Genomics in Healthcare

What if we could diagnose, predict, and prevent disease before it has even happened? We have been asking this question for decades. Genomics can reveal the cause of disease and hold the key to the solution. Rapid advances in technology and UK health initiatives mean that precision, individualised medicine is on the horizon.

$2.7 billion and 13 laborious years of scientific work were required to sequence the first human genome, completed in 2003 [1]. This was the largest international collaborative effort in the history of biological research – deciphering the key to human health and disease. The sheer cost and time required to sequence the genome meant that implementing genomics clinically was almost unimaginable.

This year (just two decades later), the cost of whole-genome sequencing (WGS) is predicted to drop below $200 per single genome, with a run time of just 13–48 hours (Illumina NovaSeq X series [2]). The advantage of WGS is that it enables interrogation of the entire genome to identify the causes of disease, rather than focusing solely on coding regions (about 2% of the genome) [3], which more traditional methods are limited to. Evidently, advancements in DNA sequencing technology have rapidly revolutionised the way we can approach rare disease diagnostics and therapeutics. This blog will discuss the current landscape of genomics and its relationship with the UK healthcare system.

The 100,000 Genomes Project

10 years ago, David Cameron announced the initiation of the innovative 100,000 Genomes Project, which saw the origin of (and was led by) Genomics England [4]. At the time, amassing a database of this many genomes was an immense task that had been attempted by no other country – but it gave us a head start.

?The overarching aims of the project were to [4]:

• Make genomics a routine part of healthcare, bringing direct benefit to patients in the NHS
• Enhance genomic healthcare research, by kickstarting the UK genomics industry
• Maintain trust, ethicality, and transparency, ensuring that programmes are underpinned by informed patient consent

The idea was that the unique structure of the NHS, which provides equitable access to healthcare throughout the country, would enable genomic medicine to be scaled nationwide. Now, any rare disease patient suffering at the hands of the diagnostic odyssey* (which you can read about in our rare disease blog ) can be offered WGS, in the hope of identifying a genetic cause, providing a diagnosis, and informing treatment.

Genomics England describe their dataset, called the National Genomic Research Library (NGRL) as ‘sitting at the heart of an infinity loop’ (figure 1) [5]. In this loop, a patient’s genetic and health data is first obtained in the clinic through the NHS Genomic Medicine Service, to investigate the cause of their disease. Meanwhile, the patient data is consensually de-identified and entered into the NGRL. This secure dataset is accessible to researchers in both academia and industry, which facilitates continual investigation of the data, fuelling diagnostic and therapeutic discoveries [6]. Insights gained from research (such as emerging treatments produced by pharmaceutical and biotech companies) can then be fed back into the healthcare system, where the data was originally obtained, finalising the ‘loop’.

This model allows the direct coupling of healthcare and research, which are too often distinct from one another in the field of genetics [7]. It is also instrumental in the development of rare disease therapies, which is crucial since 95% of rare diseases have no available therapeutic [8]. Genomics England’s partnership with the life sciences industry enables access to larger sets of patient data and their correlated clinical outcomes. This allows research to be scaled, particularly for the rarest diseases, where recruiting patient groups for trials is difficult [9].

What are the outcomes so far?

100,000 whole genome sequences were completed by 2018. A preliminary study (published in 2021 [10]) on 2,183 participants showed that 25% received a genetic diagnosis due to testing. A quarter of these diagnoses had immediate consequences for clinical decision-making. Notably, of the diagnoses made, 14% required additional investigation on top of automated methods, revealing more nuanced causes of genetic disease, such as mutations in non-coding DNA, mitochondrial DNA, and structural variants. Such changes are often missed using more traditional exome-sequencing methods (which focus on coding regions of the genome), highlighting the value of WGS in identifying a causal genetic change [10]. This pilot study has demonstrated the promise of the 100,000 Genomes Project in the NHS Genomic Medicine Service for those experiencing the diagnostic odyssey.

Why is this so important?

As mentioned in our blog series, rare diseases are ‘perhaps not so rare’ . Though defined as a condition affecting <0.05% of the population, around 6% of individuals will be impacted by any type of rare disease throughout their lifetime. As you can imagine, this has a very tangible impact on the NHS, with a 2018 report estimating that over a 10-year period, the diagnostic odyssey has cost NHS England over ￡3.4 billion [11].

To further this, relatives of those diagnosed may also seek genetic testing. Knowledge of genetic status may empower patients to limit the risk to themselves through preventative measures, or to their children through pre-implantation genetic diagnosis [12]. For example, awareness of cancer-associated variants segregating within a family may justify additional screening or prophylactic surgery for carriers [13].

Development in the field of oncology has also been facilitated by genomics [14]. WGS of the somatic genome has been instrumental in tailoring cancer treatment, with 24% of cancer patients now receiving targeted treatments, informed by the mutations detected in their tumour subtype [15]. The 100,000 Genomes Project has improved the way cancer is analysed for precision treatment in the NHS [16].

What’s next?

Government policy papers, such as the Genome UK policy [17] and the Rare Disease Framework action plan [18] have set out some key commitments to tackle rare diseases, assisted by the following initiatives:

Our Future Health [20]. This is perhaps the most exciting collaboration, which will eventually build a database of 5 million SNP-array based genotypes (for which selected variants throughout the human genome are sequenced, rather than the entirety of it [19]), linked to healthcare data, in close partnership with the NHS. This will be the largest genomic dataset to date, providing unprecedented statistical power to fuel drug target discovery and risk stratification. Importantly the initiative will seek to address the stark issue of Eurocentrism in genomic research, by prioritising the recruitment of a diverse and representative population

Cancer 2.0 [21]. Genomics England is now ensuring that long-read sequencing and multi-modal data (including genomic, imaging, epigenetic, and biomarker data) are incorporated into their analyses. Combining these data types will further understanding of the processes that drive tumour progression and advance precision oncology

The newborn screening project [22]. Like the heel prick test, which screens for actionable metabolic disease in newborn babies, this initiative seeks to identify actionable genetic variants linked to disease in 100,000 newborns. While carefully navigating the ethics of newborn screening, Genomics England hopes to enable early intervention for these rare diseases, improving quality of life and reducing the number of children and parents suffering the diagnostic odyssey

With these advances, precision medicine is now a reality. Will we shift from treatment-based to preventative medicine, and will genomics be the light at the end of the tunnel in an overburdened healthcare system? There’s still a huge amount of work to do, but current advances certainly provide hope for those on an arduous journey to diagnosis or struggling to find the right care. Despite the tumultuous events that have occurred in the last decade, from political issues to global pandemics, genomics has remained a constant priority for the UK Health System, and I’m excited to see where it takes us [23].

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*For many individuals with a rare disease (~6% of the population), the journey to a diagnosis is long and frustrating – bouncing between healthcare professionals, undergoing countless tests, and eliminating all other possibilities before reaching a conclusion. The average time to diagnosis is 4–5 years [24], while a large proportion never receive one [25]. This concept is coined ‘the diagnostic odyssey’ [24].

Bibliography

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