The next frontier in genomic technologies for rare diseases

Genomic technologies for rare diseases

By Neil Ward, VP and General Manager at PacBio EMEA

It’s been 40 years since the passage of the Orphan Drug Act, which catalyzed the development of hundreds of therapies for rare diseases, with more than half approved in the last decade. More recently in 2022, the U.K. government launched a Rare Diseases Action Plan in a bid to keep rare diseases in the spotlight.

One of the major contributing factors to rare disease breakthroughs is rapid advancements in genomic sequencing technology. Since more than 70% of rare diseases have genetic origins, deploying genomic technologies enables researchers to better understand the causal mechanisms of diseases, help improve the accuracy of diagnoses, and identify potential new drug targets and biomarkers that can be used to develop treatments.

Despite positive progress, there are still more than 300 million people worldwide living with a rare condition, half of whom are children. Many of these cases remain unexplained, with the rare disease mystery ongoing for patients and their families. But this is about to change, with a wave of recent innovations in genomics set to arm researchers with the ability to gain the deepest insight yet into the genetic underpinnings of rare diseases.

How have genomic technologies evolved over time? 

As genomic technology has evolved, researchers have deepened their insight into the complex genetic variations that underpin many rare diseases. Karyotyping was the first technology to provide a view of the genome in the 1950s, and made it possible to confirm Turner syndrome by revealing a chromosomal abnormality of one X chromosome instead of two in a female. Later, microarrays provided a higher-resolution view that identified large copy number variants, such as those that result in DiGeorge syndrome. 

Then, 2009 saw the arrival of exome sequencing and a significant increase in the number of conditions that could be identified. Exome sequencing allows scientists to accurately look for small genetic changes – under 50bp – in most of the 20,000 genes in the human genome. Today, exome sequencing is the first line test for suspected genetic disease in many countries.

The National Health Service (NHS) in England, in partnership with Genomics England, was the first healthcare service in the world to offer short-read whole genome sequencing (srWGS) as part of routine care. Short-read whole genome sequencing offers a slight improvement over exome sequencing. It represents a simpler, quicker workflow in the laboratory and has less amplification bias than exomes. More of the 20,000 genes are characterized and srWGS enables an improvement in detecting structural changes. 

What are the disadvantages of the srWGS method?

However, there are drawbacks here too. The srWGS method is more expensive than exome sequencing and still explains less than half of rare disease cases. For example, 8% of the human genome cannot be assessed effectively with srWGS and these regions are often excluded from any analysis. Essentially, short-read whole genome sequencing is full of holes.

There are hundreds of genes known to be clinically important that are challenging to assess by srWGS. Some, such as the HLA genes, are highly polymorphic; high amounts of variation between the individual’s sequence and the reference genome make it difficult to correctly align and variant call with short sequencing reads. Other genes, such as SMN1 and SMN2, have copies in the human genome that are almost identical to one another. In these genes, the short fragments of 300bp or less cannot distinguish between the different regions of the human genome, often leading to incorrect variant calls. 

There are also many genes that are flanked by repetitive or low complexity stretches of DNA and the orientation of these genes is often impossible to determine using short-read genomes. Structural variations are also a challenge to reliably detect with srWGS. There are tens of thousands of genomic regions that vary in copy number or orientation, and many instances where these changes in the number of copies can influence traits such as drug metabolism.

There is another way, though; long-read sequencing, which makes it possible to sequence the strands of DNA that are tens of thousands of bases long in a single stretch.

What are the advantages of long-read sequencing compared to other genomic technologies in rare disease research? 

Long-read sequencing offers many benefits in rare disease research. First, long reads generate runs of DNA that span tens of thousands of base pairs, so can detect the larger and more complex variants that short-reads miss. The method also maintains molecular integrity to increase accuracy, since whole strands of DNA are sequenced in a single read rather than broken up and reassembled.

Moreover, long reads enable researchers to phase or determine which variations occur together on the same maternal or paternal strand. This is useful for studying how rare diseases may be passed on through generations, or in the determination of compound heterozygous mutations when only the individual affected by the rare disease is available for sequencing. 

Finally, long reads enable the detection of 5-methylcytosine profiles without the need for additional sample preparation or workflows. This capability is useful in interrogating known imprinting disorders such as Prader-Willi syndrome, and to detect novel epigenetic causes of disease. Short-read technologies, without this functionality, seem incomplete by comparison.

For patients, the accuracy of long-reads can help shed light on rare diseases and potentially eliminate the need for frequent and repeated tests. Even if researchers are unable to use the data immediately, having some of the most comprehensive data sets opens the door for improved reanalysis in the future.

Despite the advantages of long-read sequencing to date, the technology has been inaccessible to many due to affordability and lower throughput. This has made it challenging for researchers to establish long reads as a first-line test – but this is about to change.

Revolutionizing genomic testing: the impact of third-generation long-read technology on rare disease research 

The arrival of third generation long-reads in the past year has exponentially decreased the cost of running a comprehensive genomic test from over $100 million in 2001 to under $1,000 today. The scale of samples has also increased, with a single machine now delivering more than 1,300 human genomes per year, with reduced sample input and far fewer consumables. Given that it took decades for the first human genome to be decoded – only completed last year – this represents a serious leap in capability.

The growing accessibility of long-read technology is facilitating a global rare disease ecosystem that is already realizing benefits. One study by the Genomic Answers for Kids programme found long-read technology yielded a much higher discovery rate compared to srWGS, with four times as many rare coding structural variants revealed. 

Another study in Japan deployed long reads to find the possible cause of an unexplained syndrome in twin 12-year-old young women, suspected to be Dravet syndrome. By sequencing one of the twins and both parents, researchers identified a novel 12kb inversion in a region that had previously been associated with the same symptoms affecting the young women.

Ending rare disease mysteries

We can expect more of these kinds of breakthroughs as the increased accessibility of long-read technology means it can be applied further and faster than ever before. Given the accuracy and utility of long reads over other available methods, it’s likely it will replace srWGS as the next logical step after exome sequencing fails to yield an explanation. We’re already seeing this approach in action in Scotland’s Genome Vision plan, as well as other world leading institutions such as Boston Childrens’ Hospital in the U.S. and Bioscientia in Germany.

High-quality, long-read data has the potential to unravel the mystery of unsolved rare diseases in a substantially reduced timeframe. With a deeper understanding of the underpinnings of rare diseases, researchers can now create improved diagnostics and aid the development of new therapies that will better the lives of patients and their families.


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