Diagnostic Analyses of Retinal Dystrophy Genes: Current Status and Perspective

Abstract

Over the past decade, novel high-throughput DNA sequencing technologies have revolutionised both research and diagnostic testing for monogenic disorders. This applies particularly to genetically very heterogeneous disorders like retinal dystrophies (RDs). Next-generation sequencing (NGS) today is considered as reliable as Sanger sequencing, which had been the gold standard for decades. Today, comprehensive NGS-based diagnostic testing reveals the causative mutations in the majority of RD patients, with important implications for genetic counselling for recurrence risks and personalised medical management (from interdisciplinary surveillance to prophylactic measures and, albeit yet rare, [gene] therapy). While DNA sequencing is – in most cases – no longer the diagnostic bottleneck, one needs to be aware of interpretation pitfalls and dead ends. The advent of new (NGS) technologies will solve some of these issues. However, specialised medical geneticists who are familiar with the peculiarities of certain RD genes and closely interact with ophthalmologists will remain key to successful RD research and diagnostic testing for the benefit of the patients. This review sheds light on the current state of the field, its challenges and potential solutions.

Zusammenfassung

Während des vergangenen Jahrzehnts haben neue Hochdurchsatz-DNA-Sequenziertechnologien Forschung und Diagnostik im Bereich monogener Erkrankungen revolutioniert. Dies trifft insbesondere auf Erkrankungen mit ausgeprägter genetischer Heterogenität, wie die retinalen Dystrophien (RD), zu. Next-Generation Sequencing (NGS) gilt heute als ebenso verlässlich wie die Sanger-Sequenzierung, die über Jahrzehnte den Goldstandard darstellte. Heute ermöglicht die umfassende genetische Diagnostik die Stellung einer genetischen Diagnose bei den meisten RD-Patienten, was für humangenetische Beratung und personalisierte Betreuung (von interdisziplinärer Begleitung bis hin zu prophylaktischen Maßnahmen sowie, wenngleich noch selten, [Gen-]Therapie) von großer Bedeutung ist. Während die Sequenzierung nicht mehr das Nadelöhr darstellt, muss man sich der Gefahr von Interpretationsfehlern und der Existenz „toter Winkel“ in der Diagnostik bewusst sein. Die Einführung neuer NGS-Ansätze wird einen Teil dieser Probleme lösen. Schlüssel zu einer erfolgreichen Forschung und Diagnostik bleibt jedoch die Interaktion von mit RD intensiv vertrauten Humangenetikern und behandelnden Augenärzten. Diese Übersicht behandelt den aktuellen Stand des Themas, seine Herausforderungen und mögliche Lösungen.

Key words

next-generation sequencing - retinal dystrophy - genetics

Schlüsselwörter

Genetik - Retina - Next Generation Sequencing - Netzhautdystrophie

Publication History

Received: 14 December 2020

Accepted: 03 February 2021

Article published online:
30 March 2021

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