Expanding Access to Whole-Genome Testing for Children: Q&A with Drs. Ryan Taft and Stacy Musone

Earlier this year, PacBio announced a collaboration with global rare disease genomics program iHope (part of the Genetic Alliance). This partnership will combine PacBio’s HiFi long-read whole genome sequencing with iHope’s international network, which supports more than 1,000 patients across the globe.

Dr. Ryan Taft, chief scientific officer at iHope, and Dr. Stacy Musone, of PacBio, spoke with Pharmaceutical Executive about new advancements in genomic testing and how collaborations like this can spark new research into precision medicine in rare diseases. Due to comparatively small patient populations, research for rare diseases can be difficult to perform. By combining new technology with an existing network, the two organizations hope to bring whole-genome testing to children in impoverished or otherwise medically underserved areas.

Pharmaceutical Executive: How has new technology impacted treating and diagnosing rare diseases?
Dr. Ryan Taft: The improvements in rare disease diagnostics over the past decade have been nothing short of transformational. Prior to the introduction of broad-based sequencing tests, diagnostic yield averaged less than 15%. It is not now uncommon to see diagnostic yield reach up to 60% in certain cohorts. This has set the foundation for true precision management and interventions. Recent publications have estimated that 70% of individuals who receive genomic testing see benefit – from improved clinical decision making to the use of tailored and precision therapeutics.

Dr. Stacy Musone: Genomic testing has been beneficial to rare disease patients across the board, but highly accurate long-read WGS provides a complete and continuous view of the genome in a single test. By generating runs of DNA reads that span thousands of base pairs, long-read WGS detects larger and more complex variants that short-read sequencing misses. Because long-reads sequence kilobase-length DNA strands in a single read rather than breaking it into small fragments and reconstructing them, long-reads preserve molecular integrity while improving precision.

This improved resolution increases diagnostic yield and decreases the need for follow-up tests, significantly reducing patient burden. Beyond diagnosis, comprehensive genomic insights support the development of precision therapies, including antisense oligonucleotides, where understanding the exact variant and its genomic context is essential for designing safe treatments.

PE: How can equitable access to advanced genomics change issues with inconclusive testing and low diagnosis rates?
Taft: Equitable access to advanced genomics is central to addressing persistently low diagnosis rates in rare diseases. Globally, rare diseases affect more than 300 million people, yet access to testing remains uneven. In many regions, sequencing is unavailable. In others, even with well-resourced health systems, advanced sequencing is limited to those who can afford it. This inequity only prolongs the diagnostic odyssey and leaves many families without answers.

Initiatives like iHope were founded on the principle that a patient’s birthplace should not determine access to genetic testing or treatment. By integrating long-read WGS into a global network of clinical sites, we further increase access for patients who would otherwise have no pathway to testing. When equitable access is paired with cutting edge technology, diagnosis rates improve, care pathways become more informed, and patients have more opportunity to take part in clinical trials and emerging therapies.

PE: What is the long-read method, and how does it impact the rare disease space?
Musone: Short-read approaches fragment DNA into small pieces and computationally reconstruct the genome against a reference – this can obscure complex regions and structural variation. In contrast, long-read WGS analyzes extended stretches of native DNA in a single pass, preserving genomic context and improving accuracy across repetitive or structurally complex regions.

This difference in sequencing technology is especially important for detecting pathogenic variants in rare diseases. Many of these variants involve repeat expansions, structural rearrangements, copy number changes, or reside in so-called “dark” regions of the genome that short reads struggle to resolve. Long-reads span entire repeat regions, determine whether variants occur on the same maternal or parental chromosome through phasing, and detect epigenetic signatures all within the same workflow.

This visibility increases diagnostic yield and consolidates multiple legacy assays into a single genome-wide test. As sequencing costs decrease and throughput increases, long-read WGS is becoming an increasingly viable earlier step in the rare disease diagnostic pathway.

PE: Where has long read been proven transformative?
Musone: Long-read WGS has already transformed rare disease research and clinical investigation. Research led by Radboud University Medical Center illustrated that advanced long-read sequencing could replace multiple diagnostic tests with a single complete run. In this study, HiFi WGS identified 93% of pathogenic variants in a cohort of challenging rare disease cases and detected genetic variants that had been missed by short-reads, including complex structural changes and DNA methylation abnormalities.

Collaborative initiatives such as the Undiagnosed Hackathon have also highlighted the value of HiFi sequencing. By combining international expertise with long-read technology, potential diagnoses were identified for 10 previously unsolved cases within two days, offering new hope to families who had spent years looking for answers.

Beyond rare disease, long read WGS has made significant strides in understanding the human genome. In 2022, the Telomere-to-Telomere (T2T) Consortium used HiFi long reads to publish the first fully complete human genome, revealing nearly 200 million base pairs of previously missing sequence. This complete reference genome will help scientists identify disease‑associated variants and better understand genetic diseases and human biology.

PE: What complications do patients around the world face in receiving testing for rare diseases?
Taft: Unfortunately, patients with rare genetics still face considerable hurdles. These disorders are under-recognized, and the first challenge a patient with a rare disorder often is having the healthcare system identify them as someone who may have a genetic disorder and therefore could benefit from genomic testing. Access to testing varies dramatically. In many low- and middle-income countries, advanced sequencing is simply unavailable. Even in wealthy, nationalised health systems, comprehensive testing is still often gated by funding, extensive wait time and insufficient interpretation capacity.

As a result, patients can wait years for a diagnosis, and many will never receive one. Without a diagnosis, families lack clarity about prognosis, disease management, and recurrence risk, and patients may be excluded from clinical trials or targeted therapies. It is essential that we to shorten the diagnostic odyssey and improve outcomes for rare disease patients worldwide.