Stage 2 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: testing the double hit hypothesis [version 2; peer review: 2 approved]

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.