This is a plain English summary of an original research article. The views expressed are those of the author(s) and reviewer(s) at the time of publication.
Many parents of children with a chance (de novo) genetic change (or mutation) could be reassured by a personalised risk assessment. These parents are often told that the risk of a future child having the same mutation is 1 – 2%. However, this does not reflect the variation in risk among different families. Research found that the personal risk of most couples was much lower (less than 1 in 1000).
Over the last decade, it has become apparent that chance genetic changes can cause so-called developmental disorders. Affected children can have severe lifelong physical and intellectual symptoms. Parents with a child with a disorder caused by a chance mutation are likely to be concerned that any future children will be similarly affected.
This study included families with a child who had a condition caused by a chance mutation. Researchers inspected the genetic code around the mutation site of 60 couples and their children. They analysed samples from different areas of the body to determine the risk of the same chance mutation recurring in a future pregnancy.
Knowing how likely it is that another child will have a chance mutation could help parents make an informed choice about future pregnancies. In most couples, the mutation occurred as a one-off event in egg or sperm and their risk is very low; these parents are likely to be reassured.
However, for a few families, the mutation was found in one or more of the parents’ samples (blood, spit and urine). These couples were at higher risk and likely to need additional support in future pregnancies.
This work is at an early stage and more research is needed to make this analysis available on the NHS.
More information about genetic and genomic testing is available on the NHS website.
What’s the issue?
Mutations are changes in the genetic code, which can be passed down from one or both parents. But sometimes these mutations arise out of the blue in an egg or sperm, or even after conception.
Disorders caused by chance genetic mutations affect 1 in 295 births, or half a million babies a year worldwide. They are often life-changing for children and parents. In addition, parents may fear that future children could be similarly affected. There is currently no test to determine a future child’s risk.
Most parents with affected children do not themselves carry a mutated gene. Usually, the chance mutations are caused by a one-off event in a single sperm or egg, and the risk of recurrence in another pregnancy is very low. If a mutation occurred within a fertilised egg, some but not all of the child’s cells will carry the mutation. There is no risk of recurrence in this situation (since the mutation was never present in the parents).
The risk of reoccurrence arises because occasionally, parents are so-called genetic mosaics. This means that in one parent or the other, the chance mutation occurred earlier. Large numbers of their sperm or egg cells therefore carry the mutation. The same mutation may also exist in some (but not all) parts of their body. The risk to their future children is much higher (up to 50%) but current standard genetic tests would not detect these harmful mutations.
In this study, researchers developed a method to tell these different situations apart and give parents a personalised risk assessment.
What’s new?
The study included 60 families in England who had at least one child with a condition caused by a chance mutation. Blood and spit samples were taken from parents and children; urine was taken from both parents and sperm from fathers.
The researchers analysed all these samples in detail, to detect the chance mutation responsible for the child’s condition. This allowed them to determine when and where the mutation had arisen (mother, father or child) and if any of the family were a genetic mosaic. From this, they predicted a couples’ personalised risk of having another child with a chance mutation.
The study found that:
- most (59%) families had a mutation in a single sperm cell; their recurrence risk was less than 1 in 1000
- in 4 families, the father was the genetic mosaic; analysis of sperm DNA gave a personalised estimate of fathers’ risk (which ranged from 0.25% to 12%)
- in another 4 families, the mother was a genetic mosaic; the risk was likely to be higher than 1 – 2% but could not be accurately assessed as testing their eggs is not possible
- in one child, a chance mutation occurred after the egg was fertilised; the risk of recurrence for this family was zero.
Some fathers who were genetic mosaics had a low risk of recurrence. This is likely to be true also for some mothers, but it is not possible to test eggs. Overall, the researchers say that approximately 8 in 10 couples had a recurrence risk lower than the standard figure of 1 – 2%.
Why is this important?
In this study, most couples received an individualised risk assessment of a chance mutation recurring in their future children. The researchers say that parents who have had one child with a chance mutation can therefore be given a more accurate risk of recurrence than the standard 1 – 2% currently given to all.
It is easy to collect sperm for genetic analysis and the risk for fathers who were genetic mosaics could be predicted accurately.
Personalised risk assessments could be offered to parents in genetic counselling, to allow them to make informed decisions about future pregnancies. Currently, couples who have a child with a chance mutation may opt to have a second child through IVF (in vitro fertilisation). Fertilised eggs can then be screened for harmful mutations in the lab, so that unaffected embryos can be selected and implanted in the mother’s womb.
Couples may also opt for extra tests during pregnancy. Some tests, before and during pregnancy, are invasive and expensive. Non-invasive tests are available on the NHS for couples with a risk of more than 10%.
Since most couples have a very low risk of recurrence, a personalised assessment could reduce their anxiety, and the need for these tests. This would release resources to be spent on the few families at much higher risk of recurrence.
What’s next?
The researchers hope their approach will become part of the standard NHS service for parents who have had one child with a chance mutation. However, the genetic analyses used in this study are not routinely available. This is because the test needs to be adapted for the specific chance mutation, which is different in every family.
The team is exploring with clinicians and affected couples whether personalised risk assessments would be useful and practical. One of their studies found that clinicians believe that this approach would be a valuable addition to current services and could avoid the need for more invasive tests during pregnancy.
Sperm is routinely collected from men in fertility clinics but not in genetic clinics. The researchers say this study and others provide clear evidence for widespread collection and genetic analysis of sperm for recurrence risk assessments.
You may be interested to read
This Alert is based on: Bernkopf M, and others. Personalized recurrence risk assessment following the birth of a child with a pathogenic de novo mutation. Nature Communications 2023;14: 1–11.
Easy-to-read information about de novo mutations on the UCL website.
The Genetic Alliance UK website, which supports people with genetic, rare and undiagnosed conditions.
Funding: This study was supported by the NIHR Oxford Biomedical Research Centre Programme.
Conflicts of Interest: None declared.
Disclaimer: NIHR Alerts are not a substitute for professional medical advice. They provide information about research which is funded or supported by the NIHR. Please note that views expressed in NIHR Alerts are those of the author(s) and reviewer(s) at the time of publication. They do not necessarily reflect the views of the NHS, the NIHR or the Department of Health and Social Care.
