{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T05:11:56Z","timestamp":1772169116415,"version":"3.50.1"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.13828.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T00:00:00Z","timestamp":1524528000000}}],"reference-count":76,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T00:00:00Z","timestamp":1524528000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Wellcome Trust","award":["082498"],"award-info":[{"award-number":["082498"]}]},{"name":"European Research Council","award":["694189"],"award-info":[{"award-number":["694189"]}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    <ns4:bold>Background<\/ns4:bold>\n                    : 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.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Hypothesis:<\/ns4:bold>\n                    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.\n                    <ns4:italic>Neuroligin-4<\/ns4:italic>\n                    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.\n                  <\/ns4:p>\n                  <ns4:p>\u00a0We 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<\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    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,\n                    <ns4:italic>CNTNAP2<\/ns4:italic>\n                    and\n                    <ns4:italic>NRXN1<\/ns4:italic>\n                    , 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.\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.13828.2","type":"journal-article","created":{"date-parts":[[2018,4,24]],"date-time":"2018-04-24T11:20:18Z","timestamp":1524568818000},"page":"10","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Stage 1 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: protocol for a test of the double hit hypothesis"],"prefix":"10.12688","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9557-268X","authenticated-orcid":false,"given":"Dianne F.","family":"Newbury","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3390-9993","authenticated-orcid":false,"given":"Nuala H.","family":"Simpson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9940-6913","authenticated-orcid":false,"given":"Paul A.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2448-4033","authenticated-orcid":false,"given":"Dorothy V. 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.15855.r32984, Armin Raznahan, Developmental Neurogenomics Unit\u00a0(DNU), \u00a0National Institute of Mental Health\u00a0(NIMH)\u00a0, Bethesda, MD, USA, 16 May 2018, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-10\/v2#referee-response-32984","order":0,"name":"referee-response-32984","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.15031.r31717, Beate St Pourcain, Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands, 26 Mar 2018, version 1, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-10\/v1#referee-response-31717","order":1,"name":"referee-response-31717","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Dorothy Bishop<\/b>; \n<i>Posted: 16 Apr 2018<\/i>; Many thanks for the thoughtful comments on our protocol.&nbsp;  The point about possible variation between karyotypes agrees with one of the main points raised by Skuse (see above). It makes sense that there are some variations across karyotypes that will need another explanatory account. Nevertheless, we think it worth starting by testing a general mechanism, for two reasons. First, language impairment seems to be more like height \u2013 just as there is a tendency to be tall in all three karyotypes, so there is a tendency to have poor language skills.&nbsp; On our quantitative measures of language, the three groups do not look very different (though there is large variance around means). So there appears to be a general influence affecting all three karyotypes, even if there are karyotype-specific effects superimposed. NLGN4X does, at least in part, escape inactivation, so provides a plausible mechanism. Second, we have limited statistical power. If we take seriously correction for multiple comparisons, then we can either investigate several potential explanations with a stringent alpha, or reduce the number of tests we do and have a less stringent alpha. We have opted for the latter approach. As noted in the text, focusing on two genes so we can optimise power&nbsp; will not preclude us from doing further exploratory analyses, which would include investigating karyotype-specific effects, but we would then need to replicate findings in another sample. It would, of course, be great to extend the analyses and not just confine it to two candidates, but we would rapidly lose power if we applied appropriate corrections. More minor point: inclusion of variants on XIST and TSIX would pose problems as they are on the X chromosome. Improved account of LD patterns \u2013 please see response to Raznahan below.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-10\/v2#referee-comment-3589","order":2,"name":"referee-comment-3589","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.15855.r33083, David H. Skuse, Behavioural & Brain Sciences Lab, UCL Great Ormond Street Institute of Child Health, London, UK, 04 May 2018, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-10\/v2#referee-response-33083","order":3,"name":"referee-response-33083","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was funded by Wellcome Trust Programme Grants 082498, and European Research Council Advanced Grant 694189. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}