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Vol. 135, No. 3-4, 2011
Issue release date: December 2011
Cytogenet Genome Res 2011;135:212–221

SNP Array Analysis in Constitutional and Cancer Genome Diagnostics – Copy Number Variants, Genotyping and Quality Control

de Leeuw N. · Hehir-Kwa J.Y. · Simons A. · Geurts van Kessel A. · Smeets D.F. · Faas B.H.W. · Pfundt R.
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

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Array-based comparative genomic hybridization analysis of genomic DNA was first applied in postnatal diagnosis for patients with intellectual disability (ID) and/or congenital anomalies (CA). Genome-wide single-nucleotide polymorphism (SNP) array analysis was subsequently implemented as the first line diagnostic test for ID/CA patients in our laboratory in 2009, because its diagnostic yield is significantly higher than that of routine cytogenetic analysis. In addition to the detection of copy number variations, the genotype information obtained with SNP array analysis enables the detection of stretches of homozygosity and thereby the possible identification of recessive disease genes, mosaic aneuploidy, or uniparental disomy. Patient-parent (trio) information analysis is used to screen for the presence of any form of uniparental disomy in the patient and can determine the parental origin of a de novo copy number variation. Moreover, the outcome of a genotype analysis is used as a final quality control by ruling out potential sample mismatches due to non-paternity or sample mix-up. SNP array analysis is now also used in our laboratory for patients with disorders for which locus heterogeneity is known (homozygosity pre-screening), in prenatal diagnosis in case of structural ultrasound anomalies, and for patients with leukemia. In this report, we summarize our array findings and experiences in the various diagnostic applications and demonstrate the power of a SNP-based array platform for molecular karyotyping, because it not only significantly improves the diagnostic yield in both constitutional and cancer genome diagnostics, but it also enhances the quality of the diagnostic laboratory workflow.

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  1. Brunetti-Pierri N, Berg JS, Scaglia F, Belmont J, Bacino CA, et al: Recurrent reciprocal 1q21.1 deletions and duplications associated with microcephaly or macrocephaly and developmental and behavioral abnormalities. Nat Genet 40:1466–1471 (2008).
  2. Buysse K, Delle Chiaie B, Van Coster R, Loeys B, De Paepe A, et al: Challenges for CNV interpretation in clinical molecular karyotyping: lessons learned from a 1001 sample experience. Eur J Med Genet 52:398–403 (2009).
  3. Collin RW, van den Born LI, Klevering BJ, de Castro-Miró M, Littink KW, et al: High-resolution homozygosity mapping is a powerful tool to detect novel mutations causative of autosomal recessive RP in the Dutch population. Invest Ophthalmol Vis Sci 52:2227–2239 (2011).
  4. Collins-Underwood JR, Mullighan CG: Genomic profiling of high-risk acute lymphoblastic leukemia. Leukemia 24:1676–1685 (2010).
  5. Conrad DF, Andrews TD, Carter NP, Hurles ME, Pritchard JK: A high-resolution survey of deletion polymorphism in the human genome. Nat Genet 38:75–81 (2006).
  6. de Leeuw N, Pfundt R, Koolen DA, Neefs I, Scheltinga I, et al: A newly recognised microdeletion syndrome involving 2p15p16.1: narrowing down the critical region by adding another patient detected by genome wide tiling path array comparative genomic hybridisation analysis. J Med Genet 45:122–124 (2008).
  7. de Vries BB, Pfundt R, Leisink M, Koolen DA, Vissers LE, et al: Diagnostic genome profiling in mental retardation. Am J Hum Genet 77:606–616 (2005).
  8. Faas BH, van der Burgt I, Kooper AJ, Pfundt R, Hehir-Kwa JY, et al: Identification of clinically significant, submicroscopic chromosome alterations and UPD in fetuses with ultrasound anomalies using genome-wide 250k SNP array analysis. J Med Genet 47:586–594 (2010).
  9. Feenstra I, Fang J, Koolen DA, Siezen A, Evans C, et al: European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations (ECARUCA); an online database for rare chromosome abnormalities. Eur J Med Genet 49:279–291 (2006).
  10. Friedman J, Adam S, Arbour L, Armstrong L, Baross A, et al: Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization. BMC Genomics 10:526 (2009).
  11. Gijsbers AC, Lew JY, Bosch CA, Schuurs-Hoeijmakers JH, van Haeringen A, et al: A new diagnostic workflow for patients with mental retardation and/or multiple congenital abnormalities: test arrays first. Eur J Hum Genet 17:1394–1402 (2009).
  12. Hagenkord JM, Chang CC: The rewards and challenges of array-based karyotyping for clinical oncology applications. Leukemia 23:829–833 (2009).
  13. Hagenkord JM, Monzon FA, Kash SF, Lilleberg S, Xie Q, Kant JA: Array-based karyotyping for prognostic assessment in chronic lymphocytic leukemia. Performance comparison of Affymetrix 10K2.0, 250K Nsp, and SNP6.0 arrays. J Mol Diagn 12:184–196 (2010).
  14. Hannes FD, Sharp AJ, Mefford HC, de Ravel T, Ruivenkamp CA, et al: 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 46:223–232 (2009).
  15. Hehir-Kwa J, Egmont-Petersen M, Janssen I, Smeets D, van Kessel A, et al: Genome-wide copy number profiling on high-density bacterial artificial chromosomes, single-nucleotide polymorphisms, and oligonucleotide microarrays: a platform comparison based on statistical power analysis. DNA Res 14: 1–11 (2007).
  16. Hehir-Kwa JY, Wieskamp N, Webber C, Pfundt R, Brunner HG, et al: Accurate distinction of pathogenic from benign CNVs in mental retardation. PLoS Comput Biol 6:e1000752 (2010).
  17. Heinrichs S, Li C, Look AT: SNP array analysis in hematologic malignancies: avoiding false discoveries. Blood 115:4157–4161 (2010).
  18. Hildebrandt F, Heeringa SF, Rüschendorf F, Attanasio M, Nürnberg G, et al: A systematic approach to mapping recessive disease genes in individuals from outbred populations. PLoS Genet 5:e1000353 (2009).
  19. Hochstenbach R, van Binsbergen E, Engelen J, Nieuwint A, Polstra A, et al: 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 52:161–169 (2009).
  20. Huang J, Wei W, Zhang J, Liu G, Bignell GR, et al: Whole genome DNA copy number changes identified by high density oligonucleotide arrays. Hum Genomics1:287–299 (2004).
  21. Kidd JM, Cooper GM, Donahue WF, Hayden HS, Sampas N, et al: Mapping and sequencing of structural variation from eight human genomes. Nature 453:56–64 (2008).
  22. Koolen DA, Vissers LE, Pfundt R, de Leeuw N, Knight SJ, et al: A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet 38:999–1001 (2006).
  23. Koolen DA, Pfundt R, de Leeuw N, Hehir-Kwa JY, Nillesen WM, et al: Genomic microarrays in mental retardation: a practical workflow for diagnostic applications. Hum Mutat 30:283–292 (2009).
  24. Kuiper RP, Schoenmakers EF, van Reijmersdal SV, Hehir-Kwa JY, Geurts van Kessel A, et al: High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia 21:1258–1266 (2007).
  25. Kuiper RP, Waanders E, van der Velden VH, van Reijmersdal SV, Venkatachalam R, et al: IKZF1 deletions predict relapse in uniformly treated pediatric precursor B-ALL. Leukemia 24:1258–1264 (2010).
  26. Langemeijer SM, Kuiper RP, Berends M, Knops R, Aslanyan MG, et al: Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat Genet 41:838–842 (2009).
  27. Lee C, Iafrate AJ, Brothman AR: Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nat Genet 39:S48–S54 (2007).
  28. McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, et al: Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet 41:1223–1227 (2009).
  29. McMullan DJ, Bonin M, Hehir-Kwa JY, de Vries BB, Dufke A, et al: Molecular karyotyping of patients with unexplained mental retardation by SNP arrays: a multicenter study. Hum Mutat 30:1082–1092 (2009).
  30. Mefford HC, Sharp AJ, Baker C, Itsara A, Jiang Z, et al: Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 359:1685–1699 (2008).
  31. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, 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, 86:749–764 (2010).
  32. Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, et al: Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature 446:758–764 (2007).
  33. Mullighan CG, Su X, Zhang J, Radtke I, Phillips LA, et al: Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med 360:470–480 (2009).
  34. Nannya Y, Sanada M, Nakazaki K, Hosoya N, Wang L, et al: A robust algorithm for copy number detection using high-density oligonucleotide single-nucleotide polymorphism genotyping arrays. Cancer Res 65:6071–6079 (2005).
  35. Nowakowska B, de Leeuw N, Ruivenkamp CA, Sikkema-Raddatz B, Crolla JA, et al: Parental insertional balanced translocations are an important cause of apparently de novo CNVs in patients with developmental anomalies. Eur J Hum Genet, in press (2011).
  36. Patel A, Kang SH, Lennon PA, Li YF, Rao PN, et al: Validation of a targeted DNA microarray for the clinical evaluation of recurrent abnormalities in chronic lymphocytic leukemia. Am J Hematol 83:540–546 (2008).
  37. Perry GH, Tchinda J, McGrath SD, Zhang J, Picker SR, et al: Hotspots for copy number variation in chimpanzees and humans. Proc Natl Acad Sci USA 103:8006–8011 (2006).
  38. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, et al: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81:559–575 (2007).
  39. Rauch A, Hoyer J, Guth S, Zweier C, Kraus C, et al: Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet A 140A:2063–2074 (2006).

    External Resources

  40. Raymond FL, Tarpey P: The genetics of mental retardation. Hum Mol Genet 15 Spec No 2:R110–R116 (2006).
  41. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, et al: Global variation in copy number in the human genome. Nature 444:444–454 (2006).
  42. Schuurs-Hoeijmakers JH, Hehir-Kwa JY, Pfundt R, van Bon BW, de Leeuw N, et al: Homozygosity mapping in outbred families with mental retardation. Eur J Hum Genet 19:597–601 (2011).
  43. Sharp AJ, Mefford HC, Li K, Baker C, Skinner C, et al: A recurrent 15q13.3 microdeletion syndrome associated with mental retardation and seizures. Nat Genet 40:322–328 (2008).
  44. Shinawi M, Liu P, Kang SH, Shen J, Belmont JW, et al: Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size. J Med Genet 47:332–341 (2010).
  45. Simons A, Stevens-Kroef M, El Idrissi-Zaynoun N, van Gessel S, Olde Weghuis D, et al: Microarray-based genomic profiling as a diagnostic tool in acute lymphoblastic leukemia. Genes, Chromosomes and Cancer, 2011 Aug 31. doi: 10.1002/gcc.20919 PMID:21882283 (2011).
  46. Snijders AM, Nowak N, Segraves R, Blackwood S, Brown N, et al: Assembly of microarrays for genome-wide measurement of DNA copy number. Nat Genet 29:263–264 (2001).
  47. Stankiewicz P, Beaudet AL: Use of genome-wide array analysis in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev 17:182–192 (2007).
  48. Stefansson H, Rujescu D, Cichon S, Pietiläinen OP, Ingason A, et al: Large recurrent microdeletions associated with schizophrenia. Nature 455:232–236 (2008).
  49. Stegelmann F, Bullinger L, Griesshammer M, Holzmann K, Habdank M, et al: High-resolution single-nucleotide polymorphism array-profiling in myeloproliferative neoplasms identifies novel genomic aberrations. Haematologica 95:666–669 (2010).
  50. Ting JC, Roberson ED, Miller ND, Lysholm-Bernacchi A, Stephan DA, et al: Visualization of uniparental inheritance, Mendelian inconsistencies, deletions, and parent of origin effects in single nucleotide polymorphism trio data with SNPtrio. Hum Mutat 28:1225–1235 (2007).
  51. Tyreman M, Abbott KM, Willatt LR, Nash R, Lees C, et al: High resolution array analysis: diagnosing pregnancies with abnormal ultrasound findings. J Med Genet 46:531–541 (2009).
  52. Ullmann R, Turner G, Kirchhoff M, Chen W, Tonge B, et al: Array CGH identifies reciprocal 16p13.1 duplications and deletions that predispose to autism and/or mental retardation. Hum Mutat 28:674–682 (2007).
  53. van Bon BW, Mefford HC, Menten B, Koolen DA, Sharp AJ, et al: Further delineation of the 15q13 microdeletion and duplication syndromes: a clinical spectrum varying from non-pathogenic to a severe outcome. J Med Genet 46:511–523 (2009).
  54. van Bon BW, Balciuniene J, Fruhman G, Nagamani SC, Broome DL, et al: The phenotype of recurrent 10q22q23 deletions and duplications. Eur J Hum Genet 19:400–408 (2011).
  55. Vissers LE, de Vries BB, Osoegawa K, Janssen IM, Feuth T, et al: Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. J Hum Genet 73:1261–1270 (2003).
  56. Vissers LE, de Vries BB, Veltman JA: Genomic microarrays in mental retardation: from copy number variation to gene, from research to diagnosis. J Med Genet 47: 289–297 (2010).
  57. Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, et al: Association between microdeletion and microduplication at 16p11.2 and autism. N Engl J Med 358:667–675 (2008).
  58. Zhang J, Feuk L, Duggan GE, Khaja R, Scherer SW: Development of bioinformatics resources for display and analysis of copy number and other structural variants in the human genome. Cytogenet Genome Res 115:205–214 (2006).

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