Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis [version 1; referees: 1 approved, 2 approved with reservations]
Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. Group averages, however, obscure a wide range of outcomes. Hypothesis: The 'double hit' hypothesis proposes that the adverse impact of the extra s...
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doaj-774cb83d9c2646608418b99bbdd843aa2020-11-24T22:28:09ZengWellcomeWellcome Open Research2398-502X2018-02-01310.12688/wellcomeopenres.13828.115031Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis [version 1; referees: 1 approved, 2 approved with reservations]Dianne F. Newbury0Nuala H. Simpson1Paul A. Thompson2Dorothy V. M. Bishop3Department of Biological and Medical Sciences, Oxford Brookes University, Oxford, Oxfordshire, OX3 0BP, UKDepartment of Experimental Psychology, University of Oxford, Oxford, Oxfordshire, OX1 3UD, UKDepartment of Experimental Psychology, University of Oxford, Oxford, Oxfordshire, OX1 3UD, UKDepartment of Experimental Psychology, University of Oxford, Oxford, Oxfordshire, OX1 3UD, UKBackground: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. Group averages, however, obscure a wide range of outcomes. Hypothesis: 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. Neuroligin-4 genes are expressed from X and Y chromosomes; they play an important role in synaptic development and have been implicated in neurodevelopment. We predict that the impact of an additional sex chromosome on neurodevelopment will be correlated with common autosomal variants involved in related synaptic functions. We describe here an analysis plan for testing this hypothesis using existing data. The analysis of genotype-phenotype associations will be conducted after this plan is published and peer-reviewed Methods: Neurodevelopmental data and DNA are available for 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Children from a twin study using the same phenotype measures will form two comparison groups (Ns = 184 and 186). Three indicators of a neurodevelopment disorder phenotype will be used: (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. Autosomal genes were identified by literature search on the basis of prior association with (a) speech/language/reading phenotypes and (b) synaptic function. Preselected regions of two genes scoring high on both criteria, CNTNAP2 and NRXN1, will be tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. We predict the association with one or both genes will be detectable in children with SCTs and stronger than in the comparison samples.https://wellcomeopenresearch.org/articles/3-10/v1 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Dianne F. Newbury Nuala H. Simpson Paul A. Thompson Dorothy V. M. Bishop |
spellingShingle |
Dianne F. Newbury Nuala H. Simpson Paul A. Thompson Dorothy V. M. Bishop Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis [version 1; referees: 1 approved, 2 approved with reservations] Wellcome Open Research |
author_facet |
Dianne F. Newbury Nuala H. Simpson Paul A. Thompson Dorothy V. M. Bishop |
author_sort |
Dianne F. Newbury |
title |
Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis [version 1; referees: 1 approved, 2 approved with reservations] |
title_short |
Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis [version 1; referees: 1 approved, 2 approved with reservations] |
title_full |
Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis [version 1; referees: 1 approved, 2 approved with reservations] |
title_fullStr |
Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis [version 1; referees: 1 approved, 2 approved with reservations] |
title_full_unstemmed |
Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis [version 1; referees: 1 approved, 2 approved with reservations] |
title_sort |
stage 1 registered report: variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis [version 1; referees: 1 approved, 2 approved with reservations] |
publisher |
Wellcome |
series |
Wellcome Open Research |
issn |
2398-502X |
publishDate |
2018-02-01 |
description |
Background: The presence of an extra sex chromosome is associated with an increased rate of neurodevelopmental difficulties involving language. Group averages, however, obscure a wide range of outcomes. Hypothesis: 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. Neuroligin-4 genes are expressed from X and Y chromosomes; they play an important role in synaptic development and have been implicated in neurodevelopment. We predict that the impact of an additional sex chromosome on neurodevelopment will be correlated with common autosomal variants involved in related synaptic functions. We describe here an analysis plan for testing this hypothesis using existing data. The analysis of genotype-phenotype associations will be conducted after this plan is published and peer-reviewed Methods: Neurodevelopmental data and DNA are available for 130 children with sex chromosome trisomies (SCTs: 42 girls with trisomy X, 43 boys with Klinefelter syndrome, and 45 boys with XYY). Children from a twin study using the same phenotype measures will form two comparison groups (Ns = 184 and 186). Three indicators of a neurodevelopment disorder phenotype will be used: (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. Autosomal genes were identified by literature search on the basis of prior association with (a) speech/language/reading phenotypes and (b) synaptic function. Preselected regions of two genes scoring high on both criteria, CNTNAP2 and NRXN1, will be tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis. We predict the association with one or both genes will be detectable in children with SCTs and stronger than in the comparison samples. |
url |
https://wellcomeopenresearch.org/articles/3-10/v1 |
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