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Molekulare Karyotypisierung in der klinischen Diagnostik

Molecular karyotyping in clinical diagnosis

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medizinische genetik

Zusammenfassung

Molekulare Karyotypisierung bezeichnet die genomweite Analyse bezüglich genetischer Kopienzahlveränderungen mit Hilfe von Arrays, welche das Genom mehr oder weniger dicht mit molekularen Markern abdecken. Die Hauptanwendung in der klinischen Diagnostik liegt derzeit bei der Analyse von Patienten mit geistiger Behinderung und multiplen Anomalien unbekannter Ursache. Bei ihnen lassen sich nach Ausschluss von konventionell-zytogenetisch sichtbaren Aberrationen, kryptischen subtelomerischen Aberrationen und klinisch gut erkennbaren, häufigen Mikrodeletionssyndromen in rund 10% der Fälle mittels molekularer Karyotypisierung chromosomale Mikroaberrationen nachweisen. Hierdurch konnten in den letzten Jahren zahlreiche neue Mikrodeletions- und -duplikationssyndrome charakterisiert werden, jedoch wurde auch ersichtlich, dass die Interpretation von Einzelbefunden aufgrund der großen Anzahl an genomischen Kopienzahlpolymorphismen nicht trivial ist.

Abstract

The term “molecular karyotyping” refers to the genome-wide analysis of copy number variations using arrays that cover the genome with genomic markers with varying density. Currently the main application is the investigation of patients with otherwise unexplained mental retardation and multiple congenital anomalies. Studies of such patients who remained without etiological diagnosis after conventional karyotyping, subtelomeric screening, and targeted molecular–cytogenetic studies for well-known microdeletion syndromes revealed chromosomal microaberrations in about 10% of cases and allowed the delineation of several new microdeletion and microduplication syndromes. Nevertheless, because of the large number of copy number polymorphisms, interpretation of unique findings needs thorough consideration.

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Literatur

  1. Ballif BC, Rorem EA, Sundin K et al (2006) Detection of low-level mosaicism by array CGH in routine diagnostic specimens. Am J Med Genet A 140:2757–2767

    PubMed  Google Scholar 

  2. Burger J, Horn D, Tonnies H et al (2002) Familial interstitial 570 kbp deletion of the UBE3A gene region causing Angelman syndrome but not Prader-Willi syndrome. Am J Med Genet 111:233–237

    Article  PubMed  Google Scholar 

  3. Coe BP, Ylstra B, Carvalho B et al (2007) Resolving the resolution of array CGH. Genomics 89:647–653

    Article  PubMed  CAS  Google Scholar 

  4. De Gregori M, Ciccone R, Magini P et al (2007) Cryptic deletions are a common finding in „balanced“ reciprocal and complex chromosome rearrangements: a study of 59 patients. J Med Genet 44:750–762

    Article  Google Scholar 

  5. De Vries BB, Pfundt R, Leisink M et al (2005) Diagnostic genome profiling in mental retardation. Am J Hum Genet 77:606–616

    Article  Google Scholar 

  6. Eichler EE, Nickerson DA, Altshuler D et al (2007) Completing the map of human genetic variation. Nature 447:161–165

    Article  PubMed  CAS  Google Scholar 

  7. Flint J, Knight S (2003) The use of telomere probes to investigate submicroscopic rearrangements associated with mental retardation. Curr Opin Genet Dev 13:310–316

    Article  PubMed  CAS  Google Scholar 

  8. Friedman JM, Baross A, Delaney AD et al (2006) Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation. Am J Hum Genet 79:500–513

    Article  PubMed  CAS  Google Scholar 

  9. Gohring I, Blumlein HM, Hoyer J et al (2008) 6.7 Mb interstitial duplication in chromosome band 11q24.2q25 associated with infertility, minor dysmorphic features and normal psychomotor development. Eur J Med Genet Aug 12 [Epub ahead of print]

  10. Hehir-Kwa JY, Egmont-Petersen M, Janssen IM et al (2007) 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

    Article  PubMed  CAS  Google Scholar 

  11. Hollox EJ, Huffmeier U, Zeeuwen PL et al (2008) Psoriasis is associated with increased beta-defensin genomic copy number. Nat Genet 40:23–25

    Article  PubMed  CAS  Google Scholar 

  12. Hoyer J, Dreweke A, Becker C et al (2007) Molecular karyotyping in patients with mental retardation using 100 K single-nucleotide polymorphism arrays. J Med Genet 44:629–636

    Article  PubMed  CAS  Google Scholar 

  13. Lejeune J, Gautier M, Turpin R (1959) [Study of somatic chromosomes from 9 mongoloid children.]. C R Hebd Seances Acad Sci 248:1721–1722

    PubMed  CAS  Google Scholar 

  14. Lesnik Oberstein SA, Kriek M, White SJ et al (2006) Peters Plus syndrome is caused by mutations in B3GALTL, a putative glycosyltransferase. Am J Hum Genet 79:562–566

    Article  Google Scholar 

  15. Lupski JR (1998) Genomic disorders:structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet 14:417–422

    Article  PubMed  CAS  Google Scholar 

  16. Mefford HC, Sharp AJ, Baker C et al (2008) Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med 359:1685-1699

    Article  PubMed  CAS  Google Scholar 

  17. Pergament E (2007) Controversies and challenges of array comparative genomic hybridization in prenatal genetic diagnosis. Genet Med 9:596–599

    PubMed  Google Scholar 

  18. Pinkel D, Segraves R, Sudar D et al (1998) High resolution analysis of DNA copy number variation using comparative genomic hybridization to microarrays. Nat Genet 20:207–211

    Article  PubMed  CAS  Google Scholar 

  19. Rauch A, Ruschendorf F, Huang J et al (2004) Molecular karyotyping using an SNP array for genomewide genotyping. J Med Genet 41:916–922

    Article  PubMed  CAS  Google Scholar 

  20. Rauch A, Hoyer J, Guth S et al (2006) Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J Med Genet A 140:2063–2074

    PubMed  Google Scholar 

  21. Redon R, Ishikawa S, Fitch KR et al (2006) Global variation in copy number in the human genome. Nature 444:444–454

    Article  PubMed  CAS  Google Scholar 

  22. Rooms L, Reyniers E, Kooy RF (2005) Subtelomeric rearrangements in the mentally retarded: a comparison of detection methods. Hum Mutat 25:513–524

    Article  PubMed  Google Scholar 

  23. Ropers HH, Hamel BC (2005) X-linked mental retardation. Nat Rev Genet 6:46–57

    Article  PubMed  CAS  Google Scholar 

  24. Sebat J, Lakshmi B, Malhotra D et al (2007) Strong association of de novo copy number mutations with autism. Science 316:445–449

    Article  PubMed  CAS  Google Scholar 

  25. Slavotinek AM (2008) Novel microdeletion syndromes detected by chromosome microarrays. Hum Genet 124:1–17

    Article  PubMed  CAS  Google Scholar 

  26. Solinas-Toldo S, Lampel S, Stilgenbauer S et al (1997) Matrix-based comparative genomic hybridization:biochips to screen for genomic imbalances. Genes Chromosomes Cancer 20:399–407

    Article  PubMed  CAS  Google Scholar 

  27. Thienpont B, Mertens L, de Ravel T et al (2007) Submicroscopic chromosomal imbalances detected by array-CGH are a frequent cause of congenital heart defects in selected patients. Eur Heart J 28:2778–2784

    Article  PubMed  CAS  Google Scholar 

  28. Thorland EC, Gonzales PR, Gliem TJ et al (2007) Comprehensive validation of array comparative genomic hybridization platforms: how much is enough? Genet Med 9:632–641

    Article  PubMed  CAS  Google Scholar 

  29. Veltman JA, De Vries BB (2006) Diagnostic genome profiling: unbiased whole genome or targeted analysis? J Mol Diagn 8:534–539

    Article  PubMed  CAS  Google Scholar 

  30. Veltman JA, De Vries BB (2007) Whole-genome array comparative genome hybridization: the preferred diagnostic choice in postnatal clinical cytogenetics. J Mol Diagn 9:277

    Article  PubMed  Google Scholar 

  31. Vermeesch JR, Rauch A (2006) Reply to Hochstenbach et al. ‚Molecular karyotyping’. Eur J Hum Genet 14:1063–1064

    Article  PubMed  Google Scholar 

  32. Vermeesch JR, Fiegler H, De Leeuw N et al (2007) Guidelines for molecular karyotyping in constitutional genetic diagnosis. Eur J Hum Genet 15:1105–1114

    Article  PubMed  CAS  Google Scholar 

  33. Vissers LE, De Vries BB, Osoegawa K et al (2003) Array-based comparative genomic hybridization for the genomewide detection of submicroscopic chromosomal abnormalities. Am J Hum Genet 73:1261–1270

    Article  PubMed  CAS  Google Scholar 

  34. Wong KK, dDeLeeuw RJ, Dosanjh NS et al (2007) A comprehensive analysis of common copy-number variations in the human genome. Am J Hum Genet 80:91–104

    Article  PubMed  CAS  Google Scholar 

  35. Zweier C, Peippo MM, Hoyer J et al (2007) Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). Am J Hum Genet 80:994–1001

    Article  PubMed  CAS  Google Scholar 

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  1. Humangenetisches Institut, Friedrich-Alexander Universität Erlangen-Nürnberg , Schwabachanlage 10, 91054 , Erlangen, Deutschland

    A. Rauch

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Rauch, A. Molekulare Karyotypisierung in der klinischen Diagnostik. medgen 20, 386–394 (2008). https://doi.org/10.1007/s11825-008-0135-6

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  • DOI: https://doi.org/10.1007/s11825-008-0135-6

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