Ryan Taft, (Genetic Alliance/iHope Network), and Stacy Musone, PhD (PacBio) discuss equitable access to sequencing, the power of long-read genomics, and the systemic changes needed to end the rare disease diagnostic odyssey.
Can you explain the mission behind iHope and why equitable access to genomic testing remains such an urgent issue globally?
Ryan Taft: iHope was founded on a simple idea: where a child is born should not determine whether they receive genetic testing. We’ve now grown iHope into the world’s largest equitable rare disease genomic testing network, supporting more than 1,000 patients annually across 25 clinical sites in 14 countries.
Our global network provides no-cost clinical genome and exome sequencing to children who would otherwise have no pathway to testing. The need for our support is significant, as rare diseases affect more than 300 million people worldwide, yet access to advanced genomic technologies remains deeply uneven. In some regions, sequencing technology simply isn’t available. In others – even well-resourced health systems – comprehensive testing is reserved for only those who can afford it.
A diagnosis can have a tremendous impact. Answers guide clinical care, connect patients and clinicians to a community, and increasingly determine eligibility for targeted or precision therapies.
What does rare disease distribution look like globally, and why do certain regions or communities experience higher prevalence of specific conditions?
Stacy Musone: Rare diseases are individually uncommon, but risk is not evenly distributed worldwide. It varies between populations due to social, historical, and environmental factors that shape genetic makeup.
One area of research helping us understand rare disease distribution is the rate at which new mutations arise in each generation. For years, scientists estimated that each child was born with around 60 new genetic mutations not present in either parent. With long-read sequencing, we now know the number is closer to 150, because we can detect larger structural changes previously missed. For example, parts of the Y chromosome show mutation rates up to 30 times higher than the genome-wide average, differences that were underappreciated when technology could not fully resolve these regions.
Population history is another contributing factor. In communities where marriages between relatives are more common, there is a higher likelihood of inheriting two altered copies of the same gene, increasing the prevalence of autosomal recessive disorders. In other settings, the founder effect can amplify rare variants when a population descends from a small number of ancestors, leading to higher rates of specific conditions over generations.
These dynamics reinforce the need for diverse, population-scale genomics. Without representative datasets, we risk misinterpreting variant frequency and overlooking population-specific disease risk.
What does the typical rare disease diagnostic pathway look like today, and what are the biggest scientific and systemic barriers preventing patients from receiving a definitive diagnosis?
Musone: In many healthcare systems, the diagnostic pathway still follows a piecemeal model that leads to increased cost and patient burden. Diagnostics often begin with targeted gene panels or exome sequencing that look for specific markers associated with known conditions. If those tests are inconclusive, scientists examine the whole genome using an approach called short-read whole genome sequencing (WGS). Some countries, including the UK, have implemented short-read WGS as a first line test for suspected rare genetic disease, which represents meaningful progress. However, even with these advances, more than half of rare disease cases remain unsolved.
Scientifically, the issue is often not that the variant isn’t present, but the technology cannot resolve it. Short-read WGS approaches fragment DNA, making it difficult to detect complex structural variants, repeat expansions and episignatures that are frequently implicated in rare disease. As a result, patients undergo multiple tests, each capturing only part of the picture and delaying answers.
Taft: Systemic barriers are equally significant. Access to genomic testing varies dramatically across regions. In many parts of the world, sequencing is unavailable altogether. Elsewhere, there are long wait times, limited interpretation capacity, or insufficient follow-up care. The science and technology are no longer the issue. We have a last mile problem that is fundamentally a systems problem and its entirely within our power to solve it.
A diagnosis is more than merely a label. It informs management, connects families to support networks and enables access to trials or emerging therapies. Addressing both technological and accessibility barriers is essential to shortening the diagnostic odyssey.
How does long-read sequencing increase diagnostic yield, and can you share examples of the types of genomic variation that long-read sequencing may help uncover?
Musone: HiFi long-read whole-genome sequencing increases diagnostic yield by providing a more complete and contiguous view of the genome in a single test. Instead of reconstructing the genome from short-read fragments, PacBio sequences long stretches of native DNA. This preserves context, improves accuracy across complex regions and enables phasing, allowing scientists to see which variants are inherited together on the same chromosome, which can be crucial in rare disease diagnosis.
One example is repeat expansions that occur when DNA sequences are repeated too many times in a row, disrupting normal gene function. These repeats can stretch across thousands of bases, making them difficult to measure accurately with short-read technologies. Disorders such as Huntington’s disease and certain forms of amyotrophic lateral sclerosis (ALS) are caused by pathogenic repeat expansions. Long-reads can span the entire repeat region in one continuous sequence, allowing us to determine its exact length and structure.
The partnership also mentions future research into precision therapeutic approaches, including antisense oligonucleotide strategies. How important is resolving the full genomic context when moving from diagnosis to personalized intervention?
Taft: Precision therapies require truly personalized characterization of a patient’s genome. The more information that is available to clinicians and scientists, the more likely the therapy will be effective. Identifying the gene is only the first step. Precision treatments require understanding the exact variant, its structure and its functional impact.
Antisense oligonucleotides are designed to bind to specific RNA sequences to modify splicing or knock-down harmful transcripts. Designing them safely depends on precise sequence information. If a variant involves a repeat expansion or structural rearrangement, incomplete data can misdirect therapeutic development.
Musone: Comprehensive genomic resolution also clarifies whether a variant sits on the maternal or paternal chromosome and whether additional changes nearby could influence treatment response. As we move toward increasingly personalized and even single-patient therapies, that level of detail becomes critical. Diagnosis opens the door, but genomic clarity enables truly targeted intervention.
What other changes – such as data sharing, funding models, or policy – are needed to meaningfully advance rare disease research and improve outcomes for patients worldwide?
Taft: To truly advance rare disease research, we must move from fragmented efforts to coordinated global systems. That includes establishing interoperable international registries to accurately quantify patient populations – information that strengthens epidemiologic understanding, supports trial design, and provides the evidence base needed to justify therapeutic investment. Countries should adopt national-scale diagnostic and therapeutic models that demonstrate both individual benefit and health system return on investment, particularly when early genomic diagnosis prevents years of ineffective care. Sustainable public–private funding, modern regulatory pathways for ultra-rare therapies, and real-world evidence frameworks are essential to translate discovery into access. Above all, patients must be treated as active data partners, with transparency and control over their information, because trust and scale are the true accelerators of progress.
Musone: One area that deserves attention is how we define and prioritize rare diseases at a policy level. There is no single global standard for what constitutes a rare disease. Definitions differ between regions. In the European Union a rare disease affects fewer than 1 in 2,000 people, while in the United States it is defined as affecting fewer than 200,000 individuals nationally. That lack of alignment can complicate research priorities and funding decisions.
Rigid thresholds also create unintended consequences. Disease risk exists along a spectrum, but funding, reimbursement and regulatory frameworks often rely on binary classifications: rare or not rare. If a condition falls just outside a defined threshold, patients may lose access to dedicated research funding or policy support. Greater international collaboration, harmonized data standards, and more flexible funding models are needed to reflect the complexity and diversity of genetic disease.
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