by Dr Jess Buxton
The Progress Educational Trust (PET), in partnership with the Scottish Government, brought together a group of experts to cut through the hype and jargon and explain the latest developments in genetics/genomics in the context of assisted conception...RCOG and HFEA voice concerns over NHS gynaecology waiting times (progress.org.uk)
PET director, Sarah Norcross, chairing, began by highlighting the general need for more information about developments in this fast-moving area of science. Last year, PET commissioned a survey of the UK public to measure people's understanding of, and attitudes towards, areas of science and medicine including genetics and genomics. In the subsequent report 'Fertility, Genomics and Embryo Research: Public Attitudes and Understanding', 33 percent of respondents chose the option 'don't know' when asked to describe the term 'human genome'.
The first speaker was Dr Jonathan Berg, consultant clinical geneticist at NHS Tayside and clinical senior lecturer at the University of Dundee. He explained that the human genome contains around three billion DNA base-pairs. If each of these were a single letter, then this 'book' of our genetic information would be equivalent to around 6000 copies of Tolstoy's 'War and Peace'. Identifying the single genetic variant that causes a genetic condition can be challenging, and he stressed the importance of knowing where to look – and of knowing what is being tested for before a test is arranged.
Dr Berg described some examples of monogenic conditions that can potentially be detected in the embryo using preimplantation genetic testing (PGT-M, previously known as preimplantation genetic diagnosis), as the specific genes involved are known. These include achondroplasia, cystic fibrosis and Duchenne muscular dystrophy (DMD) (a full list of the conditions for which the use of PGT-M is currently approved in the UK is available here).
Not all genetic variants are inherited from a parent: 'de novo' variants are novel genetic changes that appear for the first time in the egg cell, sperm or early embryo. Variants of this type are responsible for over 40 percent of previously undiagnosed cases of severe development delay. Dr Berg said that although prenatal genetic testing is just becoming available in the UK for such cases, PGT-M is not available unless there is a family history of the condition being tested for.
Dr Nicola Williams, consultant clinical scientist at NHS National Services Scotland's Strategic Network for Genomic Medicine, then gave a talk on PGT provision in Scotland. She started by explaining how cells are removed from the embryo in order to carry out a genetic test. The preferred time to carry out this embryo biopsy is on day five, when the embryo is at the blastocyst stage and several cells can be removed. She went on to describe the difference between PGT-M for monogenic conditions and PGT-SR, which can be used to detect chromosome structural rearrangements.
Dr Williams explained that when PGT-M is performed, genetic markers are currently used to identify the 'high-risk' chromosome that carries the gene variant responsible for the condition. This approach requires testing other family members, including grandparents if possible. She showed the results for a PGT-M test carried out for a condition with an autosomal dominant inheritance pattern, in which half of the six embryos tested were identified as 'high-risk' and the other three were 'low-risk'. Dr Williams said there is now a move towards using whole-genome sequencing (WGS) when testing for monogenic conditions, which would identify the genetic variant directly.
The next speaker was Professor Zosia Miedzybrodzka, director of the University of Aberdeen's Centre for Genome-Enabled Biology and Medicine and service clinical director of genetics at NHS Grampian. Her talk focused on carrier screening for genetic conditions, which can identify unaffected carriers of autosomal recessive genetic conditions, either antenatally or pre-conception. She explained that in the UK, such testing is only carried out routinely for the inherited blood disorders sickle cell disease and thalassaemia. Additional carrier testing is carried out in sperm and egg donors, for example for cystic fibrosis and chromosome structural rearrangements.
Professor Miedzybrodzka went on to discuss expanded carrier testing, a commercial service in which many more genetic conditions are tested for (typically 400 or more). She stressed that this approach wouldn't detect de novo genetic variants, chromosomal disorders, or non-genetic conditions.
This approach also raises broader questions about what to screen for. What counts as serious? Should adult-onset disorders be tested, as well as those present from childhood? And what if donors find out they have a condition of which they were not previously aware?
Professor Miedzybrodzka also highlighted the challenges of interpreting genomic information and implementing the findings, areas currently affected by a skills shortage. She gave the example of a DMD gene variant identified in a fetus, which was wrongly classified as harmful. The same variant was discovered in two healthy brothers in the same family. Given these problems of delivery, implementation and effectiveness, she explained, expanded carrier testing is not currently part of NHS services.
The final speaker was Dr Francesca Forzano, a consultant in clinical genetics at Guy's Hospital, and honorary senior lecturer at King's College London. She is also chair of the Public and Professional Policy Committee of the European Society of Human Genetics, and lead author of this Committee's statement on the use of polygenic risk scores (PRSs) in PGT (see BioNews 1130 and 1137). Her talk covered the potential use of PRSs in embryos to assess the likelihood of common diseases or traits in adulthood.
Dr Forzano outlined the limitations of PRSs, which are constructed by testing hundreds of variants associated with risk of a common, complex disease. However, such conditions are the result of interactions between genetic predisposition, environmental factors and lifestyle choices – and a PRS will only capture part of the genetic component.
Another issues with PRSs highlighted by Dr Forzano is that a relative rather than an absolute risk is calculated. For example, a PRS for schizophrenia could identify a subset of the population who have 50 percent less risk, however this would still be an overall risk of 0.5 percent compared to one percent. Furthermore, most genetic variants associated with common disorders have been identified in European populations, so may be inaccurate in people of non-European descent.
In addition to these limitations, a PRS could be affected by variants with opposite or multiple associations, and would be confounded by the presence of a single genetic variant that greatly affected risk. Dr Forzano concluded that the clinical utility of PRS remains to be demonstrated, and they are certainly not yet validated for use in relation to embryos. She cautioned that PGT for polygenic risk (PGT-P) is not a diagnostic or a screening test, and no guidelines or best practice have been established.
A wide-ranging audience Q&A session followed the presentations, which included a discussion of controversies surrounding PGT for aneuploidy (PGT-A, previously known as PGS), which is not currently available via the NHS, and the fact that PRSs have potential applications that go beyond disease and risk. Speakers also signposted reliable sources for those seeking further information on the topics covered: PET, the HFEA, and the patient support organisations Unique and Genetic Alliance UK.