Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/ijms22062943
Keywords
inherited hearing loss; inherited retinal dystrophies; genetic diagnostics; diagnostic yield; next-generation sequencing; third-generation sequencing; variant interpretation
Funding
- Foundation Fighting Blindness USA Project Program Award [PPA-0517-0717-RAD]
- DCMN Radboudumc grant
- Algemene Nederlandse Vereniging ter Voorkoming van Blindheid, Oogfonds, Landelijke Stichting voor Blinden en Slechtzienden
- Rotterdamse Stichting Blindenbelangen, Stichting Blindenhulp, Stichting tot Verbetering van het Lot der Blinden
- Stichting Blinden-Penning
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The review outlines the historical development of molecular diagnosis of monogenic diseases and the evolution of DNA sequencing technologies from Sanger to next-generation sequencing to third-generation sequencing. It also highlights the potential of novel approaches like optical mapping and multiomics in identifying genetic defects.
The identification of pathogenic variants in monogenic diseases has been of interest to researchers and clinicians for several decades. However, for inherited diseases with extremely high genetic heterogeneity, such as hearing loss and retinal dystrophies, establishing a molecular diagnosis requires an enormous effort. In this review, we use these two genetic conditions as examples to describe the initial molecular genetic identification approaches, as performed since the early 90s, and subsequent improvements and refinements introduced over the years. Next, the history of DNA sequencing from conventional Sanger sequencing to high-throughput massive parallel sequencing, a.k.a. next-generation sequencing, is outlined, including their advantages and limitations and their impact on identifying the remaining genetic defects. Moreover, the development of recent technologies, also coined third-generation sequencing, is reviewed, which holds the promise to overcome these limitations. Furthermore, we outline the importance and complexity of variant interpretation in clinical diagnostic settings concerning the massive number of different variants identified by these methods. Finally, we briefly mention the development of novel approaches such as optical mapping and multiomics, which can help to further identify genetic defects in the near future.
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