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Neurodevelopmental risk copy number variants in adults with intellectual disabilities and comorbid psychiatric disorders

  • Johan H. Thygesen (a1), Kate Wolfe (a1), Andrew McQuillin (a1), Marina Viñas-Jornet (a2), Neus Baena (a2), Nathalie Brison (a3), Greet D'Haenens (a4), Susanna Esteba-Castillo (a5), Elisabeth Gabau (a2), Núria Ribas-Vidal (a5), Anna Ruiz (a2), Joris Vermeesch (a6), Eddy Weyts (a4), Ramon Novell (a5), Griet Van Buggenhout (a7), André Strydom (a8), Nick Bass (a1), Miriam Guitart (a2) and Annick Vogels (a9)...

Copy number variants (CNVs) are established risk factors for neurodevelopmental disorders. To date the study of CNVs in psychiatric illness has focused on single disorder populations. The role of CNVs in individuals with intellectual disabilities and psychiatric comorbidities are less well characterised.


To determine the type and frequency of CNVs in adults with intellectual disabilities and comorbid psychiatric disorders.


A chromosomal microarray analysis of 599 adults recruited from intellectual disabilities psychiatry services at three European sites.


The yield of pathogenic CNVs was high – 13%. Focusing on established neurodevelopmental disorder risk loci we find a significantly higher frequency in individuals with intellectual disabilities and comorbid psychiatric disorder (10%) compared with healthy controls (1.2%, P<0.0001), schizophrenia (3.1%, P<0.0001) and intellectual disability/autism spectrum disorder (6.5%, P < 0.00084) populations.


In the largest sample of adults with intellectual disabilities and comorbid psychiatric disorders to date, we find a high rate of pathogenic CNVs. This has clinical implications for the use of genetic investigations in intellectual disability psychiatry.

Declaration of interest


Corresponding author
Correspondence: Annick Vogels, Department of Human Genetics, Centre for Human Genetics, University Hospitals Leuven, O&N I Herestraat 49 - Box 602, KU Leuven, 3000 Leuven, Belgium. Email:
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This work has not been presented previously, but a subset of data from 202 samples included here has previously been presented in Wolfe et al (2016), four cases in Vogels et al (2014) and one case in each of Vanmarsenille et al (2014), Denayer et al (2012) and Hannes et al (2009); see Supplementary File 1 (available at for the full references for these papers.


These authors contributed equally to the work as first authors.


These authors contributed equally to the work as last authors.

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1Vissers, LELM, Gilissen, C, Veltman, JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet 2015; 17: 918.
2Malhotra, D, Sebat, J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 2012; 148: 1223–41.
3Redon, R, Ishikawa, S, Fitch, KR, Feuk, L, Perry, GH, Andrews, TD, et al. Global variation in copy number in the human genome. Nature 2006; 444: 444–54.
4Marshall, CR, Howrigan, DP, Merico, D, Thiruvahindrapuram, B, Wu, W, Greer, DS, et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet 2017; 49: 2735.
5Sanders, S, Ercan-Sencicek, AG, Hus, V, Luo, R, Murtha, MT, Moreno-De-Luca, D, et al. Multiple recurrent de novo copy number variations (CNVs), including duplications of the 7q11.23 Williams-Beuren syndrome region, are strongly associated with autism. Neuron 2011; 70: 863–85.
6Coe, BP, Witherspoon, K, Rosenfeld, JA, van Bon, BWM, Vulto-van Silfhout, AT, Bosco, P, et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay. Nat Genet 2014; 46: 1063–71.
7Rees, E, Kendall, K, Pardiñas, AF, Legge, SE, Pocklington, A, Escott-Price, V, et al. Analysis of intellectual disability copy number variants for association with schizophrenia. JAMA Psychiatry 2016; 73: 963–9.
8Vorstman, JAS, Parr, JR, Moreno-De-Luca, D, Anney, RJL, Nurnberger, JI, Hallmayer, JF. Autism genetics: opportunities and challenges for clinical translation. Nat Rev Genet 2017; 18: 362–76.
9Palmer, E, Speirs, H, Taylor, PJ, Mullan, G, Turner, G, Einfeld, S, et al. Changing interpretation of chromosomal microarray over time in a community cohort with intellectual disability. Am J Med Genet A 2014; 164: 377–85.
10Miller, DT, Adam, MP, Aradhya, S, Biesecker, LG, Brothman, AR, Carter, NP, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 2010; 86: 749–64.
11World Health Organization. The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. WHO, 1992.
12American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorder (4th edn) (DSM-IV). APA, 1994.
13Kearney, HM, Thorland, EC, Brown, KK, Quintero-Rivera, F, South, ST. American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med 2011; 13: 680–5.
14Association for Clinical Genetic Science.Association for Clinical Genetic Science Best Practice Guidelines. ACGS, 2017 (
15Kendall, KM, Rees, E, Escott-Price, V, Einon, M, Thomas, R, Hewitt, J, et al. Cognitive performance among carriers of pathogenic copy number variants: analysis of 152,000 UK biobank subjects. Biol Psychiatry 2017; 82: 103–10.
16Perneger, TV. What's wrong with Bonferroni adjustments. BMJ 1998; 316: 1236–8.
17Rothman, KJ. No adjustments are needed for multiple comparisons. Epidemiology 1990; 1: 43–6.
18R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, 2013.
19Wolfe, K, Strydom, A, Morrogh, D, Carter, J, Cutajar, P, Eyeoyibo, M, et al. Chromosomal microarray testing in adults with intellectual disability presenting with comorbid psychiatric disorders. Eur J Hum Genet 2016; 25: 6672.
20Zuko, A, Kleijer, KTE, Oguro-ando, A, Kas, MJH, Daalen, EV, Zwaag, BVD, et al. Contactins in the neurobiology of autism. Eur J Pharmacol 2013; 719: 6374.
21Pinto, D, Pagnamenta, AT, Klei, L, Anney, R, Merico, D, Regan, R, et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 2010; 466: 368–72.
22Daalen, EV, Kemner, C, Verbeek, NE, Zwaag, BVD, Burbach, JPH, Kristian, H, et al. Social responsiveness scale-aided analysis of the clinical impact of copy number variations in autism. Neurogenetics 2011; 12: 315–23.
23Kashevarova, AA, Nazarenko, LP, Schultz-Pedersen, S, Skryabin, NA, Salyukova, OA, Chechetkina, NN, et al. Single gene microdeletions and microduplication of 3p26.3 in three unrelated families: CNTN6 as a new candidate gene for intellectual disability. Mol Cytogenet 2014; 7: 97.
24Hu, J, Liao, J, Sathanoori, M, Kochmar, S, Sebastian, J, Yatsenko, SA, et al. CNTN6 copy number variations in 14 patients: a possible candidate gene for neurodevelopmental and neuropsychiatric disorders. J Neurodev Disord 2015; 7: 26.
25Oguro-Ando, A, Zuko, A, Kleijer, KTE, Burbach, JPH. A current view on contactin-4, -5, and -6: implications in neurodevelopmental disorders. Mol Cell Neurosci 2017; 81: 7283.
26Warnica, W, Merico, D, Costain, G, Alfred, SE, Wei, J, Marshall, CR, et al. Copy number variable micrornas in schizophrenia and their neurodevelopmental gene targets. Biol Psychiatry 2015; 77: 158–66.
27Zahir, F, Firth, HV, Baross, A, Delaney, AD, Eydoux, P, Gibson, WT, et al. Novel deletions of 14q11.2 associated with developmental delay, cognitive impairment and similar minor anomalies in three children. J Med Genet 2007; 44: 556–61.
28Bernier, R, Golzio, C, Xiong, B, Stessman, Ha, Coe, BP, Penn, O, et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell 2014; 158: 263–76.
29Prontera, P, Ottaviani, V, Toccaceli, D, Rogaia, D, Ardisia, C, Romani, R, et al. Recurrent ~100 Kb microdeletion in the chromosomal region 14q11.2, involving CHD8 gene, is associated with autism and macrocephaly. Am J Med Genet A 2014; 164: 3137–41.
30Smyk, M, Poluha, A, Jaszczuk, I, Bartnik, M, Bernaciak, J, Nowakowska, B. Novel 14q11.2 microduplication including the CHD8 and SUPT16H genes associated with developmental delay. Am J Med Genet A 2016; 170: 1325–9.
31Breckpot, J, Vercruyssen, M, Weyts, E, Vandevoort, S, D'Haenens, G, Van Buggenhout, G, et al. Copy number variation analysis in adults with catatonia confirms haploinsufficiency of SHANK3 as a predisposing factor. Eur J Med Genet 2016; 59: 436–43.
32Courage, C, Houge, G, Gallati, S, Schjelderup, J, Rieubland, C. 15q26.1 microdeletion encompassing only CHD2 and RGMA in two adults with moderate intellectual disability, epilepsy and truncal obesity. Eur J Med Genet 2014; 57: 520–3.
33Chénier, S, Yoon, G, Argiropoulos, B, Lauzon, J, Laframboise, R, Ahn, J, et al. CHD2 haploinsufficiency is associated with developmental delay, intellectual disability, epilepsy and neurobehavioural problems. J Neurodev Disord 2014; 6: 9.
34Rees, E, Walters, JTR, Georgieva, L, Isles, AR, Chambert, KD, Richards, AL, et al. Analysis of copy number variations at 15 schizophrenia-associated loci. Br J Psychiatry 2014; 204: 108–14.
35Baker, K, Costain, G, Fung, WLA, Bassett, AS. Chromosomal microarray analysis—a routine clinical genetic test for patients with schizophrenia. Lancet Psychiatry 2014; 1: 329–31.
36Habel, A, Herriot, R, Kumararatne, D, Allgrove, J, Baker, K, Baxendale, H, et al. Towards a safety net for management of 22q11.2 deletion syndrome: Guidelines for our times. Eur J Pediatr 2014; 173: 757–65.
37Understanding Chromosome Disorders |(Unique). Unique - Disorder Guidelines. Unique, 2017 (
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Neurodevelopmental risk copy number variants in adults with intellectual disabilities and comorbid psychiatric disorders

  • Johan H. Thygesen (a1), Kate Wolfe (a1), Andrew McQuillin (a1), Marina Viñas-Jornet (a2), Neus Baena (a2), Nathalie Brison (a3), Greet D'Haenens (a4), Susanna Esteba-Castillo (a5), Elisabeth Gabau (a2), Núria Ribas-Vidal (a5), Anna Ruiz (a2), Joris Vermeesch (a6), Eddy Weyts (a4), Ramon Novell (a5), Griet Van Buggenhout (a7), André Strydom (a8), Nick Bass (a1), Miriam Guitart (a2) and Annick Vogels (a9)...
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