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Exom-Sequenzierung zur Identifizierung von Krankheitsgenen

Disease gene identification by exome sequencing

Zusammenfassung

Neueste Sequenziertechnologien („next-generation sequencing“) erlauben die gleichzeitige Sequenzierung aller proteinkodierender Sequenzen, das sog. Exom. Die Identifizierung der jeweiligen pathogenen Mutation unter den Tausenden detektierten Varianten stellt dabei eine große Herausforderung dar, und neue Strategien für die Priorisierung von Varianten sind unerlässlich. Die jeweilige Wahl einer Strategie ist dabei von verschiedenen Faktoren abhängig, wie z. B. dem Vorhandensein gut charakterisierter Patienten und deren Familien, von der Art der Vererbung, der Schwere der Krankheit sowie deren Frequenz in der allgemeinen Bevölkerung. In dem vorliegenden Übersichtsartikel diskutieren wir die heute gebräuchlichen Strategien zur Identifizierung von neuen Krankheitsgenen mittels Exom-Sequenzierung und beschreiben die Lehren der ersten Exom-Studien. Wir glauben, dass die Sequenzierung von Exomen in den folgenden Jahren die am häufigsten angewandte Methode zur Identifizierung von Krankheitsgenen sein wird und dabei gleichzeitig auch ein großes diagnostisches Potenzial aufweist.

Abstract

Next generation sequencing can be used to search for Mendelian disease genes in an unbiased manner by sequencing the entire protein-coding sequence, known as the exome. Identifying the pathogenic mutation amongst thousands of genomic variants is a major challenge, and novel variant prioritization strategies are required. The choice of these strategies depends on the availability of well-phenotyped patients and family members, the mode of inheritance, the severity of the disease and its population frequency. In this review we discuss the current strategies for Mendelian disease gene identification by exome resequencing, and we describe the lessons learned from the first exome sequencing studies. Exome sequencing is likely to become the most commonly used tool for Mendelian disease gene identification for the coming years and bears a great diagnostic potential as well.

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Danksagung

Die Autoren danken Dr. Christian Gilissen und der gesamten Genomic Disorders Group für deren Hilfe bei der Erstellung dieses Manuskripts. Die Autoren wurden unterstützt durch: Netherlands Organization for Health Research and Development (ZonMW 916.12.095, AH), EU-FP7 Projekt TECHGENE (Health-F5–2009-223143, KN) und das EU-FP6 Projekt AnEUploidy (LSHG-CT-2006–37627, AH).

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Die Autoren geben an, dass kein Interessenkonflikt besteht.

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Correspondence to K. Neveling or A. Hoischen.

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Neveling, K., Hoischen, A. Exom-Sequenzierung zur Identifizierung von Krankheitsgenen. medgen 24, 4–11 (2012). https://doi.org/10.1007/s11825-012-0313-4

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Schlüsselwörter

  • Mendel’sche Erkrankungen
  • Exom
  • Monogene Erkrankungen
  • „Next-generation sequencing“
  • Kandidatengen-Identifizierung

Keywords

  • Mendelian diseases
  • Exome
  • Monogenic disorders
  • Next generation sequencing
  • Candidate gene identification