PacBio has announced the publication of a new preprint from the HiFi Solves EMEA Consortium, “HiFi sequencing accurately identifies clinically relevant variants in paralogous genes.”
PacBio
The study shows that PacBio HiFi sequencing combined with Paraphase, a dedicated haplotype-based variant caller, uncovered all known clinically relevant variants present in the study population – even in the hardest-to-sequence regions of the genome – demonstrating its readiness to power the future of clinical discovery.
From five institutions across Europe, in a cohort of 86 individuals carrying 125 known pathogenic variants across 11 complex genomic regions, HiFi sequencing combined with Paraphase detected all 125 clinically relevant variants in the study. The work represents the strongest validation to date of HiFi Solves’ founding goal: to show that high-accuracy long reads can bridge today’s research with tomorrow’s clinical utility.
“When we launched HiFi Solves, we knew that HiFi sequencing could bridge the gap between research and clinical utility,” said Christian Henry, president and chief executive officer of PacBio. “The results of this study show that a single HiFi genome can replace multiple separate tests, helping researchers find answers faster and more efficiently while saving time, resources, and significant costs.”
Each sample was sequenced on a single SMRT Cell with a median read length of 15.5 kb and accuracy, generating highly accurate HiFi reads with mean per-base accuracy above 99.9%. The multi-centre team proved that HiFi sequencing could accurately phase variants, resolve copy-number changes between genes and pseudogenes, and detect complex events such as gene conversions, providing a new a level of full haplotype resolution and copy-number precision that surpasses traditional short-read and targeted approaches.
“This first clinical utility study from the HiFi Solves EMEA Consortium demonstrates the potential of PacBio HiFi long-read sequencing for use in clinical genetics. Across multiple diagnostic laboratories and variant types, HiFi sequencing with Paraphase consistently and accurately identified all known pathogenic variants in the study, including those in regions long considered inaccessible by standard technologies. This multi-centre validation provides compelling evidence that HiFi long-read sequencing is robust, reproducible, and capable of addressing some of the most challenging cases in genomic medicine. We believe these results mark a pivotal step toward the widespread adoption of long-read genomes in routine clinical testing and rare disease diagnostics,” stated the senior authors of this study, professors Spielmann, Zschocke, Bolz and Hoischen on behalf of the HiFi Solves EMEA Consortium.
Founded in 2023, HiFi Solves unites leading clinical and research institutions worldwide to evaluate the real-world utility of PacBio HiFi sequencing for human health applications. The consortium now includes 23 institutions across 16 countries, spanning Europe, Asia Pacific, and North America.
“I am excited about the convincing outcome of the first multi-centre clinical utility study of our HiFi Solves EMEA consortium. What’s most remarkable is that this technology performs robustly across multiple centers, with 100% detection rate of very challenging, clinically relevant variants. That reproducibility is key to establishing long-read genomes as part of routine clinical testing,” said Prof. Alexander Hoischen, from the Department of Human Genetics in Nijmegen. “Genes that have pseudogene copies – or paralogous sequences with >99% sequence homology – such as CYP21A2, SMN1/SMN2 and IKBKG have long been amongst the toughest to study. HiFi sequencing illuminates them, allowing now to accurately detect pathogenic variants of all variant types including gene conversions that previously posed extreme challenges to genetic laboratories.”
By uniting leading research centres and clinicians around the world, the HiFi Solves Consortium is turning data into deeper understanding and showing how complete genomes can fundamentally change what’s possible in rare disease research.