Unlock Rare Disease Genomics
Improvements in sequencing technology are increasing the ability of scientists to shed light on previously unresolved medical mysteries and enable the development of rare disease diagnostics.
Rare Diseases Need Better Solutions
Although rare diseases are individually rare, collectively they are common, affecting 1 in 2,000 people worldwide with 80% of cases being genetic in origin and >50% of cases remaining unsolved. This is despite many people undergo diagnostic tests using approaches including microarrays, whole exome, or short-read whole genome sequencing.
Highly accurate long-read sequencing, known as HiFi sequencing, provides a higher resolution approach compared to previously used technologies to better understand the genetic causes of rare disease.
The Benefits of HiFi Sequencing for Rare Diseases
With accuracy >99.9% and long read lengths up to 25 kb, HiFi sequencing allows scientists to find causative pathogenic variants and identify novel disease-associated genes with:
- Best-in-class variant calling for all variant types including single nucleotide variants (SNV), indels, copy number variants (CNVs), and structural variants (SVs)
- Complete, accurate, and phased assemblies of the human genome— including regions previously inaccessible to other technologies— for accurate typing of genes including HLA and CYP2D6
Spotlight: Children's Mercy Hospital Uses HiFi Sequencing in Genomic Answers for Kids Study
Genomic Answers 4 Kids
Children’s Mercy Kansas City has expanded its investment in PacBio Sequel IIe Systems to scale up whole genome research initiatives focused on rare disease research, and the results are already beginning to add up. Read about their success in resolving the mysteries of rare and inherited disease in children in our newly released customer success story.
How HiFi Sequencing Helps Answer Difficult Rare Disease Questions
In the video below, Dr. Emily G. Farrow of Children’s Mercy Kansas City discusses three studies in which PacBio HiFi sequencing was able to explain genetic mysteries where other technologies had failed due to several challenges including phasing of variants, achieving even sequence coverage, and sequencing repetitive regions.
Explore the Range of HiFi Sequencing Applications
 |
Whole Genome Sequencing Generate reference-quality de novo genome assemblies |
 |
Variant Detection Comprehensively detect all variants in the human genome |
 |
Targeted Sequencing Focus on variation in even the most difficult regions of the genome, and explore our No-Amp method of targeted sequencing |
 |
RNA Sequencing Get a complete view of transcript isoform diversity – no assembly required |
Scalable Human Whole Genome HiFi Sequencing for Rare and Inherited Disease Research
Explore our efficient and scalable workflow, developed in collaboration with Children’s Mercy Kansas City, for high-throughput sequencing and comprehensive variant detection to better understand the genetic causes of rare and inherited diseases.
Spotlight: 12 kb Inversion Identified as Causative in Syndromic Intellectual Disability
HiFi sequencing of a trio identifies a pathogenic heterozygous 12 kb de novo inversion that disrupts BRPF1 the gene. SNVs (marked with “*”) show that the inversion occurred on the maternal allele #3. Read more about this study in the blog post.
Mizuguchi, T., et al. (2021) Pathogenic 12-kb copy-neutral inversion in syndromic intellectual disability identified by high-fidelity long-read sequencing. Genomics. 113(1).
Selected Resources
- Takeshi Mizuguchi et al. (2021) Pathogenic 12-kb copy-neutral inversion in syndromic intellectual disability identified by high-fidelity long-read sequencing Genomics
- Mitsuhashi, Satomi et al. (2019) Long-read sequencing for rare human genetic diseases. Journal of human genetics
- Wenger, Aaron M et al. (2019) Accurate circular consensus long-read sequencing improves variant detection and assembly of a human genome. Nature biotechnology
- Reiner, Jennifer et al. (2018) Cytogenomic identification and long-read single molecule real-time (SMRT) sequencing of a Bardet-Biedl Syndrome 9 (BBS9) deletion. NPJ Genomic Medicine
- Asur, Rajalakshmi S et al. (2018) Somatic mosaicism of an intragenic FANCB duplication in both fibroblast and peripheral blood cells observed in a Fanconi anemia patient leads to milder phenotype. Molecular genetics & genomic medicine
- Merker, Jason D et al. (2017) Long-read genome sequencing identifies causal structural variation in a Mendelian disease. Genetics in medicine
- Lapinski, Philip E et al. (2018) Somatic second hit mutation of RASA1 in vascular endothelial cells in capillary malformation-arteriovenous malformation. European journal of medical genetics
- Hickey, Luke et al. (2017) Hunting structural variants: Population by population Front line genomics magazine
- Hickey, L. et al. (2017) Structural variation offers new home for disease associations and gene discovery Drug discovery and development magazine
- Poster: Harting, John et al. (2021) Resolving Highly Diverse HLA and CYP2D6 Alleles Using HiFi Sequencing for Long-Range Amplicon Data with a New Clustering Algorithm
- Poster: Dhillon, Harsharan et al. (2021) Simplified and Robust Library Construction for High-Throughput HiFi Sequencing for Human Variant Detection
- Poster: McLaughlin, Ian et al. (2021) Targeting Clinically Significant Dark Regions of the Human Genome with High-Accuracy, Long-Read Sequencing
- Poster: Zhu, Lei et al. (2021) Full-Length Sequencing of CYP2D6 Locus with HiFi Reads Increasing Genotypes Accuracy
- Poster: McLaughlin, Ian et al. (2021) Targeting Clinically Significant Dark Regions of the Human Genome with High-Accuracy, Long-Read Sequencing
- Poster: Zhu, Lei et al. (2021) Full-Length Sequencing of CYP2D6Variants with PacBio HiFi Reads
- Poster: Harting, John et al. (2021) Resolving Complex Pathogenic Alleles using HiFi Long-range Amplicon Data and a New Clustering Algorithm
- Poster: McLaughlin, Ian et al. (2021) Targeting Clinically Significant Dark Regions of the Human Genome with High-Accuracy, Long-Read Sequencing
- Poster: Ekholm, Jenny et al. (2020) Amplification-free targeted enrichment powered by CRISPR-Cas9 and long-read Single Molecule Real-Time (SMRT) Sequencing can efficiently and accurately sequence challenging repeat expansion disorders
- Poster: Rowell, William J. et al. (2020) Comprehensive variant detection in a human genome with highly accurate long reads
- Poster: Rowell, William J. et al. (2020) A workflow for the comprehensive detection and prioritization of variants in human genomes with PacBio HiFi reads
- Poster: Underwood, Jason et al. (2020) A complete solution for full-length transcript sequencing using the PacBio Sequel II System
- Poster: Tsai, Yu-Chih et al. (2020) Amplification-free protocol for targeted enrichment of repeat expansion genomic regions and SMRT Sequencing
- Poster: Wenger, Aaron M. et al. (2020) Copy-number variant detection with PacBio long reads
- Poster: Baybayan, Primo et al. (2020) New advances in SMRT Sequencing facilitate multiplexing for de novo and structural variant studies
- Poster: van Min, M. et al. (2019) TLA & long-read sequencing: Efficient targeted sequencing and phasing of the CFTR gene
- Poster: Audano, Peter A. et al. (2018) Improving the reference with a diversity panel of sequence-resolved structural variation
- Poster: Vogelsang, R. et al. (2018) Population-scale discovery of structural variants with PacBio SMRT Sequencing
- Henry, Christian and Shen, Richard and Stone, Jennifer (2021) With Long Reads and Short Reads, the Possibilities are Endless – PacBio ASHG 2021 Fireside Chat
- Stone, Jennifer (2021) HiFi Sequencing: See What You’ve Been Missing
- Hiatt, Susan and Korlach, Jonas (2021) Long-Read Genome Sequencing for the Molecular Understanding of Neurodevelopmental Disorders
- Wenger, Aaron (2021) Complete and Accurate Human Genomes with HiFi Reads
- Hoischen, Alexander (2021) Long Reads to Identify Hidden Structural Variants in Rare Disease
- Matsumoto, Naomichi (2021) The Utility of HiFi Long-Read WGS in Solving Patients with Rare Diseases
- Rowell, William and LIeras, Roberto (2021) A Bioinformatics Workflow for Comprehensive Detection and Prioritization of Variants with PacBio HiFi Reads
- Pastinen, Tomi (2021) Genomic Answers for Kids
- Ekholm, Jenny (2021) Increasing Solve Rates in Rare and Mendelian Disease Research with Long-Read Sequencing
- Lambert, Christine (2021) Scalable Workflow for Constructing HiFi Libraries
- Wenger, Aaron (2021) The Present and Future of HiFi Whole-Genome Sequencing for Rare Disease
- Blethrow, Justin and Smith, Melissa L. and Vinnere Pettersson, Olga (2021) Webinar: Unleashing the Power of HiFi Sequencing – How the Sequel IIe System Removes Barriers and Empowers Life Scientists
- Miller, Dave and Hernandez, Alvaro (2021) Creating Core Demand with HiFi Sequencing
- Wenger, Aaron (2021) Not All Long Reads Are Equal – High Accuracy Sets PacBio Apart
- Miller, David and Smith, Melissa Laird (2021) The Long and Short of Sequencing – Why HiFi Reads are the Future
- Becker, Aaron and Ekholm, Jenny and Harris, Charlotte and Kingham, Brewster and Vinnere Pettersson, Olga (2021) SMRT Sequencing as a Service – How to Bring Long-Read Technology to Your Core Lab
- Korlach, Jonas (2021) AGBT Presentation: Increasing the Solve Rate of Rare and Undiagnosed Genetic Diseases with HiFi Sequencing
- (2020) Application Tutorial: Introduction to Variant Detection with HiFi Reads
- (2020) Introduction to highly accurate long-read sequencing (HiFi Sequencing)
- Ekholm, Jenny (2020) Virtual Global Summit: Increasing Solve Rates for Rare and Mendelian Diseases with Long-Read Sequencing
- Miller, Neil (2020) Virtual Global Summit: Third generation sequencing for diagnosis of rare disease
- Hernandez, Alvaro (2020) Virtual Global Summit: Using the unique capabilities of the Sequel II System for de novo genome assembly and full-length 16S sequencing
- Farrow, Emily (2020) ASHG PacBio Workshop: Applications of third generation sequencing in unsolved disease
- Korlach, Jonas (2020) ASHG PacBio Workshop: Latest product and application updates
- Wenger, Aaron (2020) Educational Video: Variant Detection with HiFi Reads – Understanding Results from the precisionFDA Truth Challenge
- Sund, Kristen and Wenger, Aaron (2020) Webinar: Increasing solve rates for rare and Mendelian diseases with long-read sequencing
- Matsumoto, Naomichi (2019) ASHG PacBio Workshop: Long-read sequencing for disease genome analysis: Our experiences
- Korlach, Jonas and Lleras, Roberto (2018) User Group Meeting: Structural variant calling in SMRT Link 6.0
- Sedlazeck, Fritz (2018) Webinar: Size Matters: Accurate detection and phasing of structural variations
- Hoischen, A. and Wenger, A (2018) Webinar: Sequencing structural variants for disease gene discovery and population genetics
- Application Brochure: What can you do with one SMRT Cell? (2021)
- SMRT Sequencing Brochure: Delivering highly accurate long reads to drive discovery in life science (2021)
- Informational Guide: Whole genome sequencing for understanding rare diseases (2021)
- Application Brief: Variant detection using whole genome sequencing with HiFi reads – Best Practices (2021)
- Application Brief: Whole genome sequencing for de novo assembly – Best Practices (2021)
- Application Brochure: Scalable human whole genome HiFi sequencing for rare and inherited disease research (2021)
- Application Brief: No-Amp targeted sequencing – Best Practices (2020)
- Application Brief: Single-cell RNA sequencing with HiFi reads – Best Practices (2020)
- Product Brochure: Sequel IIe System – Sequencing evolved (2020)
- Informational Guide: Understanding accuracy in DNA sequencing (2020)
- Application Brochure: HiFi reads for highly accurate long-read sequencing (2020)
- Application Brief: Long-read RNA sequencing – Best Practices (2019)
- Infographic: Identify the cause of unsolved genetic disease with long-read sequencing (2018)