion is not deterministic, but rather acts as a risk factor that can increase the impact of deletions or duplications elsewhere on the genome. Further circumstantial evidence for the burden hypothesis and the impact of CNVs in cases of SCT comes from Le Gall et al (2017), who focused on a group of 14 patients with SCTs in whom an additional causative autosomal copy number event was suspected because of an unusually severe phenotype involving intellectual disability or other severe developmental disorder They found seven patients carried a pathogenic CNV (one with Williams–Beuren syndrome, one with 7q11.23 duplication, one with 17q12 duplication, three with 16p11.2 duplication and one with a 15q11.3 deletion). We focused on a measure of global neurodevelopmental impairment, as this would be sensitive to the conditions that are usually associated with CNVs: intellectual impairment and autism
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
