Long-read sequencing: one genetic technology for all rare disease research
Rare diseases (RDs) are associated with high morbidity, mortality, and economic burden to society. More than 70% of the 6,000-8,000 RDs are genetic, and collectively, they will affect ~6% of individuals over their lifetime. Time-to-diagnosis of RDs often takes years, and the initial diagnosis is often incorrect. A correct diagnosis, however, provides information on the prognosis, precludes further unnecessary (invasive) testing, and may lead to personalized therapy, as well as appropriate medical and supportive care. Also, family members may benefit from knowledge of the risk of recurrence, reproductive counseling, and possible prenatal diagnosis. Current standard of care, including exome and short read genome sequencing, but often also requiring complementary diagnostic assays, still leaves ~50% of RD patients without a diagnosis.
In this Radboudumc-PacBio partnership will use highly accurate HiFi long-read sequencing technology (HiFi genomes) to determine whether these genomes can replace (all) other genetic diagnostic test modalities to serve as a cost-effective ‘one-test-fits-all’ strategy, while simultaneously increasing diagnostic yield, and unravelling novel insights into rare disease pathophysiology. For Radboudumc and PacBio will use three complementary approaches: 1) A technical evaluation whether lrGS is able to capture all clinically relevant genetic variation; 2) An assessment to determine the additional diagnostic yield of lrGS by applying lrGS to individuals whose genetic diagnosis remained elusive after reaching the end of routine diagnostic care; and 3) a pilot study in which lrGS is performed alongside current standard-of-care to determine concordance with routine care.
The outcome of our studies are expected to impact genetic medicine. With rare disease gaining attention and becoming mainstream, an annual increase of the number of patients is expected, while health care budget will not increase. Optimizing laboratory efficiency to a one-test-fits-all strategy will improve the diagnostic process for rare diseases by providing more definitive diagnoses within a shorter time-frame.
