PacBio HiFi Sequencing Achieves 100% Detection Rate for Pathogenic Variants in Multi-Center Clinical Study
Key Insights
The HiFi Solves EMEA Consortium (search) published a landmark multi-center study demonstrating that PacBio (search) HiFi sequencing combined with Paraphase detected all 125 known pathogenic variants across 86 individuals from five European institutions.
The technology achieved 100% detection accuracy even in the most challenging genomic regions, including paralogous genes like CYP21A2 (search), SMN1 (search)/SMN2 (search), and IKBKG (search) that have been historically difficult to sequence with traditional methods.
HiFi sequencing generated reads with mean per-base accuracy above 99.9% and median read length of 15.5 kb, enabling accurate phasing of variants and detection of complex genomic events like gene conversions.
PacBio (search)'s HiFi long-read sequencing technology has achieved a perfect detection rate in the largest clinical validation study to date, successfully identifying all 125 known pathogenic variants across 86 individuals in a multi-center European study. The breakthrough results, published by the HiFi Solves EMEA Consortium (search), demonstrate the technology's readiness for clinical implementation and its potential to revolutionize genetic diagnostics.
Perfect Detection Across Challenging Genomic Regions
The study, conducted across five institutions in Europe, tested HiFi sequencing combined with Paraphase, a dedicated haplotype-based variant caller, on 11 complex genomic regions known for their difficulty in genetic analysis. Each sample was sequenced on a single SMRT Cell, generating highly accurate HiFi reads with mean per-base accuracy above 99.9% and a median read length of 15.5 kb.
"What's most remarkable is that this technology performs robustly across multiple centers, with 100% detection rate of very challenging, clinically relevant variants," said Prof. Alexander Hoischen from the Department of Human Genetics in Nijmegen. "That reproducibility is key to establishing long-read genomes as part of routine clinical testing."
Breakthrough in Paralogous Gene Analysis
The study particularly excelled in analyzing paralogous genes—sequences with greater than 99% sequence homology that have historically posed extreme challenges to genetic laboratories. HiFi sequencing successfully illuminated genes such as CYP21A2 (search), SMN1 (search)/SMN2 (search), and IKBKG (search), which have pseudogene copies that make them among the toughest genomic regions to study.
The technology demonstrated its ability to accurately phase variants, resolve copy-number changes between genes and pseudogenes, and detect complex events such as gene conversions. This level of full haplotype resolution and copy-number precision surpasses what traditional short-read and targeted approaches can achieve.
Clinical Implementation Potential
According to Christian Henry, President and Chief Executive Officer of PacBio (search), the results 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."
The senior authors of the study—professors Spielmann, Zschocke, Bolz and Hoischen—stated that the multi-center 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."
Global Consortium Expansion
The HiFi Solves Consortium, founded in 2023, has grown to include 23 institutions across 16 countries, spanning Europe, Asia Pacific, and North America. The consortium unites leading clinical and research institutions worldwide to evaluate the real-world utility of PacBio (search) HiFi sequencing for human health applications.
The consortium's work represents the strongest validation to date of its founding goal: to demonstrate that high-accuracy long reads can bridge today's research with tomorrow's clinical utility. The results mark what researchers believe is a pivotal step toward the widespread adoption of long-read genomes in routine clinical testing and rare disease (search) diagnostics.