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Molekulare Karyotypisierung in der Diagnostik neurokognitiver Entwicklungsstörungen

Molecular karyotyping in the diagnosis of developmental neurocognitive disorders

Zusammenfassung

Die Ursache neurokognitiver Entwicklungsstörungen mit Intelligenzminderung stellt eine der häufigsten Fragestellungen in der genetischen Sprechstunde dar. Obwohl mehr als 400 krankheitsverursachende Einzelgendefekte bekannt sind, machen Chromosomenaberrationen derzeit den größten Anteil der bekannten Ursachen aus. Mittels hochauflösender Array-Techniken lassen sich nach Ausschluss des Down-Syndroms bei unselektionierten Patienten in 18% der Fälle relevante chromosomale Imbalancen nachweisen, wobei die Aberrationen nur in 4% der Fälle auch primär mikroskopisch sichtbar wären. Mit zunehmender Auflösung steigt jedoch auch die Rate an detektierten Kopienzahl-Normvarianten, welche die Beurteilung der Befunde erschweren können. Indikatoren für krankheitsrelevante Aberrationen sind Aberrationsgröße, Gengehalt und Segregation innerhalb der Familie. Eine Kausalität kann letztlich aber nur dann belegt werden, wenn Vergleichsfälle mit ähnlichem Genotyp und Phänotyp vorliegen.

Abstract

Establishing an etiological diagnosis in patients with developmental neurocognitive disorders involving intellectual disability represents a common challenge in clinical genetics. Although more than 400 monogenic diseases with intellectual disability as a trait have been delineated, chromosomal disorders represent the majority of known causes to date. Excluding Down syndrome, high-resolution molecular karyotyping is able to reveal a causative chromosomal imbalance in 18% of unselected patients, while microscopic karyotyping would detect a causal aberration in only 4% of cases. Increasing resolution, however, also increases the number of benign copy number variants detected, which may hamper the interpretation of results. Indicators of disease associated copy number changes include aberration size, gene content and segregation of the aberration with the phenotype within a family. Ultimately, causality can only be proven when multiple cases with a similar genotype and phenotype have been observed.

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Literatur

  1. 1.

    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 

  2. 2.

    Vissers LE, Vries BB de, 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

    PubMed  Article  CAS  Google Scholar 

  3. 3.

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

    PubMed  Article  CAS  Google Scholar 

  4. 4.

    Vissers LE, Vries BB de, Veltman JA (2010) Genomic microarrays in mental retardation: from copy number variation to gene, from research to diagnosis. J Med Genet 47:289–297

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    de Leeuw N, Hehir-Kwa JY, Simons A et al (2011) SNP array analysis in constitutional and cancer genome diagnostics–copy number variants, genotyping and quality control. Cytogenet Genome Res 135:212–221

    Article  Google Scholar 

  6. 6.

    Hochstenbach R, Buizer-Voskamp JE, Vorstman JA, Ophoff RA (2011) Genome arrays for the detection of copy number variations in idiopathic mental retardation, idiopathic generalized epilepsy and neuropsychiatric disorders: lessons for diagnostic workflow and research. Cytogenet Genome Res 135:174–202

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Barber JC (2005) Directly transmitted unbalanced chromosome abnormalities and euchromatic variants. J Med Genet 42:609–629

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    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 51:666–671

    PubMed  Article  Google Scholar 

  9. 9.

    Gijsbers AC, Schoumans J, Ruivenkamp CA (2011) Interpretation of array comparative genome hybridization data: a major challenge. Cytogenet Genome Res 135:222–227

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Coman DJ, Gardner RJ (2007) Deletions that reveal recessive genes. Eur J Hum Genet 15:1103–1104

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Vermeesch JR, Balikova I, Schrander-Stumpel C et al (2011) The causality of de novo copy number variants is overestimated. Eur J Hum Genet 19:1112–1113

    PubMed  Article  Google Scholar 

  12. 12.

    Itsara A, Wu H, Smith JD et al (2010) De novo rates and selection of large copy number variation. Genome Res 20:1469–1481

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Hannes FD, Sharp AJ, Mefford HC et al (2009) 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

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Campbell IM, Kolodziejska KE, Quach MM et al (2011) TGFBR2 deletion in a 20-month-old female with developmental delay and microcephaly. Am J Med Genet A 155A:1442–1447

    PubMed  Google Scholar 

  15. 15.

    Scott SA, Cohen N, Brandt T et al (2010) Detection of low-level mosaicism and placental mosaicism by oligonucleotide array comparative genomic hybridization. Genet Med 12:85–92

    PubMed  Article  CAS  Google Scholar 

  16. 16.

    Conlin LK, Thiel BD, Bonnemann CG et al (2010) Mechanisms of mosaicism, chimerism and uniparental disomy identified by single nucleotide polymorphism array analysis. Hum Mol Genet 19:1263–1275

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Bruno DL, White SM, Ganesamoorthy D et al (2011) Pathogenic aberrations revealed exclusively by single nucleotide polymorphism (SNP) genotyping data in 5000 samples tested by molecular karyotyping. J Med Genet 48:831–839

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Gijsbers AC, Lew JY, Bosch CA et al (2009) A new diagnostic workflow for patients with mental retardation and/or multiple congenital abnormalities: test arrays first. Eur J Hum Genet 17:1394–1402

    PubMed  Article  Google Scholar 

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Interessenkonflikt

Der korrespondierende Autor weist auf folgende Beziehung(en) hin: Drittmittel von Novartis für FiaX-Therapiestudie.

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Correspondence to A. Rauch.

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Oneda, B., Rauch, A. Molekulare Karyotypisierung in der Diagnostik neurokognitiver Entwicklungsstörungen. medgen 24, 94–98 (2012). https://doi.org/10.1007/s11825-012-0327-y

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Schlüsselwörter

  • „Comparative genomic hybridization“
  • Chromosomenaberrationen
  • Geistige Behinderung
  • Neurokognitive Entwicklungsstörungen
  • Einzelnukleotidpolymorphismen

Keywords

  • Comparative genomic hybridization
  • Chromosome aberrations
  • Intellectual disability
  • Neurocognitive disorders
  • Single nucleotide polymorphism