Genomic Structural Variants pp 77-95

Part of the Methods in Molecular Biology book series (MIMB, volume 838)

Structural Genomic Variation in Intellectual Disability

Protocol

Abstract

The genetic causes of mental retardation are highly heterogeneous and for a large proportion unknown. Mutations as well as large chromosomal abnormalities are known to contribute to mental retardation, and recently more subtle structural genomic variations have been shown to contribute significantly to this common and complex disorder. Genomic microarrays with increasing resolution levels have revealed the presence of rare de novo CNVs in approximately 15% of all mentally retarded patients. Microarray-based CNV screening is rapidly replacing conventional karyotyping in the diagnostic workflow, resulting in an increased diagnostic yield as well as biological insight into this disorder. In this chapter, an overview is given of the detection and interpretation of copy number variations in mental retardation, with a focus on diagnostic applications. In addition, a detailed protocol is provided for the diagnostic interpretation of copy-number variations in mental retardation.

Key words

Copy-number variation Intellectual disability Genomic microarrays Genetic diagnosis 

References

  1. 1.
    Leonard H and Wen X (2002) The epidemiology of mental retardation: challenges and opportunities in the new millennium. Ment Retard Dev Disabil Res Rev 8, 1174.PubMedCrossRefGoogle Scholar
  2. 2.
    Luckasson R, Reeve A. (2001) Naming, defining, and classifying in mental retardation. Ment Retard. 39, 47–52.PubMedCrossRefGoogle Scholar
  3. 3.
    de Vries BB, van den Ouweland AM, Mohkamsing S, Duivenvoorden HJ, Mol E, Gelsema K, van RM, Halley DJ, Sandkuijl LA, Oostra BA, Tibben A, and Niermeijer MF (1997) Screening and diagnosis for the fragile X syndrome among the mentally retarded: an epidemiological and psychological survey. Collaborative Fragile X Study Group. Am J Hum Genet 61, 660–7.Google Scholar
  4. 4.
    Moog U (2005) The outcome of diagnostic studies on the etiology of mental retardation: considerations on the classification of the causes. Am J Med Genet A 137, 228–31.PubMedGoogle Scholar
  5. 5.
    Rauch A, Hoyer J, Guth S, Zweier C, Kraus C, Becker C, Zenker M, Huffmeier U, Thiel C, Ruschendorf F, Nurnberg P, Reis A, and Trautmann U (2006) Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet A 140, 2063–74.PubMedGoogle Scholar
  6. 6.
    Ropers HH and Hamel BC (2005) X-linked mental retardation. Nat Rev Genet 6, 46–57.PubMedCrossRefGoogle Scholar
  7. 7.
    Gécz J, Shoubridge C, Corbett M (2009) The genetic landscape of intellectual disability arising from chromosome X. Trends Genet 25, 308–16.PubMedCrossRefGoogle Scholar
  8. 8.
    Graham SM, Selikowitz M (1993) Chromosome testing in children with developmental delay in whom the aetiology is not evident clinically. J Paediatr Child Health 29, 360–2.PubMedCrossRefGoogle Scholar
  9. 9.
    van Karnebeek CD, Jansweijer MC, Leenders AG, Offringa M, Hennekam RC (2005) Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet 13, 6–25.PubMedCrossRefGoogle Scholar
  10. 10.
    Shapira SK (1998) An update on chromosome deletion and microdeletion syndromes. Curr Opin Pediatr 10, 622–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Flint J, Wilkie AO, Buckle VJ, Winter RM, Holland AJ, McDermid HE (1995) The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nat Genet 9, 132–40.PubMedCrossRefGoogle Scholar
  12. 12.
    De Vries BB, Winter R, Schinzel A, van Ravenswaaij-Arts C. (2003) Telomeres: a diagnosis at the end of the chromosomes. J Med Genet 40, 385–98.PubMedCrossRefGoogle Scholar
  13. 13.
    Veltman JA, Schoenmakers EF, Eussen BH, Janssen I, Merkx G, van Cleef B, van Ravenswaaij CM, Brunner HG, Smeets D, Geurts van Kessel AG (2002) High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization. Am J Hum Genet 70, 1269–76.PubMedCrossRefGoogle Scholar
  14. 14.
    Vissers LE, de Vries BB, Osoegawa K, Janssen IM, Feuth T, Choy CO, Straatman H, van der Vliet W, Huys EH, van Rijk A, Smeets D, van Ravenswaaij-Arts CM, Knoers NV, van der Burgt I, de Jong PJ, Brunner HG, Geurts van Kessel A, Schoenmakers EF, Veltman JA (2003) Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. Am J Hum Genet 73, 1261–70.PubMedCrossRefGoogle Scholar
  15. 15.
    Shaw-Smith C, Redon R, Rickman L, Rio M, Willatt L, Fiegler H, Firth H, Sanlaville D, Winter R, Colleaux L, Bobrow M, Carter NP (2004) Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features. J Med Genet 41, 241–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Schoumans J, Ruivenkamp C, Holmberg E, Kyllerman M, Anderlid BM, Nordenskjöld M (2005) Detection of chromosomal imbalances in children with idiopathic mental retardation by array based comparative genomic hybridisation (array-CGH). J Med Genet 42, 699–705.PubMedCrossRefGoogle Scholar
  17. 17.
    Tyson C, Harvard C, Locker R, Friedman JM, Langlois S, Lewis ME, Van Allen M, Somerville M, Arbour L, Clarke L, McGilivray B, Yong SL, Siegel-Bartel J, Rajcan-Separovic E (2005) Submicroscopic deletions and duplications in individuals with intellectual disability detected by array-CGH. Am J Med Genet A 139, 173–85.PubMedGoogle Scholar
  18. 18.
    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 mental retardation and multiple congenital anomalies: a new series of 140 patients and review of published reports. J Med Genet 43, 625–33.PubMedCrossRefGoogle Scholar
  19. 19.
    Rosenberg C, Knijnenburg J, Bakker E, Vianna-Morgante AM, Sloos W, Otto PA, Kriek M, Hansson K, Krepischi-Santos AC, Fiegler H, Carter NP, Bijlsma EK, van Haeringen A, Szuhai K, Tanke HJ (2006) Array-CGH detection of micro rearrangements in mentally retarded individuals: clinical significance of imbalances present both in affected children and normal parents. J Med Genet 43, 180–6.PubMedCrossRefGoogle Scholar
  20. 20.
    de Vries BB, Pfundt R, Leisink M, Koolen DA, Vissers LE, Janssen IM, Reijmersdal S, Nillesen WM, Huys EH, Leeuw N, Smeets D, Sistermans EA, Feuth T, van Ravenswaaij-Arts CM, Geurts van Kessel A, Schoenmakers EF, Brunner HG, Veltman JA (2005) Diagnostic genome profiling in mental retardation. Am J Hum Genet 77, 606–16.CrossRefGoogle Scholar
  21. 21.
    Veltman JA. Genomic microarrays in clinical diagnosis (2006) Curr Opin Pediatr 18, 598–603.PubMedCrossRefGoogle Scholar
  22. 22.
    Knight SJ, Regan R (2006) Idiopathic learning disability and genome imbalance. Cytogenet Genome Res 115, 215–24.PubMedCrossRefGoogle Scholar
  23. 23.
    Koolen DA, Pfundt R, de Leeuw N, Hehir-Kwa JY, Nillesen WM, Neefs I, Scheltinga I, Sistermans E, Smeets D, Brunner HG, Geurts van Kessel A, Veltman JA, de Vries BB (2009) Genomic microarrays in mental retardation: a practical workflow for diagnostic applications. Hum Mutation 30, 283–92.CrossRefGoogle Scholar
  24. 24.
    Hehir-Kwa JY, Egmont-Petersen M, Janssen IM, Smeets D, Geurts van Kessel A, Veltman JA (2007) Genome-wide copy number profiling on high-density BAC, SNP and oligonucleotide microarrays: a platform comparison based on statistical power analysis. DNA research 14, 1–11.PubMedCrossRefGoogle Scholar
  25. 25.
    McMullan DJ, Bonin M, Hehir-Kwa JY, de Vries BB, Dufke A, Rattenberry E, Steehouwer M, Moruz L, Pfundt R, de Leeuw N, Riess A, Altug-Teber O, Enders H, Singer S, Grasshoff U, Walter M, Walker JM, Lamb CV, Davison EV, Brueton L, Riess O, Veltman JA (2009) Molecular karyotyping of patients with unexplained mental retardation by SNP arrays: A multicenter study. Hum Mutation 30, 1082–92.CrossRefGoogle Scholar
  26. 26.
    De Gregori M, Ciccone R, Magini P, Pramparo T, Gimelli S, Messa J, Novara F, Vetro A, Rossi E, Maraschio P, Bonaglia MC, Anichini C, Ferrero GB, Silengo M, Fazzi E, Zatterale A, Fischetto R, Previderé C, Belli S, Turci A, Calabrese G, Bernardi F, Meneghelli E, Riegel M, Rocchi M, Guerneri S, Lalatta F, Zelante L, Romano C, Fichera M, Mattina T, Arrigo G, Zollino M, Giglio S, Lonardo F, Bonfante A, Ferlini A, Cifuentes F, Van Esch H, Backx L, Schinzel A, Vermeesch JR, Zuffardi O (2007). Cryptic deletions are a common finding in “balanced” reciprocal and complex chromosome rearrangements: a study of 59 patients. J Med Genet 44, 750–62.PubMedCrossRefGoogle Scholar
  27. 27.
    Hochstenbach R, van Binsbergen E, Engelen J, Nieuwint A, Polstra A, Poddighe P, Ruivenkamp C, Sikkema-Raddatz B, Smeets D, Poot M (2009). Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. Eur J Med Genet 52(4), 161–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Schluth-Bolard C, Delobel B, Sanlaville D, Boute O, Cuisset JM, Sukno S, Labalme A, Duban-Bedu B, Plessis G, Jaillard S, Dubourg C, Henry C, Lucas J, Odent S, Pasquier L, Copin H, Latour P, Cordier MP, Nadeau G, Till M, Edery P, Andrieux J (2009) Cryptic genomic imbalances in de novo and inherited apparently balanced chromosomal rearrangements: array CGH study of 47 unrelated cases. Eur J Med Genet 52, 291–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Levy S, Sutton G, Ng PC, Feuk L, Halpern AL, Walenz BP, Axelrod N, Huang J,Kirkness EF, Denisov G, Lin Y, MacDonald JR, Pang AW, Shago M, Stockwell TB, Tsiamouri A, Bafna V, Bansal V, Kravitz SA, Busam DA, Beeson KY, McIntosh TC, Remington KA, Abril JF, Gill J, Borman J, Rogers YH, Frazier ME, Scherer SW, Strausberg RL, Venter JC (2007) The Diploid Genome Sequence of an Individual Human. PLoS Biol 5, e254.PubMedCrossRefGoogle Scholar
  30. 30.
    Korbel JO, Urban AE, Affourtit JP, Godwin B, Grubert F, Simons JF, Kim PM, Palejev D, Carriero NJ, Du L, Taillon BE, Chen Z, Tanzer A, Saunders AC, Chi J, Yang F, Carter NP, Hurles ME, Weissman SM, Harkins TT, Gerstein MB, Egholm M, Snyder M (2007) Paired-End Mapping Reveals Extensive Structural Variation in the Human Genome. Science 318, 420–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Conrad DF, Pinto D, Redon R, Feuk L, Gokcumen O, Zhang Y, Aerts J, Andrews TD, Barnes C, Campbell P, Fitzgerald T, Hu M, Ihm CH, Kristiansson K, Macarthur DG, Macdonald JR, Onyiah I, Pang AW, Robson S, Stirrups K, Valsesia A, Walter K, Wei J; Wellcome Trust Case Control Consortium, Tyler-Smith C, Carter NP, Lee C, Scherer SW, Hurles ME (2010) Origins and functional impact of copy number variation in the human genome. Nature 464, 704–12.CrossRefGoogle Scholar
  32. 32.
    Lee C, Iafrate AJ, Brothman AR (2007) Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nat Genet 39, S48–54.PubMedCrossRefGoogle Scholar
  33. 33.
    Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, Van Vooren S, Moreau Y, Pettett RM, Carter NP (2009) DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet 84, 524–33.PubMedCrossRefGoogle Scholar
  34. 34.
    Feenstra I, Fang J, Koolen DA, Siezen A, Evans C, Winter RM, Lees MM, Riegel M, de Vries BB, Van Ravenswaaij CM, Schinzel A (2006) European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA); an online database for rare chromosome abnormalities. Eur J Med Genet 49, 279–91.PubMedCrossRefGoogle Scholar
  35. 35.
    Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, González JR, Gratacòs M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME (2006) Global variation in copy number in the human genome. Nature 444, 444–54.PubMedCrossRefGoogle Scholar
  36. 36.
    Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, Sahoo T, Lalani SR, Graham B, Lee B, Shinawi M, Shen J, Kang SH, Pursley A, Lotze T, Kennedy G, Lansky-Shafer S, Weaver C, Roeder ER, Grebe TA, Arnold GL, Hutchison T, Reimschisel T, Amato S, Geragthy MT, Innis JW, Obersztyn E, Nowakowska B, Rosengren SS, Bader PI, Grange DK, Naqvi S, Garnica AD, Bernes SM, Fong CT, Summers A, Walters WD, Lupski JR, Stankiewicz P, Cheung SW, Patel A. (2008) Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet 40, 1466–71.PubMedCrossRefGoogle Scholar
  37. 37.
    Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, Buysse K, Huang S, Maloney VK, Crolla JA, Baralle D, Collins A, Mercer C, Norga K, de Ravel T, Devriendt K, Bongers EM, de Leeuw N, Reardon W, Gimelli S, Bena F, Hennekam RC, Male A, Gaunt L, Clayton-Smith J, Simonic I, Park SM, Mehta SG, Nik-Zainal S, Woods CG, Firth HV, Parkin G, Fichera M, Reitano S, Lo Giudice M, Li KE, Casuga I, Broomer A, Conrad B, Schwerzmann M, Räber L, Gallati S, Striano P, Coppola A, Tolmie JL, Tobias ES, Lilley C, Armengol L, Spysschaert Y, Verloo P, De Coene A, Goossens L, Mortier G, Speleman F, van Binsbergen E, Nelen MR, Hochstenbach R, Poot M, Gallagher L, Gill M, McClellan J, King MC, Regan R, Skinner C, Stevenson RE, Antonarakis SE, Chen C, Estivill X, Menten B, Gimelli G, Gribble S, Schwartz S, Sutcliffe JS, Walsh T, Knight SJ, Sebat J, Romano C, Schwartz CE, Veltman JA, de Vries BB, Vermeesch JR, Barber JC, Willatt L, Tassabehji M, Eichler EE. (2008) Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes. N Engl J Med 359, 1685–99.PubMedCrossRefGoogle Scholar
  38. 38.
    Sharp AJ, Mefford HC, Li K, Baker C, Skinner C, Stevenson RE, Schroer RJ, Novara F, De Gregori M, Ciccone R, Broomer A, Casuga I, Wang Y, Xiao C, Barbacioru C, Gimelli G, Bernardina BD, Torniero C, Giorda R, Regan R, Murday V, Mansour S, Fichera M, Castiglia L, Failla P, Ventura M, Jiang Z, Cooper GM, Knight SJ, Romano C, Zuffardi O, Chen C, Schwartz CE, Eichler EE (2008) A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 40, 322–328.PubMedCrossRefGoogle Scholar
  39. 39.
    van Bon BW, Mefford HC, Menten B, Koolen DA, Sharp AJ, Nillesen WM, Innis JW, de Ravel TJ, Mercer CL, Fichera M, Stewart H, Connell LE, Ounap K, Lachlan K, Castle B, Van der Aa N, van Ravenswaaij C, Nobrega MA, Serra-Juhé C, Simonic I, de Leeuw N, Pfundt R, Bongers EM, Baker C, Finnemore P, Huang S, Maloney VK, Crolla JA, van Kalmthout M, Elia M, Vandeweyer G, Fryns JP, Janssens S, Foulds N, Reitano S, Smith K, Parkel S, Loeys B, Woods CG, Oostra A, Speleman F, Pereira AC, Kurg A,Willatt L, Knight SJ, Vermeesch JR, Romano C, Barber JC, Mortier G, Pérez-Jurado LA, Kooy F, Brunner HG, Eichler EE, Kleefstra T, de Vries BB (2009) Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 46: 511–23.CrossRefGoogle Scholar
  40. 40.
    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. Human Mutation 28, 674–82.PubMedCrossRefGoogle Scholar
  41. 41.
    Hannes FD, Sharp AJ, Mefford HC, de Ravel T, Ruivenkamp CA, Breuning MH, Fryns JP, Devriendt K, Van Buggenhout G, Vogels A, Stewart H, Hennekam RC, Cooper GM, Regan R, Knight SJ, Eichler EE, Vermeesch JR (2008) Recurrent reciprocal deletions and duplications of 16p13.11: The deletion is a risk factor for MR/MCA while the duplication may be a rare benign variant. J Med Genet 46, 223–32.PubMedCrossRefGoogle Scholar
  42. 42.
    Webber C, Hehir-Kwa JY, Nguyen DQ, de Vries BBA, Veltman JA, Ponting CP (2009) Forging links between human mental retardation-associated CNVs and mouse gene knockout models. PLoS Genetics 5, e1000531.PubMedCrossRefGoogle Scholar
  43. 43.
    Hehir-Kwa JY, Wieskamp N, Webber C, Pfundt R, Brunner HG, Gilissen C, de Vries BBA, Ponting CP, Veltman JA (2010) Accurate distinction of pathogenic from benign CNVs in Mental Retardation. PLoS Computational Biology 6, e1000752.PubMedCrossRefGoogle Scholar
  44. 44.
    Girirajan S, Rosenfeld JA, Cooper GM, Antonacci F, Siswara P, Itsara A, Vives L, Walsh T, McCarthy SE, Baker C, Mefford HC, Kidd JM, Browning SR, Browning BL, Dickel DE, Levy DL, Ballif BC, Platky K, Farber DM, Gowans GC, Wetherbee JJ, Asamoah A, Weaver DD, Mark PR, Dickerson J, Garg BP, Ellingwood SA, Smith R, Banks VC, Smith W, McDonald MT, Hoo JJ, French BN, Hudson C, Johnson JP, Ozmore JR, Moeschler JB, Surti U, Escobar LF, El-Khechen D, Gorski JL, Kussmann J, Salbert B, Lacassie Y, Biser A, McDonald-McGinn DM, Zackai EH, Deardorff MA, Shaikh TH, Haan E, Friend KL, Fichera M, Romano C, Gécz J, DeLisi LE, Sebat J, King MC, Shaffer LG, Eichler EE (2010) A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nat Genet 42, 203–9.PubMedCrossRefGoogle Scholar

Web Resources

  1. Database of Genomic Variation: http://projects.tcag.ca/variation
  2. DatabasE of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER): https://decipher.sanger.ac.uk/information
  3. European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA): www.ecaruca.net
  4. Genomic Classification of CNVs Objectively (GECCO) http://genomegecco.sourceforge.net

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Human Genetics, Nijmegen Centre for Molecular Life SciencesRadboud University Nijmegen Medical CentreNijmegenThe Netherlands

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