Whole Genome Sequencing: challenges and opportunities

You may have requested whole-genome sequencing (WGS). You may be wondering what the words mean. Is it an exciting new way to improve health and wellbeing, or is it a modern tower of Babel (Genesis 11)? This article aims to help us understand WGS to better think about what it means for us as Christian medics.

What is Whole Genome Sequencing?

Our genome is our body’s set of genetic information, including over 20,000 genes. It is present in nearly every cell in the body. We all have differences in our genomes – for example, each genome typically contains 2,100 to 2,500 structural variants. (These are missing, duplicated or rearranged sections of the genome.) Many variants are simply benign human variations and make us individuals. However, some changes can affect the functioning of genes and cause health and/or developmental problems.

WGS aims to sequence all of someone’s DNA as far as the technology will allow. Historically, genetic testing would generally involve only sequencing the relevant gene(s), or at most a ‘panel’ of genes associated with certain presentations or phenotypes. With WGS, the patient has sequencing of the whole genome, but the NHS laboratory would look at only the relevant sections (i.e. panels of genes). Since early 2021, the NHS in England has introduced WGS for many indications. There is also a ‘Paediatric disorders’ super-panel which (at the time of writing) tests for 2067 genes.

Where possible, a trio should be used for WGS. This means testing the patient and both biological parents, which helps us identify variants and understand the likely pathogenicity of any variants found.

WGS is moving into many specialties in the NHS and will become increasingly familiar to many clinicians. Rapid WGS in the neonatal and paediatric intensive care settings has the potential to provide treatment-altering diagnoses far more quickly than previously available.

Why now?

The rollout of WGS followed the success of the 100,000 genomes project launched in 2013 and found diagnoses in 25 per cent of recruited cases with rare diseases and no genetic explanation.

It is becoming much cheaper to sequence the whole of the genome, although, in reality, it would actually be an overwhelming task to analyse it fully. Bioinformatic pipelines and filters (computer algorithms) are applied to enable meaningful data processing. WGS is a platform to allow testing – the whole genome may be processed relatively fast and cost-effectively, but the whole genome is not currently being analysed as part of NHS testing.

The NHS Long Term Plan introduced many commitments around genomic medicine in England, including to be ‘the first national health care system to offer whole genome sequencing as part of routine care’ and an aim to ‘sequence 500,000 whole genomes by 2023/24’.

Consent

With WGS testing, ‘fully informed’ consent may not be possible. Findings may be complex, uncertain or unexpected. The NHS in England uses a ‘Record of Discussion’ for documentation rather than a ‘consent’ form. We can’t list all 2000+ conditions that a ‘Paediatric disorders’ panel covers, but we can communicate types of situations such as uncertain/incidental findings.

The National Genomic Research Library and Big Data

The same ‘Record of Discussion’ form documents a discussion around the (English) National Genomic Research Library (NGRL). This is part of Genomics England, a wholly-owned subsidiary of the Department of Health and Social Care. If patients agree, the whole of their genome would be added to this resource – even though the NHS laboratory would not look specifically at the whole genome.

The NGRL keeps WGS data and can link this to the patient’s wider primary and secondary care NHS records, including admissions, scans, and problems unrelated to the diagnosis. This data is kept beyond death. Because a person’s DNA code is unique to them, their identifying demographics are not stored directly with the data – referred to as de-identifying.

The patient information leaflet states:
‘Genomics England always protects your data and controls who has access to it…Approved researchers may work for not-for-profit organisations…and for-profit (commercial) companies such as drug or technology companies.’

Potential impacts for patients (not unique to WGS):

• a label for their condition
• access to relevant patient support groups
• personalised letters for school, allowing access to funding/support
• a better understanding of prognosis
• screening (where there are known other features of the condition)
• recommended treatments for a small proportion of genetic conditions
• access to research
• reproductive ‘options’, eg natural pregnancy, adoption, donor gametes, invasive or non-invasive testing in pregnancy, pre-implantation genetic diagnosis.
• predictive testing for family members (in cancer predisposition syndromes, this may enable early access to screening)
• possibility of future treatments

Challenges (not unique to WGS):

Incidental findings

There may be incidental or unexpected findings from WGS. This may be from genes within a large panel. Or in some cases, a tool such as the Exomiser may identify pathogenic variants outside of the panel of genes applied. Recent examples include adult-onset neurological disorders or cancer predisposition genes found when testing children. Incidental findings may also have implications for other family members.

There are American guidelines on which incidental findings should be reported – including adult-onset cancer predispositions such as BRCA1/BRCA2/Lynch syndrome. UK discussions are ongoing about what should be reported.

Variant classification and uncertainty

Classification of genetic variants is an evolving field. Variants may be classified as benign, likely benign, a variant of uncertain significance (VOUS/VUS), likely pathogenic, or pathogenic. UK laboratories used American and UK guidelines to assign pathogenicity. These guidelines undergo updates, so ‘likely pathogenic’ variant can be downgraded to a VUS and vice versa.

VUSs can cause great difficulty for patients; clinicians may not be able to advise if they think the variant is significant. Further information (such as family segregation studies or research) may enable re-classification, but patients may be left with uncertainty. This can be difficult for themselves, their families, and decisions about having children. VUSs may be more common in ethnic groups that have historically been less well represented in genetic testing.

Revealing biological parentage

Because a trio would ideally be used (comparing sample to mum and dad), misattributed parentage can be identified. This unexpected information can cause complex ethical dilemmas and may not be disclosed if it is not relevant to the patient’s care.

Reproductive options

Couples may face challenging decisions about reproduction if they know their genetic status. This may feel empowering for some, whatever their views on prenatal testing. Pre-implantation genetic testing involves the discarding of affected embryos. Testing in pregnancy is particularly offered when a person plans to have an abortion if the baby is affected. For those of us who value life from the moment of conception, these options can be particularly concerning.

Other challenges

There are many other challenges. How do we remind people that everyone is equal, regardless of genetic condition? What might the future impacts on insurance be? How do we prevent any new societal inequalities from arising? How should big data be used? Can WGS data security be guaranteed in this era? How do we safeguard against a Gattaca-style future where society categorises individuals based on their genetic composition (polygenic screening of embryos is already available in the US)? Should Genomics England be permitted to receive fees for the use of patients’ data when for-profit companies conduct research? Should patients be consented for research which is so closely linked to diagnostic testing?

There are also issues around equity within the devolved nations of the UK; the NHS Long Term Plan WGS aims relate to England only. Despite the cost of WGS decreasing, this is still beyond the reach of developing countries.

Conclusion

Many potential opportunities and challenges are posed by the wider rollout of WGS in the NHS. Our genome is unique, but it is not where our identity lies. Humans are bearers of God’s image. For believers in Jesus, our primary identity is as a child of God. We should seek to prevent any inequalities from new technologies. Where possible, we should contribute to policymaking and consultations.

Dr Melody Redman is a clinical genetics registrar (ST4) in Yorkshire.

Dr Francis Sansbury is a consultant clinical geneticist with the All-Wales Medical Genomics Service, based in Cardiff.