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

Dianne F Newbury, Nuala H Simpson, Paul A Thompson, Dorothy V M Bishop, Dianne F Newbury, Nuala H Simpson, Paul A Thompson, Dorothy V M Bishop

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.

Keywords: X chromosome; Y chromosome; autism spectrum disorder; language; neuroligin; sex chromosome trisomy; synapse.

Conflict of interest statement

No competing interests were disclosed.

Copyright: © 2021 Newbury DF et al.

Figures

Figure 1.. Neurexins (such as NRXN1 ),…
Figure 1.. Neurexins (such as NRXN1), neuroligins (such as NLGN4) and contactin-associated proteins (such as CNTNAP2) all form part of the synaptic scaffolding system.
Figure 2.. Flowchart showing characteristics of children…
Figure 2.. Flowchart showing characteristics of children recruited to sex chromosome trisomies (SCT) group.
Figure 3.. Flowchart showing characteristics of children…
Figure 3.. Flowchart showing characteristics of children recruited to comparison groups.
Figure 4.. Structural equation diagram for analysis.
Figure 4.. Structural equation diagram for analysis.
Figure 5.. Pirate plots ( Phillips, 2017)…
Figure 5.. Pirate plots ( Phillips, 2017) for sex chromosome trisomies (SCT) and two twin groups, showing individual cases as points, with bold line depicting median, for Nonword repetition (scaled score), Language factor and Global neurodevelopmental impairment (inverted so low score reflects impairment).
Figure 6.. Mean scores for three phenotypes…
Figure 6.. Mean scores for three phenotypes for SCT and both twin groups, in relation to number of minor alleles for rs2710102(G) and rs7794745(T).

References

    1. Abrahams BS, Geschwind DH: Connecting genes to brain in the autism spectrum disorders. Arch Neurol. 2010;67(4):395–399. 10.1001/archneurol.2010.47
    1. Alarcón M, Abrahams BS, Stone JL, et al. : Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet. 2008;82(1):150–159. 10.1016/j.ajhg.2007.09.005
    1. American Psychiatric Association: Diagnostic and statistical manual of mental disorders, Fifth Edition.Arlington, VA: American Psychiatric Publishing.2013. 10.1176/appi.books.9780890425596
    1. Anderson CA, Pettersson FH, Clarke GM, et al. : Data quality control in genetic case-control association studies. Nat Protoc. 2010;5(9):1564–1573. 10.1038/nprot.2010.116
    1. Arking DE, Cutler DJ, Brune CW, et al. : A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet. 2008;82(1):160–164. 10.1016/j.ajhg.2007.09.015
    1. Berletch JB, Yang F, Xu J, et al. : Genes that escape from X inactivation. Hum Genet. 2011;130(2):237–245. 10.1007/s00439-011-1011-z
    1. Bishop DV: The Children's Communication Checklist, version 2 (CCC-2).London: Pearson.2003.
    1. Bishop DV: What causes specific language impairment in children? Curr Dir Psychol Sci. 2006;15(5):217–221. 10.1111/j.1467-8721.2006.00439.x
    1. Bishop DV: Specific language impairment, dyslexia, and autism: Using genetics to unravel their CF Norbury, JB Tomblin, & DVM Bishop (Eds.), Understanding developmental language disorders: from theory to practice.Hove: Psychology Press,2008;67–78.
    1. Bishop DV: Overlaps between autism and language impairment: phenomimicry or shared etiology? Behav Genet. 2010;40(5):618–629. 10.1007/s10519-010-9381-x
    1. Bishop DV, Jacobs PA, Lachlan K, et al. : Autism, language and communication in children with sex chromosome trisomies. Arch Dis Child. 2011;96(10):954–959. 10.1136/adc.2009.179747
    1. Bishop DV, North T, Donlan C: Nonword repetition as a behavioural marker for inherited language impairment: evidence from a twin study. J Child Psychol Psychiatry. 1996;37(4):391–403. 10.1111/j.1469-7610.1996.tb01420.x
    1. Bishop DV, Scerif G: Klinefelter syndrome as a window on the aetiology of language and communication impairments in children: the neuroligin-neurexin hypothesis. Acta Paediatr. 2011;100(6):903–907. 10.1111/j.1651-2227.2011.02150.x
    1. Bishop DVM, Thompson PA, Newbury D, et al. : SCT genetics: Double hit hypothesis.2019.
    1. Blasi F, Bacchelli E, Pesaresi G, et al. : Absence of coding mutations in the X-linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection. Am J Med Genet B Neuropsychiat Genet. 2006;141B(3):220–221. 10.1002/ajmg.b.30287
    1. Cao X, Tabuchi K: Functions of synapse adhesion molecules neurexin/neuroligins and neurodevelopmental disorders. Neurosci Res. 2017;116:3–9. 10.1016/j.neures.2016.09.005
    1. Carrel L, Brown CJ: When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome. Philos Trans R Soc Lond B Biol Sci. 2017;372(1733): pii: 20160355. 10.1098/rstb.2016.0355
    1. Carrion-Castillo A, Maassen B, Franke B, et al. : Association analysis of dyslexia candidate genes in a Dutch longitudinal sample. Eur J Hum Genet. 2017;25(4):452–460. 10.1038/ejhg.2016.194
    1. Chin WW, Newstead PR: Structural equation modeling analysis with small samples using partial least squares. In: Hoyle RH, (Ed.), Statistical strategies for small sample research. Thousand Oaks: Sage Publications.1999;307–341.
    1. Ching MS, Shen Y, Tan WH, et al. : Deletions of NRXN1 (neurexin-1) predispose to a wide spectrum of developmental disorders. Am J Med Genet B Neuropsychiatr Genet. 2010;153B(4):937–947. 10.1002/ajmg.b.31063
    1. Chocholska S, Rossier E, Barbi G, et al. : Molecular cytogenetic analysis of a familial interstitial deletion Xp22.2-22.3 with a highly variable phenotype in female carriers. Am J Med Genet A. 2006;140(6):604–610. 10.1002/ajmg.a.31145
    1. Constantino JN: The Social Responsiveness Scale. Los Angeles: Western Psychological Services.2005.
    1. Craig AM, Kang Y: Neurexin-neuroligin signaling in synapse development. Curr Opin Neurobiol. 2007;17(1):43–52. 10.1016/j.conb.2007.01.011
    1. Das S, Forer L, Schönherr S: Next-generation genotype imputation service and methods. Nat Genet. 2016;48(10):1284–1287. 10.1038/ng.3656
    1. Fadista J, Manning AK, Florez JC, et al. : The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants. Eur J Hum Genet. 2016;24(8):1202–5. 10.1038/ejhg.2015.269
    1. Frederickson N, Frith U, Reason R: Phonological assessment battery (PhAB). Windsor: NFER-Nelson.1997.
    1. Gauthier J, Bonnel A, St-Onge J, et al. : NLGN3/NLGN4 gene mutations are not responsible for autism in the Quebec population. Am J Med Genet B Neuropsychiatr Genet. 2005;132B(1):74–75. 10.1002/ajmg.b.30066
    1. Girirajan S, Brkanac Z, Coe BP, et al. : Relative burden of large CNVs on a range of neurodevelopmental phenotypes. PLoS Genet. 2011;7(11):e1002334. 10.1371/journal.pgen.1002334
    1. Girirajan S, Rosenfeld JA, Cooper GM, et al. : A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet. 2010;42(3):203–209. 10.1038/ng.534
    1. Goodman R, Ford T, Richards H, et al. : The Development and Well-Being Assessment: description and initial validation of an integrated assessment of child and adolescent psychopathology. J Child Psychol Psychiatry. 2000;41(5):645–655. 10.1111/j.1469-7610.2000.tb02345.x
    1. Grabitz CR, Button KS, Munafò MR, et al. : Logical and methodological issues affecting genetic studies of humans reported in top neuroscience journals. J Cogn Neurosci. 2018;30(1):25–41. 10.1162/jocn_a_01192
    1. Graham SA, Fisher SE: Understanding Language from a Genomic Perspective. Ann Rev Genet. 2015;49:131–160. 10.1146/annurev-genet-120213-092236
    1. GTEx Consortium, Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group, Statistical Methods groups—Analysis Working Group, et al.: Genetic effects on gene expression across human tissues. Nature. 2017;550(7675):204–213. 10.1038/nature24277
    1. Harris PA, Taylor R, Thielke R, et al. : Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42(2):377–381. 10.1016/j.jbi.2008.08.010
    1. Hirschhorn JN, Lohmueller K, Byrne E, et al. : A comprehensive review of genetic association studies. Genet Med. 2002;4(2):45–61. 10.1097/00125817-200203000-00002
    1. Hussain NK, Sheng M: Neuroscience. Making synapses: a balancing act. Science. 2005;307(5713):1207–1208. 10.1126/science.1110011
    1. Hwang H, Takane Y: Generalized structured component analysis. Psychometrika. 2004;69(1):81–99. 10.1007/BF02295841
    1. Jamain S, Quach H, Betancur C, et al. : Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat Genet. 2003;34(1):27–29. 10.1038/ng1136
    1. Jaramillo TC, Escamilla CO, Liu S, et al. : Genetic background effects in Neuroligin-3 mutant mice: Minimal behavioral abnormalities on C57 background. Autism Res. 2018;11(2):234–244. 10.1002/aur.1857
    1. Korkman M, Kirk U, Kemp SI: NEPSY: A developmental neuropsychological assessment.San Antonio: Psychological Corporation.1998.
    1. Laumonnier F, Bonnet-Brilhault F, Gomot M, et al. : X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family. Am J Hum Genet. 2004;74(3):552–557. 10.1086/382137
    1. Lawson-Yuen A, Saldivar JS, Sommer S, et al. : Familial deletion within NLGN4 associated with autism and Tourette syndrome. Eur J Hum Genet. 2008;16(5):614–618. 10.1038/sj.ejhg.5202006
    1. Lee S, Abecasis GR, Boehnke M, et al. : Rare-variant association analysis: study designs and statistical tests. Am J Hum Genet. 2014;95(1):5–23. 10.1016/j.ajhg.2014.06.009
    1. Leggett V, Jacobs P, Nation K, et al. : Neurocognitive outcomes of individuals with a sex chromosome trisomy: XXX, XYY, or XXY: a systematic review. Dev Med Child Neurol. 2010;52(2):119–129. 10.1111/j.1469-8749.2009.03545.x
    1. Linden MG, Bender BG: Fifty-one prenatally diagnosed children and adolescents with sex chromosome abnormalities. Am J Med Genet. 2002;110(1):11–18. 10.1002/ajmg.10394
    1. Liu Y, Du Y, Liu W, et al. : Lack of association between NLGN3, NLGN4, SHANK2 and SHANK3 gene variants and autism spectrum disorder in a Chinese population. PLoS One. 2013;8(2):e56639. 10.1371/journal.pone.0056639
    1. Lowther C, Speevak M, Armour CM, et al. : Molecular characterization of NRXN1 deletions from 19,263 clinical microarray cases identifies exons important for neurodevelopmental disease expression. Genet Med. 2017;19(1):53–61. 10.1038/gim.2016.54
    1. Lu Z, Reddy MV, Liu J, et al. : Molecular Architecture of Contactin-associated Protein-like 2 (CNTNAP2) and Its Interaction with Contactin 2 (CNTN2). J Biol Chem. 2016;291(46):24133–24147. 10.1074/jbc.M116.748236
    1. Macarov M, Zeigler M, Newman JP, et al. : Deletions of VCX-A and NLGN4: a variable phenotype including normal intellect. J Intellect Disabil Res. 2007;51(Pt 5):329–333. 10.1111/j.1365-2788.2006.00880.x
    1. Marino C, Meng H, Mascheretti S, et al. : DCDC2 genetic variants and susceptibility to developmental dyslexia. Psychiatr Genet. 2012;22(1):25–30. 10.1097/YPG.0b013e32834acdb2
    1. Marshall CR, Noor A, Vincent JB, et al. : Structural variation of chromosomes in autism spectrum disorder. Am J Hum Genet. 2008;82(2):477–488. 10.1016/j.ajhg.2007.12.009
    1. Morris AP, Zeggini E: An evaluation of statistical approaches to rare variant analysis in genetic association studies. Genet Epidemiol. 2010;34(2):188–93. 10.1002/gepi.20450
    1. Neale MD: Neale Analysis of Reading Ability Second Revised British Edition.London: GL Assessment.1999.
    1. Newbury DF, Mari F, Sadighi Akha E, et al. : Dual copy number variants involving 16p11 and 6q22 in a case of childhood apraxia of speech and pervasive developmental disorder. Eur J Hum Genet. 2013;21(4):361–365. 10.1038/ejhg.2012.166
    1. Newbury DF, Monaco AP, Paracchini S: Reading and language disorders: the importance of both quantity and quality. Genes (Basel). 2014;5(2):285–309. 10.3390/genes5020285
    1. Newbury DF, Paracchini S, Scerri TS, et al. : Investigation of dyslexia and SLI risk variants in reading- and language-impaired subjects. Behav Genet. 2011;41(1):90–104. 10.1007/s10519-010-9424-3
    1. Newbury DF, Simpson NH, Thompson PA, et al. : 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]. Wellcome Open Res. 2018;3:10. 10.12688/wellcomeopenres.13828.2
    1. Newbury DF, Winchester L, Addis L, et al. : CMIP and ATP2C2 modulate phonological short-term memory in language impairment. Am J Hum Genet. 2009;85(2):264–272. 10.1016/j.ajhg.2009.07.004
    1. Nielsen J, Wohlert M: Chromosome abnormalities found among 34,910 newborn children: results from a 13-year incidence study in Arhus, Denmark. Hum Genet. 1991;87(1):81–83. 10.1007/BF01213097
    1. Norbury CF, Gooch D, Wray C, et al. : The impact of nonverbal ability on prevalence and clinical presentation of language disorder: evidence from a population study. J Child Psychol Psychiatry. 2016;57(11):1247–1257. 10.1111/jcpp.12573
    1. Nowok B, Raab GM, Dibben C: synthpop: Bespoke Creation of Synthetic Data in R. J Stat Softw. 2016;74(11):1–26. 10.18637/jss.v074.i11
    1. Ott J: Association of genetic loci: replication or not, that is the question. Neurology. 2004;63(6):995–8. 10.1212/WNL.63.6.955
    1. Pampanos A, Volaki K, Kanavakis E, et al. : A substitution involving the NLGN4 gene associated with autistic behavior in the Greek population. Genet Test Mol Biomarkers. 2009;13(5):611–5. 10.1089/gtmb.2009.0005
    1. Phillips N: yarrr: A Companion to the e-Book "YaRrr!: The Pirate's Guide to R". R package version 0.1.5.2017.
    1. Price AL, Patterson NJ, Plenge RM, et al. : Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet. 2006;38(8):904–909. 10.1038/ng1847
    1. Purcell S, Neale B, Todd-Brown K, et al. : PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81(3):559–575. 10.1086/519795
    1. R Core Team: R: A language and environment for statistical computing.Vienna, Austria: R Foundation for Statistical Computing.2016.
    1. Rice ML, Zubrick SR, Taylor CL, et al. : Longitudinal Study of Language and Speech of Twins at 4 and 6 Years: Twinning Effects Decrease, Zygosity Effects Disappear, and Heritability Increases. J Speech Lang Hear Res. 2018;61(1):79–93. 10.1044/2017_JSLHR-L-16-0366
    1. Romdhani H, Grinek S, Hwang H, et al. : ASGSCA: Association Studies for multiple SNPs and multiple traits using Generalized Structured Equation Models.R package version 1.12.0.2014.
    1. Romdhani H, Hwang H, Paradis G, et al. : Pathway-based association study of multiple candidate genes and multiple traits using structural equation models. Genet Epidemiol. 2015;39(2):101–113. 10.1002/gepi.21872
    1. Ross JL, Roeltgen DP, Kushner H, et al. : Behavioral and social phenotypes in boys with 47,XYY syndrome or 47,XXY Klinefelter syndrome. Pediatrics. 2012;129(4):769–778. 10.1542/peds.2011-0719
    1. Scerri TS, Morris AP, Buckingham LL, et al. : DCDC2, KIAA0319 and CMIP are associated with reading-related traits. Biol Psychiatry. 2011;70(3):237–245. 10.1016/j.biopsych.2011.02.005
    1. Simmons JP, Nelson LD, Simonsohn U: A 21 word solution.2012. 10.2139/ssrn.2160588
    1. Simpson NH, Addis L, Brandler WM, et al. : Increased prevalence of sex chromosome aneuploidies in specific language impairment and dyslexia. Dev Med Child Neurol. 2014;56(4):346–353. 10.1111/dmcn.12294
    1. Simpson NH, Ceroni F, Reader RH, et al. : Genome-wide analysis identifies a role for common copy number variants in specific language impairment. Eur J Hum Genet. 2015;23(10):1370–7. 10.1038/ejhg.2014.296
    1. Skuse D: 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]. Wellcome Open Res. 2018;3:10. 10.21956/wellcomeopenres.15031.r31601
    1. Talebizadeh Z, Lam DY, Theodoro MF, et al. : Novel splice isoforms for NLGN3 and NLGN4 with possible implications in autism. J Med Genet. 2006;43(5):e21. 10.1136/jmg.2005.036897
    1. Tenenhaus M, Vinzi VE, Chatelin YM, et al. : PLS path modeling. Comput Stat Data Anal. 2005;48(1):159–205. 10.1016/j.csda.2004.03.005
    1. Thompson PA, Bishop DVM, Eising E, et al. : Generalized Structured Component Analysis in candidate gene association studies: applications and limitations [version 2; peer review: 3 approved]. Wellcome Open Res. 2020;4:142. 10.12688/wellcomeopenres.15396.2
    1. Torgesen JK, Wagner R, Rashotte C: Test of Word Reading Efficiency (TOWRE).New York: Psychological Corporation.1999.
    1. Vernes SC, Newbury DF, Abrahams BS, et al. : A functional genetic link between distinct developmental language disorders. N Engl J Med. 2008;359(22):2337–2345. 10.1056/NEJMoa0802828
    1. Vincent JB, Kolozsvari D, Roberts WS, et al. : Mutation screening of X-chromosomal neuroligin genes: no mutations in 196 autism probands. Am J Med Genet B Neuropsychiatr Genet. 2004;129B(1):82–84. 10.1002/ajmg.b.30069
    1. Wechsler D: Wechsler Abbreviated Scale of Intelligence.San Antonio: Psychological Corporation.1999.
    1. Weiner DJ, Wigdor EM, Ripke S, et al. : Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders. Nat Genet. 2017;49(7):978–85. 10.1038/ng.3863
    1. Whitehouse AJ, Bishop DV, Ang QW, et al. : CNTNAP2 variants affect early language development in the general population. Genes Brain Behav. 2011;10(4):451–6. 10.1111/j.1601-183X.2011.00684.x
    1. Wilson AC, Bishop DVM: Resounding failure to replicate links between developmental language disorder and cerebral lateralisation. PeerJ. 2018a;6:e4217. 10.7717/peerj.4217
    1. Wilson AC, Bishop DVM: Sex chromosome trisomies are not associated with atypical lateralization for language. Dev Med Child Neurol. 2018b;60(11):1123–1139. 10.1111/dmcn.13929
    1. Woodcock RW, McGrew KS, Mather N: Woodcock-Johnson III Tests of Cognitive Abilities.Rolling Meadows, IL Riverside Publishing.2007.
    1. Yan J, Feng J, Schroer R, et al. : Analysis of the neuroligin 4Y gene in patients with autism. Psychiatr Genet. 2008;18(4):204–207. 10.1097/YPG.0b013e3282fb7fe6
    1. Yan J, Oliveira G, Coutinho A, et al. : Analysis of the neuroligin 3 and 4 genes in autism and other neuropsychiatric patients. Mol Psychiatry. 2005;10(4):329–332. 10.1038/sj.mp.4001629
    1. Yanagi K, Kaname T, Wakui K, et al. : Identification of four novel synonymous substitutions in the x-linked genes neuroligin 3 and neuroligin 4X in japanese patients with autistic spectrum disorder. Autism Res Treat. 2012;2012: 724072. 10.1155/2012/724072
    1. Zhan X, Hu Y, Li B, et al. : RVTESTS: an efficient and comprehensive tool for rare variant association analysis using sequence data. Bioinformatics. 2016;32(9):1423–1426. 10.1093/bioinformatics/btw079
    1. Zweier C, de Jong EK, Zweier M, et al. : CNTNAP2 and NRXN1 are mutated in autosomal-recessive Pitt-Hopkins-like mental retardation and determine the level of a common synaptic protein in Drosophila. Am J Hum Genet. 2009;85(5):655–666. 10.1016/j.ajhg.2009.10.004

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