Stage 2 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: testing the double hit hypothesis

Abstract

Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. The 'double hit' hypothesis proposes that the adverse impact of the extra sex chromosome is amplified when genes that are expressed from the sex chromosomes interact with autosomal variants that usually have only mild effects. We predicted that the impact of an additional sex chromosome on neurodevelopment would depend on common autosomal variants involved in synaptic functions. Methods: We analysed data from 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Two comparison groups were formed from 370 children from a twin study. Three indicators of phenotype were: (i) Standard score on a test of nonword repetition; (ii). A language factor score derived from a test battery; (iii) A general scale of neurodevelopmental challenges based on all available information. Preselected regions of two genes, CNTNAP2 and NRXN1, were tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. Results: There was wide phenotypic variation in the SCT group, as well as overall impairment on all three phenotypic measures. There was no association of phenotype with CNTNAP2 or NRXN1 variants in either the SCT group or the comparison groups. Supplementary analyses found no indication of any impact of trisomy type on the results, and exploratory analyses of individual SNPs confirmed the lack of association. Conclusions: We cannot rule out that a double hit may be implicated in the phenotypic variability in children with SCTs, but our analysis does not find any support for the idea that common variants in CNTNAP2 or NRXN1 are associated with the severity of language and neurodevelopmental impairments that often accompany an extra X or Y chromosome. Stage 1 report: http://dx.doi.org/10.12688/wellcomeopenres.13828.2

Evaluating the Scope of Language Impairments in a Patient with Triple X Syndrome: A Brief Report

“…Even though females who receive their diagnosis of triple X syndrome prenatally (like our patient A) have a smaller risk of language disorders than those who receive their diagnosis postnatally [17,27] , our results from the standardized language tests as well as her brother's report indicate that patient A's language is severely impaired compared to her peers. These results are in line with recent studies, showing that also children with prenatally diagnosed sex chromosome trisomies often have lower language scores than their agematched controls, 17,28 which are noticeable from an early age. 14 Her performances on the clinical tests remain far below average, even though A was familiar with the experimenter, and experimenter familiarity usually yields higher scores as it increases patients' motivation and attention.…”

Language phenotypes in children with sex chromosome trisomies

“…Behavioural and psychiatric findings will be covered in a companion paper. To date we have not found any associations of phenotypes with variants in CNTNAP2 and NRXN1 genes; these analyses are reported elsewhere ( Newbury et al ., 2018).…”

“…All tests had published norms covering the age range of the twin sample (6 to 11 years), but some did not extend outside this range. As explained in Newbury et al . (2018), where feasible, norms were extrapolated based on data from other samples encompassing the age range (see Appendix 2 on Open Science Framework project: https://osf.io/ae8yn/).…”

“…Elsewhere we have proposed that genetic variants on autosomes may interact with neurodevelopmental consequences of extra gene product from sex chromosomes, so there is amplification of impact from variants that usually have only a mild effect. To date we have not been able to identify such effects ( Newbury et al ., 2018). This does not, of course, rule out the possibility that a mechanism of this kind does operate, but involving different genes.…”

“…To establish potential bias introduced by those with missing or unusable data, we conducted a logistic regression analysis, with CCC-2 data coded as 1 (useable data) vs 0 (missing or inconsistent), and with maternal educational level, single parent status, trisomy status, and a composite measure of the child’s language status (language factor from Newbury et al ., 2018) as predictors. Availability of CCC-2 data not predicted by parental characteristics (mother’s education or single parent status), but was predicted by whether the child came from the twin or trisomy group, and by severity of language problems.…”