Abstract
The wide implementation of next-generation sequencing (NGS) technologies has revolutionized the field of medical genetics. However, the short read lengths of currently used sequencing approaches pose a limitation for the identification of structural variants, sequencing repetitive regions, phasing of alleles and distinguishing highly homologous genomic regions. These limitations may significantly contribute to the diagnostic gap in patients with genetic disorders who have undergone standard NGS, like whole exome or even genome sequencing. Now, the emerging long-read sequencing (LRS) technologies may offer improvements in the characterization of genetic variation and regions that are difficult to assess with the prevailing NGS approaches. LRS has so far mainly been used to investigate genetic disorders with previously known or strongly suspected disease loci. While these targeted approaches already show the potential of LRS, it remains to be seen whether LRS technologies can soon enable true whole genome sequencing routinely. Ultimately, this could allow the de novo assembly of individual whole genomes used as a generic test for genetic disorders. In this article, we summarize the current LRS-based research on human genetic disorders and discuss the potential of these technologies to facilitate the next major advancements in medical genetics.
Highlights
Since its introduction over a decade ago, next-generation sequencing (NGS) of DNA has become a routine diagnostic tool for modern medical genetics and revolutionized the discovery of novel Mendelian disease genes (Gilissen et al, 2011)
We focus on the prevailing true long-read sequencing (LRS) methods that have been commercially released so far; single molecule real-time (SMRT) sequencing by Pacific Biosciences (PacBio) and nanopore sequencing by Oxford Nanopore Technologies Inc. (ONT) (Clarke et al, 2009; Eid et al, 2009) (Box 1 for technical summary)
Most of the clinically relevant examples described in this review use targeted LRS approaches, indicating that the broader use of LRS could significantly increase the diagnostic yield of genetic testing and discover novel disease genes
Summary
Since its introduction over a decade ago, next-generation sequencing (NGS) of DNA has become a routine diagnostic tool for modern medical genetics and revolutionized the discovery of novel Mendelian disease genes (Gilissen et al, 2011). With the recently demonstrated success in identifying previously intractable DNA sequences and closing gaps in the human genome assemblies (Chaisson et al, 2015a; Seo et al, 2016; Shi et al, 2016; Jain et al, 2018), long-read sequencing (LRS) technologies hold the promise to overcome specific limitations of NGS-based investigations of human diseases.
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