‘Hope is not lost’ for the 50 per cent of people with undiagnosed rare diseases, says UK genomics expert Neil Ward, of PacBio. New technologies can provide more accurate, in-depth data on the genome, and help reveal the underlying genetic causes of such mysteries.
The journey to diagnose rare diseases often follows a complex and challenging road. Until recently, technological limitations have made it difficult to analyse whole areas of the genome, determine genomic changes related to disease and understand the effects of certain mutations that may have led to a diagnosis.
However, the development of modern genomic sequencing technologies has heralded a new era, offering hope and answers where once there were none. By providing deeper insights into the causal mechanisms of rare diseases, researchers are on the horizon of being able to provide more accurate diagnoses for rare disease patients and open the door to personalised treatment plans.
The path from the 2010s’ standard of exome sequencing to short-read whole genome sequencing (srWGS) presents a series of significant leaps in unravelling the mystery of genetic disorders. Each advance in sequencing brought with it new insights and possibilities, but also revealed the inherent limitations in accuracy and comprehensiveness. Despite positive progress, accurately pinpointing the genetic underpinnings of rare diseases remains an elusive goal, but today’s innovative sequencing technologies are set to change this.
Embarking on a quest for answers
In England and Wales, the standard diagnosis pathway for rare diseases is currently srWGS. This process involves DNA being broken down into small fragments and aligned to a reference genome in order to identify variants that are potentially causative of disease. Short-read technologies typically yield more sequence reads, proving particularly useful when a deeper level of sequencing is required, such as detecting variants against a complex backdrop of normal DNA. However, its application in the realm of rare diseases is not without challenges, and srWGS fails to provide answers in more than 50% of cases.
A major limitation of srWGS is that even after piecing all the small DNA fragments back together, the final genome assembly still often contains errors and areas of missing information. This shortcoming becomes especially pronounced in the context of rare diseases, where detecting structural variations and complex genetic anomalies is crucial. The inability of srWGS to fully capture the intricacies of these diseases often leaves many questions unanswered, hindering accurate diagnosis and effective treatment.
The rise of long-read sequencing
Long-read sequencing technology has vastly improved in recent years and presents an exciting opportunity to explain many long-standing rare disease mysteries. Long reads generate runs of DNA that span tens of thousands of base pairs, providing a more complete and uninterrupted view of the genome. As a result, researchers can explore dark regions of the genome that until now have been hidden, helping them detect the larger and more complex variations missed by short reads. This comprehensive coverage is particularly beneficial in the study of rare diseases, where understanding the full genetic context is vital for accurate diagnosis.
The advent of long-read sequencing has not only enhanced our genomic understanding but has also made comprehensive genomic testing more accessible. The cost of long reads reduced from over $100m per genome in 2001 to under $1000 today. The scale of samples that can be analysed in a single experiment has also risen substantially. A single machine can now deliver more than 1,300 human genomes per year, broadening the reach of this technology and powering research at considerable scale.
Real-world applications of long-read sequencing are already showing promising results. For instance, The NY Center for Rare Diseases at Montefiore has partnered with GeneDx, PacBio, and Google Health to use long-read technology for the genetic analysis of rare diseases in under-represented populations. This collaboration is a testament to the potential of long-read sequencing in providing deeper insights into the genetic causes of rare diseases.
The future landscape of rare disease diagnoses
The possibilities unlocked by long-read sequencing are many. From improving diagnosis pathways to identifying potential new treatment opportunities, this technology is setting a new standard in the understanding and management of rare diseases. Its ability to provide a more detailed genetic picture is paving the way for significant advances in medical research and is delivering better explanations for families.
An example of this potential is seen in the efforts of Radboud University Medical Center, which is using long-read sequencing to shed light on rare diseases that eluded detection by conventional sequencing methods alone. This approach is increasing diagnostic yield in research studies, demonstrating the transformative impact of long-read sequencing.
The journey of genomic sequencing is far from over. Continued investment and innovation in these technologies are imperative to further unlock the mysteries of rare diseases. As we stand on the cusp of a new chapter in medical science, the promise of genomic sequencing remains a beacon of hope for millions affected by rare diseases worldwide.
Neil Ward is vice-president and general manager of PacBio EMEA, a biotechnology company that develops and manufactures systems for gene sequencing of genomes, transcriptomes, and epigenomes, which can be used to explore genetic variations in any organism, from identifying rare disease to improving global food supplies.
