{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T11:53:53Z","timestamp":1789386833452,"version":"build-2803163510"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.14677.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000}},{"DOI":"10.12688\/wellcomeopenres.14677.2","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000}},{"DOI":"10.12688\/wellcomeopenres.14677.3","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000}}],"reference-count":93,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T00:00:00Z","timestamp":1622505600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000781","name":"European Research Council","doi-asserted-by":"publisher","award":["AdvancedGrant694189"],"award-info":[{"award-number":["AdvancedGrant694189"]}],"id":[{"id":"10.13039\/501100000781","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["082498"],"award-info":[{"award-number":["082498"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"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. 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.\n                  <\/ns4:p>\n                  <ns4:p>\n                    \u00a0\n                    <ns4:bold>Methods:<\/ns4:bold>\n                    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,\n                    <ns4:italic>CNTNAP2<\/ns4:italic>\n                    and\n                    <ns4:italic>NRXN1<\/ns4:italic>\n                    , were tested for association with neurodevelopmental outcomes using Generalised Structural Component Analysis.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Results:<\/ns4:bold>\n                    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\n                    <ns4:italic>CNTNAP2<\/ns4:italic>\n                    or\n                    <ns4:italic>NRXN1<\/ns4:italic>\n                    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.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Conclusions:<\/ns4:bold>\n                    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\n                    <ns4:italic>CNTNAP2<\/ns4:italic>\n                    or\n                    <ns4:italic>NRXN1<\/ns4:italic>\n                    are associated with the severity of language and neurodevelopmental impairments that often accompany an extra X or Y chromosome.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Stage 1 report:<\/ns4:bold>\n                    <ns4:ext-link xmlns:ns5=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" ns5:href=\"http:\/\/dx.doi.org\/10.12688\/wellcomeopenres.13828.2\">http:\/\/dx.doi.org\/10.12688\/wellcomeopenres.13828.2<\/ns4:ext-link>\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.14677.4","type":"journal-article","created":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T06:20:11Z","timestamp":1622528411000},"page":"85","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Stage 2 Registered Report: Variation in neurodevelopmental outcomes in children with sex chromosome trisomies: testing 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":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3390-9993","authenticated-orcid":false,"given":"Nuala H.","family":"Simpson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9940-6913","authenticated-orcid":false,"given":"Paul A.","family":"Thompson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2448-4033","authenticated-orcid":false,"given":"Dorothy V. M.","family":"Bishop","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2021,6,1]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"395-399","DOI":"10.1001\/archneurol.2010.47","article-title":"Connecting genes to brain in the autism spectrum disorders.","volume":"67","author":"B Abrahams","year":"2010","journal-title":"Arch Neurol."},{"key":"ref-2","doi-asserted-by":"publisher","first-page":"150-159","DOI":"10.1016\/j.ajhg.2007.09.005","article-title":"Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene.","volume":"82","author":"M Alarc\u00f3n","year":"2008","journal-title":"Am J Hum Genet."},{"key":"ref-3","doi-asserted-by":"publisher","article-title":"Diagnostic and statistical manual of mental disorders, Fifth Edition.","year":"2013","DOI":"10.1176\/appi.books.9780890425596"},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"1564-1573","DOI":"10.1038\/nprot.2010.116","article-title":"Data quality control in genetic case-control association studies.","volume":"5","author":"C Anderson","year":"2010","journal-title":"Nat Protoc."},{"key":"ref-5","doi-asserted-by":"publisher","first-page":"160-164","DOI":"10.1016\/j.ajhg.2007.09.015","article-title":"A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism.","volume":"82","author":"D Arking","year":"2008","journal-title":"Am J Hum Genet."},{"key":"ref-6","doi-asserted-by":"publisher","first-page":"237-245","DOI":"10.1007\/s00439-011-1011-z","article-title":"Genes that escape from X inactivation.","volume":"130","author":"J Berletch","year":"2011","journal-title":"Hum Genet."},{"key":"ref-7","article-title":"The Children's Communication Checklist, version 2 (CCC-2).","author":"D Bishop","year":"2003"},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"217-221","DOI":"10.1111\/j.1467-8721.2006.00439.x","article-title":"What causes specific language impairment in children?","volume":"15","author":"D Bishop","year":"2006","journal-title":"Curr Dir Psychol Sci."},{"key":"ref-9","first-page":"67-78","article-title":"Specific language impairment, dyslexia, and autism: Using genetics to unravel their relationship.","author":"D Bishop","year":"2008"},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"618-629","DOI":"10.1007\/s10519-010-9381-x","article-title":"Overlaps between autism and language impairment: phenomimicry or shared etiology?","volume":"40","author":"D Bishop","year":"2010","journal-title":"Behav Genet."},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"954-959","DOI":"10.1136\/adc.2009.179747","article-title":"Autism, language and communication in children with sex chromosome trisomies.","volume":"96","author":"D Bishop","year":"2011","journal-title":"Arch Dis Child."},{"key":"ref-12","doi-asserted-by":"publisher","first-page":"391-403","DOI":"10.1111\/j.1469-7610.1996.tb01420.x","article-title":"Nonword repetition as a behavioural marker for inherited language impairment: evidence from a twin study.","volume":"37","author":"D Bishop","year":"1996","journal-title":"J Child Psychol Psychiatry."},{"key":"ref-13","doi-asserted-by":"publisher","first-page":"903-907","DOI":"10.1111\/j.1651-2227.2011.02150.x","article-title":"Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin-neurexin hypothesis.","volume":"100","author":"D Bishop","year":"2011","journal-title":"Acta Paediatr."},{"key":"ref-150","article-title":"SCT genetics: Double hit hypothesis","author":"D Bishop","year":"2019"},{"key":"ref-14","doi-asserted-by":"publisher","first-page":"220-221","DOI":"10.1002\/ajmg.b.30287","article-title":"Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection.","volume":"141B","author":"F Blasi","year":"2006","journal-title":"Am J Med Genet B Neuropsychiat Genet."},{"key":"ref-15","doi-asserted-by":"publisher","first-page":"3-9","DOI":"10.1016\/j.neures.2016.09.005","article-title":"Functions of synapse adhesion molecules neurexin\/neuroligins and neurodevelopmental disorders.","volume":"116","author":"X Cao","year":"2017","journal-title":"Neurosci Res."},{"key":"ref-16","doi-asserted-by":"publisher","DOI":"10.1098\/rstb.2016.0355","article-title":"When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome.","volume":"372","author":"L Carrel","year":"2017","journal-title":"Philos Trans R Soc Lond B Biol Sci."},{"key":"ref-17","doi-asserted-by":"publisher","first-page":"452-460","DOI":"10.1038\/ejhg.2016.194","article-title":"Association analysis of dyslexia candidate genes in a Dutch longitudinal sample.","volume":"25","author":"A Carrion-Castillo","year":"2017","journal-title":"Eur J Hum Genet."},{"key":"ref-18","first-page":"307-341","article-title":"Structural equation modeling analysis with small samples using partial least squares","author":"W Chin","year":"1999"},{"key":"ref-19","doi-asserted-by":"publisher","first-page":"937-947","DOI":"10.1002\/ajmg.b.31063","article-title":"Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders.","volume":"153B","author":"M Ching","year":"2010","journal-title":"Am J Med Genet B Neuropsychiatr Genet."},{"key":"ref-20","doi-asserted-by":"publisher","first-page":"604-610","DOI":"10.1002\/ajmg.a.31145","article-title":"Molecular cytogenetic analysis of a familial interstitial deletion Xp22.2-22.3 with a highly variable phenotype in female carriers.","volume":"140","author":"S Chocholska","year":"2006","journal-title":"Am J Med Genet A."},{"key":"ref-21","article-title":"The Social Responsiveness Scale","author":"J Constantino","year":"2005"},{"key":"ref-22","doi-asserted-by":"publisher","first-page":"43-52","DOI":"10.1016\/j.conb.2007.01.011","article-title":"Neurexin-neuroligin signaling in synapse development.","volume":"17","author":"A Craig","year":"2007","journal-title":"Curr Opin Neurobiol."},{"key":"ref-100","doi-asserted-by":"publisher","first-page":"1284-1287","DOI":"10.1038\/ng.3656","article-title":"Next-generation genotype imputation service and methods.","volume":"48","author":"S Das","year":"2016","journal-title":"Nat Genet."},{"key":"ref-84","doi-asserted-by":"publisher","first-page":"1202-5","DOI":"10.1038\/ejhg.2015.269","article-title":"The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants.","volume":"24","author":"J Fadista","year":"2016","journal-title":"Eur J Hum Genet."},{"key":"ref-23","article-title":"Phonological assessment battery (PhAB)","author":"N Frederickson","year":"1997"},{"key":"ref-24","doi-asserted-by":"publisher","first-page":"74-75","DOI":"10.1002\/ajmg.b.30066","article-title":"NLGN3\/NLGN4 gene mutations are not responsible for autism in the Quebec population.","volume":"132B","author":"J Gauthier","year":"2005","journal-title":"Am J Med Genet B Neuropsychiatr Genet."},{"key":"ref-87","doi-asserted-by":"publisher","first-page":"e1002334","DOI":"10.1371\/journal.pgen.1002334","article-title":"Relative burden of large CNVs on a range of neurodevelopmental phenotypes.","volume":"7","author":"S Girirajan","year":"2011","journal-title":"PLoS Genet."},{"key":"ref-25","doi-asserted-by":"publisher","first-page":"203-209","DOI":"10.1038\/ng.534","article-title":"A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay.","volume":"42","author":"S Girirajan","year":"2010","journal-title":"Nat Genet."},{"key":"ref-26","doi-asserted-by":"publisher","first-page":"645-655","DOI":"10.1111\/j.1469-7610.2000.tb02345.x","article-title":"The Development and Well-Being Assessment: description and initial validation of an integrated assessment of child and adolescent psychopathology.","volume":"41","author":"R Goodman","year":"2000","journal-title":"J Child Psychol Psychiatry."},{"key":"ref-27","doi-asserted-by":"publisher","first-page":"25-41","DOI":"10.1162\/jocn_a_01192","article-title":"Logical and methodological issues affecting genetic studies of humans reported in top neuroscience journals.","volume":"30","author":"C Grabitz","year":"2018","journal-title":"J Cogn Neurosci."},{"key":"ref-28","doi-asserted-by":"publisher","first-page":"131-160","DOI":"10.1146\/annurev-genet-120213-092236","article-title":"Understanding Language from a Genomic Perspective.","volume":"49","author":"S Graham","year":"2015","journal-title":"Ann Rev Genet."},{"key":"ref-29","doi-asserted-by":"publisher","first-page":"204-213","DOI":"10.1038\/nature24277","article-title":"Genetic effects on gene expression across human tissues.","volume":"550","year":"2017","journal-title":"Nature."},{"key":"ref-30","doi-asserted-by":"publisher","first-page":"377-381","DOI":"10.1016\/j.jbi.2008.08.010","article-title":"Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support.","volume":"42","author":"P Harris","year":"2009","journal-title":"J Biomed Inform."},{"key":"ref-80","doi-asserted-by":"publisher","first-page":"45-61","DOI":"10.1097\/00125817-200203000-00002","article-title":"A comprehensive review of genetic association studies.","volume":"4","author":"J Hirschhorn","year":"2002","journal-title":"Genet Med."},{"key":"ref-31","doi-asserted-by":"publisher","first-page":"1207-1208","DOI":"10.1126\/science.1110011","article-title":"Neuroscience. Making synapses: a balancing act.","volume":"307","author":"N Hussain","year":"2005","journal-title":"Science."},{"key":"ref-32","doi-asserted-by":"publisher","first-page":"81-99","DOI":"10.1007\/BF02295841","article-title":"Generalized structured component analysis.","volume":"69","author":"H Hwang","year":"2004","journal-title":"Psychometrika."},{"key":"ref-33","doi-asserted-by":"publisher","first-page":"27-29","DOI":"10.1038\/ng1136","article-title":"Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism.","volume":"34","author":"S Jamain","year":"2003","journal-title":"Nat Genet."},{"key":"ref-34","doi-asserted-by":"publisher","first-page":"234-244","DOI":"10.1002\/aur.1857","article-title":"Genetic background effects in Neuroligin-3 mutant mice: Minimal behavioral abnormalities on C57 background.","volume":"11","author":"T Jaramillo","year":"2018","journal-title":"Autism Res."},{"key":"ref-35","article-title":"NEPSY: A developmental neuropsychological assessment.","author":"M Korkman","year":"1998"},{"key":"ref-36","doi-asserted-by":"publisher","first-page":"552-557","DOI":"10.1086\/382137","article-title":"X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family.","volume":"74","author":"F Laumonnier","year":"2004","journal-title":"Am J Hum Genet."},{"key":"ref-37","doi-asserted-by":"publisher","first-page":"614-618","DOI":"10.1038\/sj.ejhg.5202006","article-title":"Familial deletion within NLGN4 associated with autism and Tourette syndrome.","volume":"16","author":"A Lawson-Yuen","year":"2008","journal-title":"Eur J Hum Genet."},{"key":"ref-85","doi-asserted-by":"publisher","first-page":"5-23","DOI":"10.1016\/j.ajhg.2014.06.009","article-title":"Rare-variant association analysis: study designs and statistical tests.","volume":"95","author":"S Lee","year":"2014","journal-title":"Am J Hum Genet."},{"key":"ref-38","doi-asserted-by":"publisher","first-page":"119-129","DOI":"10.1111\/j.1469-8749.2009.03545.x","article-title":"Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review.","volume":"52","author":"V Leggett","year":"2010","journal-title":"Dev Med Child Neurol."},{"key":"ref-39","doi-asserted-by":"publisher","first-page":"11-18","DOI":"10.1002\/ajmg.10394","article-title":"Fifty-one prenatally diagnosed children and adolescents with sex chromosome abnormalities.","volume":"110","author":"M Linden","year":"2002","journal-title":"Am J Med Genet."},{"key":"ref-40","doi-asserted-by":"publisher","first-page":"e56639","DOI":"10.1371\/journal.pone.0056639","article-title":"Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population.","volume":"8","author":"Y Liu","year":"2013","journal-title":"PLoS One."},{"key":"ref-41","doi-asserted-by":"publisher","first-page":"53-61","DOI":"10.1038\/gim.2016.54","article-title":"Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression.","volume":"19","author":"C Lowther","year":"2017","journal-title":"Genet Med."},{"key":"ref-42","doi-asserted-by":"publisher","first-page":"24133-24147","DOI":"10.1074\/jbc.M116.748236","article-title":"Molecular Architecture of Contactin-associated Protein-like 2 (CNTNAP2) and Its Interaction with Contactin 2 (CNTN2).","volume":"291","author":"Z Lu","year":"2016","journal-title":"J Biol Chem."},{"key":"ref-43","doi-asserted-by":"publisher","first-page":"329-333","DOI":"10.1111\/j.1365-2788.2006.00880.x","article-title":"Deletions of VCX-A and NLGN4: a variable phenotype including normal intellect.","volume":"51","author":"M Macarov","year":"2007","journal-title":"J Intellect Disabil Res."},{"key":"ref-44","doi-asserted-by":"publisher","first-page":"25-30","DOI":"10.1097\/YPG.0b013e32834acdb2","article-title":"DCDC2 genetic variants and susceptibility to developmental dyslexia.","volume":"22","author":"C Marino","year":"2012","journal-title":"Psychiatr Genet."},{"key":"ref-45","doi-asserted-by":"publisher","first-page":"477-488","DOI":"10.1016\/j.ajhg.2007.12.009","article-title":"Structural variation of chromosomes in autism spectrum disorder.","volume":"82","author":"C Marshall","year":"2008","journal-title":"Am J Hum Genet."},{"key":"ref-109","doi-asserted-by":"publisher","first-page":"188-93","DOI":"10.1002\/gepi.20450","article-title":"An evaluation of statistical approaches to rare variant analysis in genetic association studies.","volume":"34","author":"A Morris","year":"2010","journal-title":"Genet Epidemiol."},{"key":"ref-46","article-title":"Neale Analysis of Reading Ability Second Revised British Edition.","author":"M Neale","year":"1999"},{"key":"ref-47","doi-asserted-by":"publisher","first-page":"361-365","DOI":"10.1038\/ejhg.2012.166","article-title":"Dual copy number variants involving 16p11 and 6q22 in a case of childhood apraxia of speech and pervasive developmental disorder.","volume":"21","author":"D Newbury","year":"2013","journal-title":"Eur J Hum Genet."},{"key":"ref-82","doi-asserted-by":"publisher","first-page":"285-309","DOI":"10.3390\/genes5020285","article-title":"Reading and language disorders: the importance of both quantity and quality.","volume":"5","author":"D Newbury","year":"2014","journal-title":"Genes (Basel)."},{"key":"ref-48","doi-asserted-by":"publisher","first-page":"90-104","DOI":"10.1007\/s10519-010-9424-3","article-title":"Investigation of dyslexia and SLI risk variants in reading- and language-impaired subjects.","volume":"41","author":"D Newbury","year":"2011","journal-title":"Behav Genet."},{"key":"ref-78","doi-asserted-by":"publisher","first-page":"10","DOI":"10.12688\/wellcomeopenres.13828.2","article-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 2; referees: 3 approved].","volume":"3","author":"D Newbury","year":"2018","journal-title":"Wellcome Open Res."},{"key":"ref-49","doi-asserted-by":"publisher","first-page":"264-272","DOI":"10.1016\/j.ajhg.2009.07.004","article-title":"CMIP and ATP2C2 modulate phonological short-term memory in language impairment.","volume":"85","author":"D Newbury","year":"2009","journal-title":"Am J Hum Genet."},{"key":"ref-50","doi-asserted-by":"publisher","first-page":"81-83","DOI":"10.1007\/BF01213097","article-title":"Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark.","volume":"87","author":"J Nielsen","year":"1991","journal-title":"Hum Genet."},{"key":"ref-51","doi-asserted-by":"publisher","first-page":"1247-1257","DOI":"10.1111\/jcpp.12573","article-title":"The impact of nonverbal ability on prevalence and clinical presentation of language disorder: evidence from a population study.","volume":"57","author":"C Norbury","year":"2016","journal-title":"J Child Psychol Psychiatry."},{"key":"ref-52","doi-asserted-by":"publisher","first-page":"1-26","DOI":"10.18637\/jss.v074.i11","article-title":"synthpop: Bespoke Creation of Synthetic Data in R.","volume":"74","author":"B Nowok","year":"2016","journal-title":"J Stat Softw."},{"key":"ref-81","doi-asserted-by":"publisher","first-page":"995-8","DOI":"10.1212\/WNL.63.6.955","article-title":"Association of genetic loci: replication or not, that is the question.","volume":"63","author":"J Ott","year":"2004","journal-title":"Neurology."},{"key":"ref-88","doi-asserted-by":"publisher","first-page":"611-5","DOI":"10.1089\/gtmb.2009.0005","article-title":"A substitution involving the NLGN4 gene associated with autistic behavior in the Greek population.","volume":"13","author":"A Pampanos","year":"2009","journal-title":"Genet Test Mol Biomarkers."},{"key":"ref-79","article-title":"yarrr: A Companion to the e-Book \"YaRrr!: The Pirate's Guide to R\". R package version 0.1.5","author":"N Phillips","year":"2017"},{"key":"ref-53","doi-asserted-by":"publisher","first-page":"904-909","DOI":"10.1038\/ng1847","article-title":"Principal components analysis corrects for stratification in genome-wide association studies.","volume":"38","author":"A Price","year":"2006","journal-title":"Nat Genet."},{"key":"ref-54","doi-asserted-by":"publisher","first-page":"559-575","DOI":"10.1086\/519795","article-title":"PLINK: a tool set for whole-genome association and population-based linkage analyses.","volume":"81","author":"S Purcell","year":"2007","journal-title":"Am J Hum Genet."},{"key":"ref-55","article-title":"R: A language and environment for statistical computing.","year":"2016"},{"key":"ref-56","doi-asserted-by":"publisher","first-page":"79-93","DOI":"10.1044\/2017_JSLHR-L-16-0366","article-title":"Longitudinal Study of Language and Speech of Twins at 4 and 6 Years: Twinning Effects Decrease, Zygosity Effects Disappear, and Heritability Increases.","volume":"61","author":"M Rice","year":"2018","journal-title":"J Speech Lang Hear Res."},{"key":"ref-57","article-title":"ASGSCA: Association Studies for multiple SNPs and multiple traits using Generalized Structured Equation Models.","author":"H Romdhani","year":"2014"},{"key":"ref-58","doi-asserted-by":"publisher","first-page":"101-113","DOI":"10.1002\/gepi.21872","article-title":"Pathway-based association study of multiple candidate genes and multiple traits using structural equation models.","volume":"39","author":"H Romdhani","year":"2015","journal-title":"Genet Epidemiol."},{"key":"ref-59","doi-asserted-by":"publisher","first-page":"769-778","DOI":"10.1542\/peds.2011-0719","article-title":"Behavioral and social phenotypes in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome.","volume":"129","author":"J Ross","year":"2012","journal-title":"Pediatrics."},{"key":"ref-60","doi-asserted-by":"publisher","first-page":"237-245","DOI":"10.1016\/j.biopsych.2011.02.005","article-title":"DCDC2, KIAA0319 and CMIP are associated with reading-related traits.","volume":"70","author":"T Scerri","year":"2011","journal-title":"Biol Psychiatry."},{"key":"ref-61","doi-asserted-by":"publisher","DOI":"10.2139\/ssrn.2160588","article-title":"A 21 word solution","author":"J Simmons","year":"2012"},{"key":"ref-62","doi-asserted-by":"publisher","first-page":"346-353","DOI":"10.1111\/dmcn.12294","article-title":"Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia.","volume":"56","author":"N Simpson","year":"2014","journal-title":"Dev Med Child Neurol."},{"key":"ref-89","doi-asserted-by":"publisher","first-page":"1370-7","DOI":"10.1038\/ejhg.2014.296","article-title":"Genome-wide analysis identifies a role for common copy number variants in specific language impairment.","volume":"23","author":"N Simpson","year":"2015","journal-title":"Eur J Hum Genet."},{"key":"ref-63","doi-asserted-by":"publisher","first-page":"10","DOI":"10.21956\/wellcomeopenres.15031.r31601","article-title":"Referee Report For: 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].","volume":"3","author":"D Skuse","year":"2018","journal-title":"Wellcome Open Res."},{"key":"ref-64","doi-asserted-by":"publisher","first-page":"e21","DOI":"10.1136\/jmg.2005.036897","article-title":"Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism.","volume":"43","author":"Z Talebizadeh","year":"2006","journal-title":"J Med Genet."},{"key":"ref-65","doi-asserted-by":"publisher","first-page":"159-205","DOI":"10.1016\/j.csda.2004.03.005","article-title":"PLS path modeling.","volume":"48","author":"M Tenenhaus","year":"2005","journal-title":"Comput Stat Data Anal."},{"key":"ref-108","doi-asserted-by":"publisher","first-page":"142","DOI":"10.12688\/wellcomeopenres.15396.2","article-title":"Generalized Structured Component Analysis in candidate gene association studies: applications and limitations [version 2; peer review: 3 approved].","volume":"4","author":"P Thompson","year":"2020","journal-title":"Wellcome Open Res."},{"key":"ref-66","article-title":"Test of Word Reading Efficiency (TOWRE).","author":"J Torgesen","year":"1999"},{"key":"ref-67","doi-asserted-by":"publisher","first-page":"2337-2345","DOI":"10.1056\/NEJMoa0802828","article-title":"A functional genetic link between distinct developmental language disorders.","volume":"359","author":"S Vernes","year":"2008","journal-title":"N Engl J Med."},{"key":"ref-68","doi-asserted-by":"publisher","first-page":"82-84","DOI":"10.1002\/ajmg.b.30069","article-title":"Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands.","volume":"129B","author":"J Vincent","year":"2004","journal-title":"Am J Med Genet B Neuropsychiatr Genet."},{"key":"ref-69","article-title":"Wechsler Abbreviated Scale of Intelligence.","author":"D Wechsler","year":"1999"},{"key":"ref-86","doi-asserted-by":"publisher","first-page":"978-85","DOI":"10.1038\/ng.3863","article-title":"Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders.","volume":"49","author":"D Weiner","year":"2017","journal-title":"Nat Genet."},{"key":"ref-70","doi-asserted-by":"publisher","first-page":"451-6","DOI":"10.1111\/j.1601-183X.2011.00684.x","article-title":"CNTNAP2 variants affect early language development in the general population.","volume":"10","author":"A Whitehouse","year":"2011","journal-title":"Genes Brain Behav."},{"key":"ref-71","doi-asserted-by":"publisher","first-page":"e4217","DOI":"10.7717\/peerj.4217","article-title":"Resounding failure to replicate links between developmental language disorder and cerebral lateralisation.","volume":"6","author":"A Wilson","year":"2018a","journal-title":"PeerJ."},{"key":"ref-72","doi-asserted-by":"publisher","first-page":"1123-1139","DOI":"10.1111\/dmcn.13929","article-title":"Sex chromosome trisomies are not associated with atypical lateralization for language.","volume":"60","author":"A Wilson","year":"2018b","journal-title":"Dev Med Child Neurol."},{"key":"ref-73","article-title":"Woodcock-Johnson III Tests of Cognitive Abilities.","author":"R Woodcock","year":"2007"},{"key":"ref-74","doi-asserted-by":"publisher","first-page":"204-207","DOI":"10.1097\/YPG.0b013e3282fb7fe6","article-title":"Analysis of the neuroligin 4Y gene in patients with autism.","volume":"18","author":"J Yan","year":"2008","journal-title":"Psychiatr Genet."},{"key":"ref-75","doi-asserted-by":"publisher","first-page":"329-332","DOI":"10.1038\/sj.mp.4001629","article-title":"Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients.","volume":"10","author":"J Yan","year":"2005","journal-title":"Mol Psychiatry."},{"key":"ref-76","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/724072","article-title":"Identification of four novel synonymous substitutions in the x-linked genes neuroligin 3 and neuroligin 4X in japanese patients with autistic spectrum disorder.","volume":"2012","author":"K Yanagi","year":"2012","journal-title":"Autism Res Treat."},{"key":"ref-101","doi-asserted-by":"publisher","first-page":"1423-1426","DOI":"10.1093\/bioinformatics\/btw079","article-title":"RVTESTS: an efficient and comprehensive tool for rare variant association analysis using sequence data.","volume":"32","author":"X Zhan","year":"2016","journal-title":"Bioinformatics."},{"key":"ref-77","doi-asserted-by":"publisher","first-page":"655-666","DOI":"10.1016\/j.ajhg.2009.10.004","article-title":"CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila.","volume":"85","author":"C Zweier","year":"2009","journal-title":"Am J Hum Genet."}],"container-title":["Wellcome Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-85\/v4\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-85\/v4\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-85\/v4\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,1]],"date-time":"2021-06-01T06:20:15Z","timestamp":1622528415000},"score":1,"resource":{"primary":{"URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-85\/v4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,1]]},"references-count":93,"URL":"https:\/\/doi.org\/10.12688\/wellcomeopenres.14677.4","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/wellcomeopenres.18694.r44186","asserted-by":"object"}]},"ISSN":["2398-502X"],"issn-type":[{"value":"2398-502X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,1]]},"assertion":[{"value":"Indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-85\/v4#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.17228.r40445, Beate St Pourcain, Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands, 10 Nov 2020, version 3, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-85\/v3#referee-response-40445","order":0,"name":"referee-response-40445","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Dorothy Bishop<\/b>; \n<i>Posted: 19 Dec 2020<\/i>; We thank the reviewer for the additional points, which allow us to add further clarification.  1. Yes, the non-SNPs included indels and multi-alleleic SNPs.&nbsp;&nbsp;  2-3. \n<b> <\/b>Two analyses were performed within RVTESTS; the SKAT test and the Zeggini test.&nbsp;&nbsp; The Zeggini test is a test of association. This is an aggregation test which computes a cumulative score of rare variant burden across the gene of interest which is then tested for association to the phenotype of interest. The test is described in doi: 10.1002\/gepi.20450.&nbsp;&nbsp;  The Zeggini test is suited to the analysis of rare variants only, while SKAT can handle both common and rare variants within a single test. Accordingly, we applied the Zeggini test to all variants with MAF\u22640.01 and the SKAT test to all variants with MAF\u22640.5 (i.e. all variants across the gene, both common and rare).  4\n<b>.<\/b>\n<b>&nbsp;<\/b>Appendix 9 is not part of the additional content we added in version 3 of the manuscript - which is termed 'Exploratory analyses'. Appendix 9 was part of our original submission and was titled \u2018Additional exploratory analyses\u2019. We apologise for confusing labelling of sections.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-85\/v4#referee-comment-4472","order":1,"name":"referee-comment-4472","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.17228.r40439, David H. Skuse, Behavioural Sciences Unit, UCL Great Ormond Street Institute of Child Health, London, UK, 04 Jan 2021, version 3, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-85\/v3#referee-response-40439","order":2,"name":"referee-response-40439","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Dorothy Bishop<\/b>; \n<i>Posted: 20 May 2021<\/i>; Many thanks for these additional comments on our paper.&nbsp;&nbsp; We have made some modifications to the main text, and in addition offer some replies here to specific points:&nbsp;  1.\n<b>Power of GSCA.<\/b> Since writing our original paper, we have done further analysis of the power of GSCA using simulations (Thompson, P. A., Bishop, D. V. M., Eising, E., Fisher, S. E., &amp; Newbury, D. F. (2020). Generalized Structured Component Analysis in candidate gene association studies: Applications and limitations. \n<i>Wellcome Open Research<\/i>, \n<i>4<\/i>, 142. https:\/\/doi.org\/10.12688\/wellcomeopenres.15396.2). A type II error cannot be ruled out, but we have shown that the method works well with the kind of sample size and number of SNPs used here.&nbsp;&nbsp; &nbsp; 2, \n<b>Omission of data from table<\/b>. Thanks to the reviewer for for spotting the omission of one set of SNPs in Appendix 9. We have corrected Appendix 9 (on Open Science Framework) to now include the missing SNPs, and have updated the script used to generate the tables.&nbsp;  3. \n<b>Clarification regarding gene-based analyses<\/b>.\n<b> <\/b>The gene-based analyses involve a cumulative assessment of all genetic variation in a single test allowing for differences in functional variants across individuals. The results indicate that variations across the 22 genes tested do not influence language outcomes in SCT cases or twins.&nbsp; &nbsp; 4. \n<b>Role of CNVs.&nbsp;&nbsp; <\/b> Since publishing version 3, we have reported an analysis of CNVs in this sample. Once again we have null findings. See: Mountford, H. S., Bishop, D. V. M., Thompson, P. A., Simpson, N. H., &amp; Newbury, D. F. (2020). Copy number variation burden does not predict severity of neurodevelopmental phenotype in children with a sex chromosome trisomy. \n<i>American Journal of Medical Genetics Part C: Seminars in Medical Genetics<\/i>, \n<i>184<\/i>(2), 256\u2013266. https:\/\/doi.org\/10.1002\/ajmg.c.31791  5. \n<b>Skuse predictions and Table 3.<\/b> Table 3 tests for putative epistatic effects of variations across \n<i>NRXN1 <\/i>and \n<i>CNTNAP2<\/i> in SCT subgroups, in line with the analyses presented elsewhere in the manuscript. These analyses do not directly test \n<i>NLGN4<\/i> but instead focus upon epistatic interactions with neuroligins. The idea is that if there is more consistent expression of \n<i>NLGN4Y<\/i>, then this might be evident as stronger impact in epistatic interactions. We wanted to credit the reviewer for the idea of expression differences in \n<i>NLGN4YX <\/i>and\n<i> NLGN4Y, <\/i>but have now reworded to clarify that the analysis in Table 3 is indirect evidence for this effect.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-85\/v4#referee-comment-4627","order":3,"name":"referee-comment-4627","label":"Referee Comment","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"}]}}