Identification of pathogenic structural variants with SMRT Sequencing improves solve rate for rare and Mendelian diseases
MENLO PARK, Calif., June 13, 2019 (GLOBE NEWSWIRE) -- While DNA sequencing tools have been useful for determining the genetic cause of many diseases, there remain a large number that are left unexplained. Recently, scientists have adopted Single Molecule, Real-Time (SMRT) Sequencing from Pacific Biosciences of California, Inc. (Nasdaq:PACB), a leading provider of high-quality sequencing of genomes, transcriptomes and epigenomes, to study previously unsolved diseases. Many high-impact research publications report expanded variant detection in human genomes, leading to discovery of disease-causing variants and genes underlying rare and Mendelian disorders.
In a Nature Communications publication, scientists report that most structural variants (SVs) and large indels are undetected in today's human genetic studies, which likely accounts for some of the missing heritability of genetic disease1. Meanwhile, several studies have demonstrated that these missing variants can be discovered routinely using highly accurate long reads (HiFi reads) generated by the PacBio Sequel II System2,3. A review article from scientists at Radboud University Medical Center summarizes many of these findings, including genetic discovery results for ALS, Huntington's disease, Parkinsonism, epilepsy, ataxias, myotonic dystrophy, and Fragile X disorders4.
For example, scientists in Japan turned to SMRT Sequencing to explain a familial form of epilepsy that had not been solved with whole exome sequencing. PacBio whole genome sequencing data allowed the team to detect more than 17,000 SVs and quickly identify the 12.4 kb deletion responsible for the family's condition5. The team determined that "long-read sequencing ensures unbiased coverage even in GC-rich repetitive sequences, which enables the identification of previously unidentified pathogenic SVs."
"Far too many genetic diseases have gone unsolved in the genomic era, and it's becoming clear that some of the answers were simply not conducive to detection with previous technologies," said Jonas Korlach, Chief Scientific Officer of Pacific Biosciences. "It's been tremendously gratifying to see the flurry of recent publications reporting the discovery of underlying causes for some of these diseases through the use of SMRT Sequencing systems."
Additional studies describing novel disease-causing variant detection with SMRT Sequencing will be presented at the European Society of Human Genetics, taking place June 15-18 in Gothenburg, Sweden. To learn more, please visit PacBio in ESHG booth #560 or download a flyer with a list of featured presentations at: https://www.pacb.com/wp-content/uploads/2019-ESHG-Program-Flyer.pdf.
- Chaisson, M. J. P., et al. (2019) Multi-platform discovery of haplotype-resolved structural variation in human genomes (https://www.nature.com/articles/s41467-018-08148-z). Nature Communications, 10(1), 1784.
- Wenger, A. M., et al. (2019) Highly-accurate long-read sequencing improves variant detection and assembly of a human genome (https://doi.org/10.1101/519025). bioRxiv, doi:10.1101/519025.
- Vollger, M. R., et al. (2019) Improved assembly and variant detection of a haploid human genome using single-molecule, high-fidelity long reads (https://doi.org/10.1101/635037). bioRxiv, doi:10.1101/635037.
- Mantere, T., et al. (2019) Long-read sequencing emerging in medical genetics (https://www.frontiersin.org/article/10.3389/fgene.2019.00426). Frontiers in Genetics, 10, 426.
- Mizuguchi, T., et al. (2019) A 12-kb structural variation in progressive myoclonic epilepsy was newly identified by long-read whole-genome sequencing (https://www.nature.com/articles/s10038-019-0569-5). Journal of Human Genetics, 64, 359-368.
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