Copy number variation burden does not predict severity of neurodevelopmental phenotype in children with a sex chromosome trisomy

Am J Med Genet C Semin Med Genet. 2020 Jun;184(2):256-266. doi: 10.1002/ajmg.c.31791. Epub 2020 May 26.


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.

Keywords: copy number variants; double hit; language; loss-of-function intolerance; neurodevelopmental disorder; sex chromosome trisomy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child, Preschool
  • DNA Copy Number Variations / genetics*
  • Female
  • Humans
  • Klinefelter Syndrome / genetics
  • Klinefelter Syndrome / pathology
  • Loss of Function Mutation / genetics
  • Male
  • Neurodevelopmental Disorders / genetics*
  • Neurodevelopmental Disorders / pathology
  • Phenotype
  • Sex Chromosomes / genetics*
  • Sex Chromosomes / pathology
  • Trisomy / genetics*
  • Trisomy / pathology
  • XYY Karyotype / genetics
  • XYY Karyotype / pathology