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Array-CGH in children with mild intellectual disability: a population-based study

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Intellectual disability (ID) is characterized by limitation in intellectual function and adaptive behavior, with onset in childhood. Frequent identifiable causes of ID originate from chromosomal imbalances. During the last years, array-CGH has successfully contributed to improve the diagnostic detection rate of genetic abnormalities in patients with ID. Most array-CGH studies focused on patients with moderate or severe intellectual disability. Studies on genetic etiology in children with mild intellectual disability (ID) are very rare. We performed array-CGH analysis in 66 children with mild intellectual disability assessed in a population-based study and for whom no genetic etiology was identified. We found one or more copy number variations (CNVs) in 20 out of 66 (~30 %) patients with a mild ID. In eight of them (~12 %), the CNVs were certainly responsible for the phenotype and in six they were potentially pathogenic for ID. Altogether, array-CGH helped to determine the etiology of ID in 14 patients (~21 %). Conclusion: Our results underscore the clinical relevance of array-CGH to investigate the etiology of isolated idiopathic mild ID in patients or associated with even subtle dysmorphic features or congenital malformations.

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American Association on Intellectual and Developmental Disabilities


Angiotensin II receptor, type 2


Rho GTPase activating protein 24

CDH13 :

Cadherin 13


Comparative genomic hybridization


Copy number variations


Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources


Database of genomic variants




Fluorescence in situ hybridization

GPR87 :

G protein-coupled receptor 87


Hepatic and glial cell adhesion molecule


Intellectual disability


Intelligence quotient


Kaufman Assessment Battery for Children


Maison Départementale des Personnes Handicapées

MED12L :

Mediator complex subunit 12-like

MED12 :

Mediator complex subunit 12

MED13 :

Mediator complex subunit 13

MED13L :

Mediator complex subunit 13-like

MED17 :

Mediator complex subunit 17

MED23 :

Mediator complex subunit 23


Multiplex ligation-dependent probe amplification


National center for biotechnology information


Oculocerebrorenal syndrome of Lowe


Online Mendelian Inheritance in Man

P2RY :

Purinergic receptor P2Y

P2RY12 :

Purinergic receptor P2Y, G-protein coupled, 12

P2RY13 :

Purinergic receptor P2Y, G-protein coupled, 13

P2RY14 :

Purinergic receptor P2Y, G-protein coupled, 114


Registre du Handicap Et Observatoire Périnatal

TMEM130 :

Transmembrane protein 130


Transformation/transcription domain-associated protein


University of California, Santa Cruz


Variant of unknown significance


Wechsler Intelligence Scale for Children


Wechsler Preschool and Primary Scale of Intelligence Revised


  1. Asadollahi R, Oneda B, Sheth F, Azzarello-Burri S, Baldinger R, Joset P, Latal B, Knirsch W, Desai S, Baumer A, Houge G, Andrieux J, Rauch A (2013) Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability. Eur J Hum Genet 21:1100–1104

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Bartnik M, Nowakowska B, Derwińska K, Wiśniowiecka-Kowalnik B, Kędzior M, Bernaciak J, Ziemkiewicz K, Gambin T, Sykulski M, Bezniakow N, Korniszewski L, Kutkowska-Kaźmierczak A, Klapecki J, Szczałuba K, Shaw CA, Mazurczak T, Gambin A, Obersztyn E, Bocian E, Stankiewicz P (2014) Application of array comparative genomic hybridization in 256 patients with developmental delay or intellectual disability. J Appl Genet 55:125–144

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Beaudet AL (2013) The utility of chromosomal microarray analysis in developmental and behavioral pediatrics. Child Dev 84:121–132

    Article  PubMed  Google Scholar 

  4. Boutry-Kryza N, Labalme A, Till M, Schluth-Bolard C, Langue J, Turleau C, Edery P, Sanlaville D (2012) An 800 kb deletion at 17q23.2 including the MED13 (THRAP1) gene, revealed by aCGH in a patient with a SMC 17p. Am J Med Genet A 158A:400–405

    Article  PubMed  Google Scholar 

  5. Coutton C, Monnier N, Rendu J, Lunardi J (2010) Development of a multiplex ligation-dependent probe amplification (MLPA) assay for quantification of the OCRL1 gene. Clin Biochem 43:609–614

    Article  CAS  PubMed  Google Scholar 

  6. David M, Dieterich K, Billette de Villemeur A, Jouk PS, Counillon J, Larroque B, Bloch J, Cans C (2014) Prevalence and characteristics of children with mild intellectual disability in a French county. J Intellect Disabil Res

  7. des Portes V, Livet MO, Vallée L, Groupe de travail de la Société française de neuropédiatrie (SFNP) sur les retards mentaux (2002) A practical diagnostic approach to mental deficiency in 2002. Arch Pediatr 9:709–725

    Article  PubMed  Google Scholar 

  8. Dixit A, McKee S, Mansour S, Mehta SG, Tanteles GA, Anastasiadou V, Patsalis PC, Martin K, McCullough S, Suri M, Sarkar A (2013) 7q11.23 Microduplication: a recognizable phenotype. Clin Genet 83:155–161

    Article  CAS  PubMed  Google Scholar 

  9. Franke B, Faraone SV, Asherson P, Buitelaar J, Bau CH, Ramos-Quiroga JA, Mick E, Grevet EH, Johansson S, Haavik J, Lesch KP, Cormand B, Reif A (2012) International Multicentre persistent ADHD Collaboration. The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry 17:960–987

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Girirajan S, Rosenfeld JA, Coe BP, Parikh S, Friedman N, Goldstein A, Filipink RA, McConnell JS, Angle B, Meschino WS, Nezarati MM, Asamoah A, Jackson KE, Gowans GC, Martin JA, Carmany EP, Stockton DW, Schnur RE, Penney LS, Martin DM, Raskin S, Leppig K, Thiese H, Smith R, Aberg E, Niyazov DM, Escobar LF, El-Khechen D, Johnson KD, Lebel RR, Siefkas K, Ball S, Shur N, McGuire M, Brasington CK, Spence JE, Martin LS, Clericuzio C, Ballif BC, Shaffer LG, Eichler EE (2012) Phenotypic heterogeneity of genomic disorders and rare copy-number variants. N Engl J Med 367:1321–1331

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Hagberg B, Kyllerman M (1983) Epidemiology of mental retardation—a Swedish survey. Brain Dev 5:441–449

    Article  CAS  PubMed  Google Scholar 

  12. Hashimoto S, Boissel S, Zarhrate M, Rio M, Munnich A, Egly JM, Colleaux L (2011) MED23 mutation links intellectual disability to dysregulation of immediate early gene expression. Science 333:1161–1163

    Article  CAS  PubMed  Google Scholar 

  13. Hatton C (2012) Intellectual disabilities – Classification, epidemiology and causes. Clinical Psychology and People with Intellectual Disabilities, Second Edition, Chapter 1:3–22

  14. Katoh Y, Katoh M (2004) Identification and characterization of ARHGAP27 gene in silico. Int J Mol Med 14:943–947

    CAS  PubMed  Google Scholar 

  15. Kaufmann R, Straussberg R, Mandel H, Fattal-Valevski A, Ben-Zeev B, Naamati A, Shaag A, Zenvirt S, Konen O, Mimouni-Bloch A, Dobyns WB, Edvardson S, Pines O, Elpeleg O (2010) Infantile cerebral and cerebellar atrophy is associated with a mutation in the MED17 subunit of the transcription preinitiation mediator complex. Am J Hum Genet 87:667–670

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Kearney HM, Thorland EC, Brown KK, Quintero-Rivera F, South ST, Working Group of the American College of Medical Genetics Laboratory Quality Assurance Committee (2011) American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genet Med 13:680–685

    Article  PubMed  Google Scholar 

  17. Lu XY, Phung MT, Shaw CA, Pham K, Neil SE, Patel A, Sahoo T, Bacino CA, Stankiewicz P, Kang SH, Lalani S, Chinault AC, Lupski JR, Cheung SW, Beaudet AL (2008) Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis. Pediatrics 122:1310–1318

    Article  PubMed Central  PubMed  Google Scholar 

  18. Mavroconstanti T, Johansson S, Winge I, Knappskog PM, Haavik J (2013) Functional properties of rare missense variants of human CDH13 found in adult attention deficit/hyperactivity disorder (ADHD) patients. PLoS One 8:e71445

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Menten B, Maas N, Thienpont B, Buysse K, Vandesompele J, Melotte C, de Ravel T, Van Vooren S, Balikova I, Backx L, Janssens S, De Paepe A, De Moor B, Moreau Y, Marynen P, Fryns JP, Mortier G, Devriendt K, Speleman F, Vermeesch JR (2006) Emerging patterns of cryptic chromosomal imbalance in patients with idiopathic intellectual disability and multiple congenital anomalies: a new series of 140 patients and review of published reports. J Med Genet 43:625–633

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 86:749–764

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Nguyen LS, Jolly L, Shoubridge C, Chan WK, Huang L, Laumonnier F, Raynaud M, Hackett A, Field M, Rodriguez J, Srivastava AK, Lee Y, Long R, Addington AM, Rapoport JL, Suren S, Hahn CN, Gamble J, Wilkinson MF, Corbett MA, Gecz J (2012) Transcriptome profiling of UPF3B/NMD-deficient lymphoblastoid cells from patients with various forms of intellectual disability. Mol Psychiatry 17:1103–1115

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. O'Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP, Levy R, Ko A, Lee C, Smith JD, Turner EH, Stanaway IB, Vernot B, Malig M, Baker C, Reilly B, Akey JM, Borenstein E, Rieder MJ, Nickerson DA, Bernier R, Shendure J, Eichler EE (2012) Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485:246–250

    Article  PubMed Central  PubMed  Google Scholar 

  23. Portnoï MF (2009) Microduplication 22q11.2: a new chromosomal syndrome. Eur J Med Genet 52:88–93

    Article  PubMed  Google Scholar 

  24. Ramalingam A, Zhou XG, Fiedler SD, Brawner SJ, Joyce JM, Liu HY, Yu S (2011) 16p13.11 duplication is a risk factor for a wide spectrum of neuropsychiatric disorders. J Hum Genet 56:541–544

    Article  CAS  PubMed  Google Scholar 

  25. Rivero O, Sich S, Popp S, Schmitt A, Franke B, Lesch KP (2013) Impact of the ADHD-susceptibility gene CDH13 on development and function of brain networks. Eur Neuropsychopharmacol 23:492–507

    Article  CAS  PubMed  Google Scholar 

  26. Sagoo GS, Butterworth AS, Sanderson S, Shaw-Smith C, Higgins JP, Burton H (2009) Array CGH in patients with learning disability (mental retardation) and congenital anomalies: updated systematic review and meta-analysis of 19 studies and 13,926 subjects. Genet Med 11:139–146

    Article  CAS  PubMed  Google Scholar 

  27. Sato S, Tomomori-Sato C, Parmely TJ, Florens L, Zybailov B, Swanson SK, Banks CA, Jin J, Cai Y, Washburn MP, Conaway JW, Conaway RC (2004) A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology. Mol Cell 14:685–691

    Article  CAS  PubMed  Google Scholar 

  28. Schwartz CE, Tarpey PS, Lubs HA, Verloes A, May MM, Risheg H, Friez MJ, Futreal PA, Edkins S, Teague J, Briault S, Skinner C, Bauer-Carlin A, Simensen RJ, Joseph SM, Jones JR, Gecz J, Stratton MR, Raymond FL, Stevenson RE (2007) The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene. J Med Genet 44:472–477

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Simonoff E, Pickles A, Chadwick O, Gringras P, Wood N, Higgins S, Maney JA, Karia N, Iqbal H, Moore A (2006) The Croydon assessment of learning study: prevalence and educational identification of mild mental retardation. J Child Psychol Psychiatry 47:828–839

    Article  PubMed  Google Scholar 

  30. Stankiewicz P, Beaudet AL (2007) Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev 17:182–192

    Article  CAS  PubMed  Google Scholar 

  31. Stromme P, Valvatne K (1998) Mental retardation in Norway: prevalence and sub-classification in a cohort of 30037 children born between 1980 and 1985. Acta Paediatr 87:291–296

    Article  CAS  PubMed  Google Scholar 

  32. Tassé MJ, Luckasson R, Nygren M (2013) AAIDD proposed recommendations for ICD-11 and the condition previously known as mental retardation. Intellect Dev Disabil 51:127–131

    Article  PubMed  Google Scholar 

  33. Tropeano M, Ahn JW, Dobson RJ, Breen G, Rucker J, Dixit A, Pal DK, McGuffin P, Farmer A, White PS, Andrieux J, Vassos E, Ogilvie CM, Curran S, Collier DA (2013) Male-biased autosomal effect of 16p13.11 copy number variation in neurodevelopmental disorders. PLoS One 8:e61365

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Ullmann R, Turner G, Kirchhoff M, Chen W, Tonge B, Rosenberg C, Field M, Vianna-Morgante AM, Christie L, Krepischi-Santos AC, Banna L, Brereton AV, Hill A, Bisgaard AM, Müller I, Hultschig C, Erdogan F, Wieczorek G, Ropers HH (2007) Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum Mutat 28:674–682

    Article  CAS  PubMed  Google Scholar 

  35. Vincent JB, Choufani S, Horike S, Stachowiak B, Li M, Dill FJ, Marshall C, Hrynchak M, Pewsey E, Ukadike KC, Friedman JM, Srivastava AK, Scherer SW (2008) A translocation t(6;7)(p11-p12;q22) associated with autism and mental retardation: localization and identification of candidate genes at the breakpoints. Psychiatr Genet 18:101–109

    Article  PubMed  Google Scholar 

  36. Wiśniowiecka-Kowalnik B, Kastory-Bronowska M, Bartnik M, Derwińska K, Dymczak-Domini W, Szumbarska D, Ziemka E, Szczałuba K, Sykulski M, Gambin T, Gambin A, Shaw CA, Mazurczak T, Obersztyn E, Bocian E, Stankiewicz P (2013) Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders. Eur J Hum Genet 21:620–625

    Article  PubMed Central  PubMed  Google Scholar 

  37. World Health Organization (2001) International classification of functioning, disability and health. World Health Organization, Geneva

    Google Scholar 

  38. Xu B, Ionita-Laza I, Roos JL, Boone B, Woodrick S, Sun Y, Levy S, Gogos JA, Karayiorgou M (2012) De novo gene mutations highlight patterns of genetic and neural complexity in schizophrenia. Nat Genet 44:1365–1369

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Xu H, Poh WT, Sim X, Ong RT, Suo C, Tay WT, Khor CC, Seielstad M, Liu J, Aung T, Tai ES, Wong TY, Chia KS, Teo YY (2011) SgD-CNV, a database for common and rare copy number variants in three Asian populations. Hum Mutat 32:1341–1349

    Article  CAS  PubMed  Google Scholar 

  40. Yu HE, Hawash K, Picker J, Stoler J, Urion D, Wu BL, Shen Y (2012) A recurrent 1.71 Mb genomic imbalance at 2q13 increases the risk of developmental delay and dysmorphism. Clin Genet 81:257–264

    Article  CAS  PubMed  Google Scholar 

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We thank family members for their interest and cooperation. This study was supported by grants from the French Ministry (DHOS).

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Correspondence to Charles Coutton.

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Communicated by Beat Steinmann

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Coutton, C., Dieterich, K., Satre, V. et al. Array-CGH in children with mild intellectual disability: a population-based study. Eur J Pediatr 174, 75–83 (2015).

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