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Array CGH Analysis and Developmental Delay: A Diagnostic Tool for Neurologists

Published online by Cambridge University Press:  23 September 2014

F. Cameron
Affiliation:
Western University, London Health Sciences Centre and Western University Ontario, London, Ontario
J. Xu
Affiliation:
Cytogenetics, London Health Sciences Centre and Western University Ontario, London, Ontario Cytogenetics, Alberta Genetics Services, Alberta Health Services, Edmonton, Alberta, Canada
J. Jung
Affiliation:
Western University, London Health Sciences Centre and Western University Ontario, London, Ontario Paediatrics, London Health Sciences Centre and Western University Ontario, London, Ontario
C. Prasad*
Affiliation:
Western University, London Health Sciences Centre and Western University Ontario, London, Ontario Paediatrics, London Health Sciences Centre and Western University Ontario, London, Ontario Children's Health Research Institute, London Health Sciences Centre and Western University Ontario, London, Ontario
*
Genetics, Metabolism and Paediatrics, 800 Commissioners Road East, London, Ontario, N6C 2V5, Canada. Email: Chitra.Prasad@lhsc.on.ca.
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Abstract

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Developmental delay occurs in 1–3% of the population, with unknown etiology in approximately 50% of cases. Initial genetic work up for developmental delay previously included chromosome analysis and subtelomeric FISH (fluorescent in situ hybridization). Array Comparative Genomic Hybridization (aCGH) has emerged as a tool to detect genetic copy number changes and uniparental disomy and is the most sensitive test in providing etiological diagnosis in developmental delay. aCGH allows for the provision of prognosis and recurrence risks, improves access to resources, helps limit further investigations and may alter medical management in many cases. aCGH has led to the delineation of novel genetic syndromes associated with developmental delay. An illustrative case of a 31-year-old man with long standing global developmental delay and recently diagnosed 4q21 deletion syndrome with a deletion of 20.8 Mb genomic interval is provided. aCGH is now recommended as a first line test in children and adults with undiagnosed developmental delay and congenital anomalies.

Résumé

RÉSUMÉ

Le retard de développement survient chez 1 à 3% de la population et son étiologie est inconnue chez à peu près 50% des cas. L'évaluation génétique initiale pour un retard de développement incluait antérieurement une analyse chromosomique et une analyse par FISH (hybridation in situ en fluorescence) de régions subtélomériques. La puce d'hybridation génomique comparative (CGHa) est devenue un outil de détection des changements du nombre de copies géniques ainsi que de la disomie uniparentale et elle est le test le plus sensible pour fournir un diagnostic étiologique dans le retard de développement. Le CGHa permet d'offrir un pronostic et un risque de récurrence, améliore l'accès aux ressources, aide à limiter les évaluations et peut modifier le traitement médical dans bien des cas. Le CGHa a mené à la définition de nouveaux syndromes génétiques associés à un retard de développement. À titre d'exemple, nous décrivons le cas d'un homme âgé de 31 ans qui présentait un retard de développement global depuis longtemps et chez qui un syndrome associé à une délétion 4q21 a été diagnostiqué récemment, soit une délétion de 20,8 Mb. Le CGHa est maintenant recommandé comme test de première ligne chez les enfants et les adultes présentant un retard de développement et des anomalies congénitales.

Type
Review Article
Copyright
Copyright © The Canadian Journal of Neurological 2013

References

1. Curry, CJ, Stevenson, RE, Aughton, D, et al. Evaluation of mental retardation: Recommendations of a consensus conference: American college of medical genetics. Am J Med Genet. 1997 Nov 12;72(4):46877.Google Scholar
2. Battaglia, A, Carey, JC. Diagnostic evaluation of developmental delay/mental retardation: An overview. Am J Med Genet C Semin Med Genet. 2003 Feb 15;117C(1):314.Google Scholar
3. van Karnebeek, CD, Jansweijer, MC Leenders, AG Offringa, M, Hennekam, RC. Diagnostic investigations in individuals with mental retardation: A systematic literature review of their usefulness. Eur J Hum Genet. 2005 Jan;13(1):625.Google Scholar
4. White, BJ, Ayad, M, Fraser, A, et al. A 6-year experience demonstrates the utility of screening for both cytogenetic and FMR-1 abnormalities in patients with mental retardation. Genet Test. 1999;3(3):2916.Google Scholar
5. Graham, SM, Selikowitz, M. Chromosome testing in children with developmental delay in whom the aetiology is not evident clinically. J Paediatr Child Health. 1993 Oct;29(5):3602.CrossRefGoogle Scholar
6. Volcke, P, Dereymaeker, AM, Fryns, JP, van den Berghe, H. On the nosology of moderate mental retardation with special attention to X-linked mental retardation. A diagnostic genetic survey of 274 institutionalized moderately mentally retarded men. Genet Couns. 1990;1(1):4756.Google ScholarPubMed
7. Lamont, MA, Dennis, NR, Seabright, M. Chromosome abnormalities in pupils attending ESN/M schools. Arch Dis Child. 1986 Mar;61(3):2236.Google Scholar
8. Shevell, MI, Majnemer, A, Rosenbaum, P, Abrahamowicz, M. Etiologic yield of subspecialists' evaluation of young children with global developmental delay. J Pediatr. 2000 May;136(5):5938.Google Scholar
9. Battaglia, A, Bianchini, E, Carey, JC. Diagnostic yield of the comprehensive assessment of developmental delay/mental retardation in an institute of child neuropsychiatry. Am J Med Genet. 1999 Jan 1;82(1):606.Google Scholar
10. Shevell, M, Ashwal, S, Donley, D, et al. Practice parameter: Evaluation of the child with global developmental delay: Report of the quality standards subcommittee of the American Academy of Neurology and the practice committee of the Child Neurology Society. Neurology. 2003 Feb 11;60(3):36780.Google Scholar
11. Sanchez, O, Escobar, JI, Yunis, JJ. A simple G-banding technique. Lancet. 1973 Aug 4;2(7823):269.Google Scholar
12. Flint, J, Wilkie, AO, Buckle, VJ, Winter, RM, Holland, AJ, McDermid, HE. The detection of subtelomeric chromosomal rearrangements in idiopathic mental retardation. Nat Genet. 1995 Feb;9(2):13240.Google Scholar
13. de Vries, BB White, SM Knight, SJ, et al. Clinical studies on submicroscopic subtelomeric rearrangements: A checklist. J Med Genet. 2001 Mar;38(3):14550.Google Scholar
14. Shaffer, LG, Bejjani, BA. Medical applications of array CGH and the transformation of clinical cytogenetics. Cytogenet Genome Res. 2006;115(3–4):3039.Google Scholar
15. Kallioniemi, A, Kallioniemi, OP, Sudar, D, et al. Comparative genomic hybridization for molecular cytogenetic analysis of solid tumors. Science. 1992 Oct 30;258(5083):81821.Google Scholar
16. Edelmann, L, Hirschhorn, K. Clinical utility of array CGH for the detection of chromosomal imbalances associated with mental retardation and multiple congenital anomalies. Ann N Y Acad Sci. 2009 Jan;1151:15766.Google Scholar
17. Solinas-Toldo, S, Lampel, S, Stilgenbauer, S, et al. Matrix-based comparative genomic hybridization: Biochips to screen for genomic imbalances. Genes Chromosomes Cancer. 1997 Dec;20 (4):399407.Google Scholar
18. Pinkel, D, Segraves, R, Sudar, D, et al. High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet. 1998 Oct;20(2):20711.Google Scholar
19. Baldwin, EL, Lee, JY, Blake, DM, et al. Enhanced detection of clinically relevant genomic imbalances using a targeted plus whole genome oligonucleotide microarray. Genet Med. 2008 Jun;10(6):41529.Google Scholar
20. Speicher, MR, Carter, NP. The new cytogenetics: Blurring the boundaries with molecular biology. Nat Rev Genet. 2005 Oct;6 (10):78292.Google Scholar
21. Kearney, HM, Kearney, JB, Conlin, LK. Diagnostic implications of excessive homozygosity detected by SNP-based microarrays: Consanguinity, uniparental disomy, and recessive single-gene mutations. Clin Lab Med. 2011 Dec;31(4):595,613, ix.Google Scholar
22. Papenhausen, P, Schwartz, S, Risheg, H, et al. UPD detection using homozygosity profiling with a SNP genotyping microarray. Am J Med Genet A. 2011 Apr;155A(4):75768.Google Scholar
23. Toruner, GA, Streck, DL, Schwalb, MN, Dermody, JJ. An oligonucleotide based array-CGH system for detection of genome wide copy number changes including subtelomeric regions for genetic evaluation of mental retardation. Am J Med Genet A. 2007 Apr 15;143A(8):8249.Google Scholar
24. Vissers, LE, de Vries, BB, Osoegawa, K, et al. Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. Am J Hum Genet. 2003 Dec;73(6):126170.CrossRefGoogle ScholarPubMed
25. Shaw-Smith, C, Redon, R, Rickman, L, et al. 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. 2004 Apr;41(4):2418.Google Scholar
26. Schoumans, J, Ruivenkamp, C, Holmberg, E, Kyllerman, M, Anderlid, BM, Nordenskjold, M. Detection of chromosomal imbalances in children with idiopathic mental retardation by array based comparative genomic hybridisation (array-CGH). J Med Genet. 2005 Sep;42(9):699705.CrossRefGoogle ScholarPubMed
27. de Vries, BB, Pfundt, R, Leisink, M, et al. Diagnostic genome profiling in mental retardation. Am J Hum Genet. 2005 Oct;77 (4):60616.CrossRefGoogle ScholarPubMed
28. Menten, B, Maas, N, Thienpont, B, et al. 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. 2006 Aug;43(8):62533.CrossRefGoogle ScholarPubMed
29. Rosenberg, C, Knijnenburg, J, Bakker, E, et al. 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. 2006 Feb;43(2):1806.Google Scholar
30. Krepischi-Santos, AC, Vianna-Morgante, AM, Jehee, FS, et al. Whole-genome array-CGH screening in undiagnosed syndromic patients: Old syndromes revisited and new alterations. Cytogenet Genome Res. 2006;115(3–4):25461.Google Scholar
31. Shevell, MI, Bejjani, BA, Srour, M, Rorem, EA, Hall, N, Shaffer, LG. Array comparative genomic hybridization in global developmental delay. Am J Med Genet B Neuropsychiatr Genet. 2008 Oct 5;147B(7):11018.Google Scholar
32. Pickering, DL, Eudy, JD, Olney, AH, et al. Array-based comparative genomic hybridization analysis of 1176 consecutive clinical genetics investigations. Genet Med. 2008 Apr;10(4):2626.Google Scholar
33. Manolakos, E, Vetro, A, Kefalas, K, et al. The use of array-CGH in a cohort of Greek children with developmental delay. Mol Cytogenet. 2010 Nov 9;3:22.Google Scholar
34. Shoukier, M, Klein, N, Auber, B, et al. Array CGH in patients with developmental delay or intellectual disability: Are there phenotypic clues to pathogenic copy number variants? Clin Genet. 2013 Jan;83(1):5365.Google Scholar
35. Bejjani, BA, Shaffer, LG. Clinical utility of contemporary molecular cytogenetics. Annu Rev Genomics Hum Genet. 2008;9:7186.Google Scholar
36. Newman, WG, Hamilton, S, Ayres, J, et al. Array comparative genomic hybridization for diagnosis of developmental delay: An exploratory cost-consequences analysis. Clin Genet. 2007 Mar;71(3):2549.Google Scholar
37. Trakadis, Y, Shevell, M. Microarray as a first genetic test in global developmental delay: A cost-effectiveness analysis. Dev Med Child Neurol. 2011 Nov;53(11):9949.Google Scholar
38. Miller, DT, Adam, MP, Aradhya, S, 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 May 14;86(5):74964.Google Scholar
39. Manning, M, Hudgins, L, Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010 Nov;12(11):7425.Google Scholar
40. Duncan, A, Langlois, S, SOGC Genetics Committee, CCMG Prenatal Diagnosis Committee. Use of array genomic hybridization technology in prenatal diagnosis in Canada. J Obstet Gynaecol Can. 2011 Dec;33(12):12569.Google Scholar
41. Pletcher, BA, Toriello, HV, Noblin, SJ, et al. Indications for genetic referral: A guide for healthcare providers. Genet Med. 2007 Jun;9(6):3859.Google Scholar
42. Youssoufian, H, Pyeritz, RE. Mechanisms and consequences of somatic mosaicism in humans. Nat Rev Genet. 2002 Oct;3(10):74858.Google Scholar
43. Ballif, BC, Rorem, EA, Sundin, K, et al. Detection of low-level mosaicism by array CGH in routine diagnostic specimens. Am J Med Genet A. 2006 Dec 15;140(24):275767.Google Scholar
44. Sebat, J, Lakshmi, B, Troge, J, et al. Large-scale copy number polymorphism in the human genome. Science. 2004 Jul 23;305(5683):5258.Google Scholar
45. Iafrate, AJ, Feuk, L, Rivera, MN, et al. Detection of large-scale variation in the human genome. Nat Genet. 2004 Sep;36(9):94951.Google Scholar
46. Bejjani, BA, Saleki, R, Ballif, BC, et al. Use of targeted array-based CGH for the clinical diagnosis of chromosomal imbalance: Is less more? Am J Med Genet A. 2005 Apr 30;134(3):25967.Google Scholar
47. Shinawi, M, Cheung, SW. The array CGH and its clinical applications. Drug Discov Today. 2008 Sep;13(17–18):76070.Google Scholar
48. Saam, J, Gudgeon, J, Aston, E, Brothman, AR. How physicians use array comparative genomic hybridization results to guide patient management in children with developmental delay. Genet Med. 2008 Mar;10(3):1816.Google Scholar
49. Moeschler, JB, Shevell, M, American Academy of Pediatrics Committee on Genetics. Clinical genetic evaluation of the child with mental retardation or developmental delays. Pediatrics. 2006 Jun;117(6):230416.Google Scholar
50. Dale, RC, Grattan-Smith, P, Nicholson, M, Peters, GB. Microdeletions detected using chromosome microarray in children with suspected genetic movement disorders: A single-centre study. Dev Med Child Neurol. 2012 Jul;54(7):61823.Google Scholar
51. Thomas, NS, Harvey, JF, Bunyan, DJ, et al. Clinical and molecular characterization of duplications encompassing the human SHOX gene reveal a variable effect on stature. Am J Med Genet A. 2009 Jul;149A(7):140714.Google Scholar
52. Roos, L, Brondum Nielsen, K, Tumer, Z. A duplication encompassing the SHOX gene and the downstream evolutionarily conserved sequences. Am J Med Genet A. 2009 Dec;149A(12):29001.Google Scholar
53. Bonnet, C, Andrieux, J, Beri-Dexheimer, M, et al. Microdeletion at chromosome 4q21 defines a new emerging syndrome with marked growth restriction, mental retardation and absent or severely delayed speech. J Med Genet. 2010 Jun;47(6):37784.Google Scholar
54. Dukes-Rimsky, L, Guzauskas, GF, Holden, KR, et al. Microdeletion at 4q21.3 is associated with intellectual disability, dysmorphic facies, hypotonia, and short stature. Am J Med Genet A. 2011 Sep;155A(9):214653.Google Scholar
55. Friedman, JM, Baross, A, Delaney, AD, et al. Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation. Am J Hum Genet. 2006 Sep;79(3):50013.Google Scholar
56. Dobyns, WB, Mirzaa, G, Christian, SL, et al. Consistent chromosome abnormalities identify novel polymicrogyria loci in 1p36.3, 2p16.1–p23.1, 4q21.21–q22.1, 6q26–q27, and 21q2. Am J Med Genet A. 2008 Jul 1;146A(13):163754.Google Scholar
57. Harada, N, Nagai, T, Shimokawa, O, Niikawa, N, Matsumoto, N. A 4q21–q22 deletion in a girl with severe growth retardation. Clin Genet. 2002 Mar;61(3):2268.Google Scholar
58. Chikuda, H, Kugimiya, F, Hoshi, K, et al. Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes. Genes Dev. 2004 Oct 1;18(19):241829.Google Scholar