Big data in der Diagnostik genetischer Schwerhörigkeit

Zusammenfassung

Die vollständige Sequenzierung des menschlichen Genoms demonstriert als ein grundlegendes Beispiel eindrucksvoll die Entstehung einer großen Datenmenge (engl.: big data) in Wissenschaft und Medizin. Die Entschlüsselung des menschlichen Genoms stellt das bemerkenswerte Ergebnis multidisziplinärer Zusammenarbeit dar und gilt als eines der größten und erfolgreichsten Vorhaben der Menschheitsgeschichte. Die Bedeutung dieser Entdeckung lag nicht nur darin, die Sequenz von 3,2 Milliarden Nukleotiden des humanen Genoms zu identifizieren, sondern in Zukunft auch krankheitsassoziierte Variationen zu verstehen und dieses Wissen auf individualisierte Behandlungsansätze der personalisierten Medizin anzuwenden. Die Genomik hat sich seitdem mit bemerkenswerter Geschwindigkeit weiterentwickelt. Hierzu haben im Wesentlichen digitale, technologische Fortschritte in der Sequenzierung, Computer- und Bioinformatik wesentlich beigetragen. Die dadurch entstandenen großen genomischen Datenmengen haben den Begriff „big data“ hervorgebracht. Die heutige bioinformatisch geleitete Einzelfallanalyse genetischer Befunde im Krankheitskontext erfordert in der Regel die Verwendung mehrerer großer Datenmengen. Diese Datenmengen liegen in Form von strukturierten genetischen Datenbanken vor und werden bspw. im Rahmen von in silico Analyseprogramme und Allel-Häufigkeitsanalysen verwendet. Die aktuellen Technologien der Hochdurchsatzsequenzierung sind in der Lage kostengünstige und qualitativ hochwertige Daten zu erzeugen. Dies reicht von der Analyse mit gezielten krankheitsassoziierten Gen-Panels, über die Exom Analyse, bis hin zur Entschlüsselung des gesamten Genoms. Diese neuen Möglichkeiten haben die Diagnostik von Erbkrankheiten revolutioniert und wirken sich auf die Diagnostik der genetischen Schwerhörigkeit aus.

Die Analyse der genetischen Grundlagen der vererbbaren Form des Hörverlusts ist aufgrund großer genetischer Heterogenität und klinischer Variabilität in 2-facher Hinsicht eine besondere Herausforderung. Es sind bereits über 150 Gene bekannt, die an nicht-syndromalen und syndromalen Formen des Hörverlusts beteiligt sind. Das Mutationsspektrum eines einzelnen Hörverlust-assoziierten Gens kann mehrere zehn bis hunderte von pathogenen Varianten aufweisen. Darüber hinaus kann die Interpretation neuer Varianten eine Herausforderung darstellen, insbesondere, wenn widersprüchliche Informationen in Datenbanken hinterlegt wurden. Detaillierte und strukturierte phänotypische Informationen haben sich in der Diagnostik einiger Formen des Hörverlusts als äußerst vielversprechend erwiesen, sind aber bisher nicht für alle genetischen Formen von Schwerhörigkeit nutzbar. Während mit enormer Geschwindigkeit ständig neues Wissen sowohl im diagnostischen als auch im wissenschaftlichen Kontext entsteht, stellt diese überwältigende Menge an Informationen eine zunehmende Herausforderung für Fachärzte dar. Die fachärztliche Versorgung übernimmt hier neue Aufgaben und fungiert als Schnittstelle zwischen dem humangenetisch-diagnostischen Labor und dem Patienten. Zu diesen Aufgaben gehört die fachbezogene genetische Beratung und die klinische Einordnung von genetischen Befunden.

Diese Übersicht soll als Referenz für HNO-Ärzte dienen, die einen Einstieg in die Molekulargenetik der Schwerhörigkeit erhalten möchten. Es erfolgt die Darstellung von Schlüsselkonzepten der molekulargenetischen Diagnostik. Gerade die komplexen Prozesse, die der Identifizierung und Interpretation von genetischen Varianten zugrunde liegen, wären ohne die die enormen zur Verfügung stehenden Datenmengen nicht denkbar. Insofern sind „big data“ unabdingbare Voraussetzung, um genetische Daten im konkreten Einzelfall zu filtern und gerade für den klinisch tätigen Arzt im Kontakt mit dem Patienten überschaubar und nutzbar zu machen.

Schlüsselwörter

Big data - Genetik, Genomik - GJB2 - Hochdurchsatz-Sequenzierung - Genetik - Schwerhörigkeitsdiagnostik - Varianteninterpretation

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