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Review: Long-Read Sequencing Helps Uncover Genetic Basis for Rare Disease

Thursday, October 10, 2019

A new review article nicely sums up the utility of long-read sequencing for solving rare diseases that cannot be explained by other methods. The paper, published in the Journal of Human Genetics, comes from authors Satomi Mitsuhashi and Naomichi Matsumoto at Yokohama City University in Japan.

The scientists note that long-read sequencing serves as a good complementary approach for cases that are not solved with short-read sequencing alone. “The approximate current diagnostic rate is <50% using [short-read whole exome and genome sequencing], and there remain many rare genetic diseases with unknown cause,” Mitsuhashi and Matsumoto write. “There may be many reasons for this, but one plausible explanation is that the responsible mutations are in regions of the genome [or are types of variants] that are difficult to sequence using conventional technologies.”

Many recent projects have used long-read sequencing technologies to discover pathogenic variants associated with rare disease. “The results of these studies provide hope that further application of long-read sequencers to identify the causative mutations in unsolved genetic diseases may expand our understanding of the human genome and diseases,” the scientists report.

The review discusses several particular types of disease-causing variants, including tandem repeats, structural variants, complex rearrangements, and transposable elements. In addition to citing studies that have used long-read sequencing to search for pathogenic variants, the scientists also consider why long reads make a difference for each situation. With tandem repeats, for example, they note that “long tandem repeats are difficult to analyze by Sanger sequencing,” and “long reads are a straightforward way to detect repeat changes because an adequately long read can encompass an entire expanded repeat as well as flanking unique sequences.”

Mitsuhashi and Matsumoto also review studies in which researchers made use of the PacBio No-Amp targeted sequencing application  to target a region of the genome using CRISPR instead of PCR amplification. In the studies, scientists “found this approach accurate” and obtained high-coverage HiFi reads of the targeted region.

Going forward, the authors suggest a workflow for solving rare disease cases: begin with short-read exome or whole genome sequencing for small variants, and if that does not yield an answer, move on to long-read sequencing for larger variants. “Long-read sequencing is especially highly recommended when repeat diseases or complex chromosomal rearrangements are suspected,” they conclude.

Proposed workflow for identifying pathogenic mutations in rare disease cases

Matsumoto will be presenting his team’s research at our ASHG 2019 workshop on Wednesday, October 16, 2019. Register today to reserve your seat or to get the recording.

Learn more about Variant Detection with SMRT Sequencing.

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