We just got back from the Molecular Pathology (AMP) conference in Boston, where the conversation around clinical research and translational genomics was in full motion. The field is moving quickly and the technology is showing that comprehensive, high-accuracy genome sequencing is closer than ever to making an impact on clinical diagnostics.
Remarkably, this momentum is already taking shape in Europe. Recently, Radboud University Medical Center (Radboudumc) and Maastricht UMC+ announced they are among the first institutions in the world to use PacBio HiFi long-read genome sequencing to help enable clinical diagnostic findings. Radboudumc plans to sequence about 5,000 subjects per year, beginning with genetic forms of blindness and severe intellectual disabilities. Their team described this move as “the new standard”, noting that a single assay could potentially replace up to fifteen conventional ones. This shift is among one of the first of its kind aiming to deliver faster, more complete answers for families.
And that’s not all. We’re also seeing this momentum in the broader region as well. Researchers from the HiFi Solves EMEA consortium have published their first major study, with findings highlighting where HiFi sequencing can detect clinically relevant variants that remain hidden to short-read approaches.
This post explores those findings and what they signal about what’s to come for clinical genomics.
How long reads outperform short reads in the most challenging regions of the genome
Short-read sequencing still struggles to resolve “dark” or “camouflaged” regions of the genome, areas where highly similar gene and pseudogene sequences make mapping and variant calling unreliable. Many medically relevant genes, such as PMS2, SMN1/SMN2, and CYP21A2, fall into this category. Historically, these regions required complex, locus-specific testing using multiple assays just to reach a partial answer.
To combat some of these obstacles, the HiFi Solves EMEA consortium set out to test whether a HiFi whole genome could finally overcome those barriers. The study utilized HiFi long-read genome sequencing, combined with Paraphase, a dedicated haplotype-based variant caller, to see if the approach could capture the full spectrum of clinically relevant variation in these regions.
HiFi sequencing resolves all known clinically relevant variants in study
This multi-center validation study, conducted across four laboratories in Europe, analyzed 86 individuals with 125 known pathogenic variants across 11 paralogous loci, representing some of the toughest challenges in human genetics. They compared results against established clinical tests such as Sanger sequencing, multiplex ligation-dependent probe amplification (MLPA), and targeted PCR.
The results were decisive:
- Standard HiFi analysis detected 95 of 125 variants (76%).
- Additional HiFi analysis with Paraphase identified the remaining 30 variants (24%), including indels and structural variants missed by standard tools.
- Together, the methods achieved 100% detection of all known variants in the study, spanning SNVs, InDels, CNVs, SVs, and gene conversions.
This 100% detection rate is particularly startling considering it was achieved across multiple laboratories in separate institutions. Professor Johannes Zschocke, director of the Department of Human Genetics in Innsbruck, agrees:
“Reproducibility is the foundation of clinical adoption. The fact that HiFi sequencing produced consistent results across four diagnostic laboratories, each using their own workflows, demonstrates that this technology is mature, reliable, and ready for implementation at scale.”
Precise resolution with meaningful impact
HiFi sequencing also enabled accurate phasing in this study, determining whether variants occur on the same or different alleles, a distinction that’s essential for understanding inheritance patterns and disease risk. The researchers further showed that HiFi can resolve gene copy number and detect gene conversions, both of which are routinely missed by short-read technologies.
The data in the pre-print makes the advantage hard to miss. In comparisons between short-read and HiFi data, short-read alignments show gaps and mapping noise, while HiFi data provide clean, complete coverage. Paraphase separates reads by haplotype, distinguishing functional genes from pseudogenes, a breakthrough for accurate variant detection in paralogous regions.
The study also highlighted how HiFi accuracy can impact clinical interpretation. In one case, it identified a heterozygous deletion in OTOA – a hearing-related gene – that standard methods had completely missed. In another, HiFi showed that two pathogenic variants were in trans, clarifying both the diagnostic finding and the inheritance risk for the individual. Together, these examples illustrate how HiFi precision and completeness can meaningfully influence genetic insights, especially when prior tests haven’t provided answers.
A pivotal step toward widespread adoption
All 125 variants in the study were confirmed by standard-of-care methods, underscoring the accuracy and reproducibility of HiFi sequencing. The authors conclude that long-read genome sequencing is “ready for a wider implementation, possibly as a first-tier diagnostic approach for individuals with suspected variants in these paralogous regions.”
Senior authors of this study, professors Spielmann, Zschocke, Bolz and Hoischen on behalf of the HiFi Solves EMEA Consortium, emphasize the impact of this.
“This demonstrates the readiness of PacBio HiFi long-read sequencing for use in clinical genetics research. Across multiple laboratories and variant types, HiFi sequencing consistently and accurately identified all known pathogenic variants, including those in regions long considered inaccessible by standard technologies.
This multi-center validation study 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.”
A proud moment for HiFi Solves EMEA
This publication is a major ‘first’ for the HiFi Solves EMEA consortium, and a strong indicator of where HiFi sequencing is headed in clinical research. It’s one of the first multi-institutional studies providing evidence that HiFi sequencing is robust, scalable, and capable of resolving the most complex regions of the human genome that short-read and other technologies have struggled with for years.
By delivering comprehensive, clinically relevant insights in a single assay, HiFi sequencing is bringing the promise of precision diagnostics within reach for more patients and families across Europe and beyond.
Visit our genetic testing page to learn more about how HiFi sequencing can benefit pre-clinical workflows, or download our Pre-Clinical Playbook for practical guidance on adopting long reads in your laboratory.