What is genetic and genomic testing?
Diagnostic genetic testing looks for changes in genes known to cause the condition that someone has, such as deafness. It can therefore be used to try and identify if your child's deafness has a genetic cause.
Genetic testing may be able to identify a specific genetic cause for your child's deafness. However, it’s important to know that genetic testing only identifies a clear cause of deafness in up to a third of children tested, based on current figures.
If a genetic cause is not identified in your child, they may still have a variant in another gene or gene pair, but it’s not tested on the current standard test. Alternatively, there may be a non-genetic cause that cannot be identified.
Many families go through the process of aetiological investigations (which is any investigation looking for the cause of deafness, including genetic testing), without realising that there’s a good chance they won’t find out the cause of their child’s deafness by the end of it. Some of the non-genetic causes, such as a cytomegalovirus (CMV) infection, can be identified through the standard tests, but others cannot.
Where genetic testing can identify a cause, it can provide insight into:
- Related health conditions. For 30% of children whose deafness is genetic, their deafness is part of a syndrome. This means that they may have, or be at risk of, associated health conditions. Knowing this diagnosis can identify specific future screening or monitoring to be offered. Conversely, identifying a non-syndromic genetic cause means there are unlikely to be any associated health implications.
- Whether hearing will change or stay the same. Understanding the cause of deafness can give professionals more information about which part of the ear isn’t working. Sometimes this knowledge can help predict whether your child’s level of deafness is likely to stay the same or decline over time. Knowing more about your child’s type of deafness can help inform decisions about technology options (such as cochlear implants or hearing aids), communication choices and education.
- Chances of passing on a particular condition. Some parents want to know more about the chances of other children or grandchildren they may have being deaf or hearing.
- Implications for other family members. Some families want to know whether other family members may have also inherited a health condition related to their child’s deafness.
Family stories of genetic testing
Gill shares her family’s experience of genetic testing: “We were advised throughout the process that it was likely we may never know why our son is deaf and that a cause may not be found. I found this really helpful as it meant my expectations were always fairly realistic. I did still feel a little disappointed when we got the initial genetics letter advising no genetic cause had been found.”
Emma shares how genetic testing informed her family: “Ultimately the genetic results didn't stop us having more children, but it’s so useful for Isaac to have answers for himself and the information should he choose to have children of his own.”
Deciding whether to have genetic testing is a personal choice, and there’s no right or wrong answer. To make the most informed decision for your child and family, you should make sure you understand the full implications of having a genetic test and what it might mean for your family.
The health professional discussing genetic testing with you should explain the possible outcomes and implications. You and your family may want to consider in advance how you feel about these. Here are some examples of possible outcomes and implications:
- Your child, and possibly other family members, carries a gene variant known to cause non-syndromic deafness, so there are no other health implications.
- Your child, and possibly other family members, carries a gene variant known to cause syndromic deafness which might have other implications for their health in the future.
- You (or other family members) have some deafness yourself, or some chance of developing deafness, that has not previously been identified.
- Your child’s deafness was inherited from only one parent (or one side of the family).
- You learn more about the chances of any future children or grandchildren you have being deaf or hearing.
- Your child carries a variant in a gene where the gene’s implications are less well understood at present. For example, there are a few genes that can cause deafness alone (non-syndromic deafness) in some families but can cause deafness plus one or more health implications (syndromic deafness) in other families. This can be the case with a gene that causes Usher syndrome in some children and deafness alone in other families – read Leticia’s story. Although it’s likely that these genes will be better understood over the next few years, it may mean uncertainty at the moment about what this will mean for your child.
- Your child carries an uncertain variant in a gene. This means that, while the gene is a known cause of deafness, the variant itself is less understood at present. If it’s uncertain whether the variant stops the gene working, it will be classified on the report as a ‘variant of unknown significance’ (VUS). As it’s not possible immediately to say whether or not a VUS is the cause, it may bring uncertainty for you and your family. A VUS can be reassessed as knowledge about the gene and specific gene variants increases and also, sometimes, with the addition of further information about your child’s family history.
- Your child may have no significant gene variants identified, leaving uncertainty about the cause of their deafness.
While some families may find it helpful or reassuring to know the cause of their child’s deafness, others may not want to know for a variety of reasons. They may also prefer to wait until their child is grown up and able to decide for themselves.
Before going ahead with genetic testing (and/or before finding out the results), talk to your family about what you’re prepared to know. The Genetic Alliance UK website discusses the risks and benefits of genetic testing more broadly.
Until recently, genetic testing could only be offered routinely for the Connexin 26 gene. Following developments in genetic testing technologies, wider NHS genetic testing into causes of deafness is now available across the UK.
These developments mean that your child’s paediatrician, other audiology doctor or audiologist can now discuss and arrange tests for both genetic and non-genetic causes of deafness. Previously, almost all genetic testing was arranged only once you’d been seen in a genetics service.
There are different genetic tests that you may be offered, which are described below. Some families have been through genetic testing but are not clear what types of tests were done. Be sure to ask your clinician exactly what types of tests they’re doing and what each will involve. Knowing what types of tests were performed will help you better understand the results and may also be helpful for your child if they want to do their own research when they’re older.
Most genetic tests are carried out using a blood sample from the child (occasionally it’s possible to use an alternative sample such as saliva). Sometimes samples from parents are needed alongside their child’s to help with interpreting the results.
To illustrate these tests, we’ll use the analogy of a library. Each cell in your body has a library of information at its centre. Genes are like separate recipe books which give information on how to make a specific protein or substance needed by the cell. Chromosomes are like the shelves, each containing thousands of books. DNA is like the paper and ink that makes up the books.
Single gene testing looks at one gene at a time. This is like taking only one book off the library shelf at a time and reading it cover to cover to look for a variation in the spelling.
Testing for genetic causes of deafness was previously limited to a single gene test for Connexin 26 (a small gene and the most common genetic cause of deafness). If someone had clear signs or symptoms suggesting another specific gene – for example, a specific type of kidney problem or a specific eye problem – it was sometimes possible to read through one or several more genes, either in an NHS lab or as part of research. Connexin 26 testing took several months, and testing of other genes could take a very long time, especially if through research.
Your family may have had single gene carried out previously. The following tests are more recent developments.
A genetic panel test looks at many genes at once. This is now the routine test that is offered to investigate genetic causes of deafness.
The deafness panel test currently reads over 100 genes or ‘books’ all at the same time to speed up testing. The genes tested are all genes involved in hearing and deafness. Most of the genes tested cause non-syndromic deafness, but some cause syndromic deafness.
In a genetic panel test, the ‘text’ of a small number of the more common genes known to cause deafness is analysed first. If nothing is found at this stage, the rest of the genes will be analysed. The genes included in the panel may change as more is learnt about genetic causes of deafness.
Results take six months or longer at present, but this is likely to become quicker.
If your child’s medical history or family history suggests a mitochondrial gene might be the cause, an additional test using the same blood sample can look for specific changes in the mitochondrial genes associated with deafness.
A microarray test looks in detail at chromosomes. Rather than reading the ‘text’ of individual genes (or ‘books’), a microarray looks close up at the chromosomes (or ‘shelves’). This test can identify if there’s a whole chromosome missing or an extra one. It can also identify very tiny sections of a chromosome that have been deleted or duplicated. Such tiny sections may include several genes, or even just part of a gene.
If a few genes are involved, a deletion or duplication can cause a combination of health and developmental problems. This test may be suggested instead of or alongside a genetic panel test if your child has deafness together with problems with their health and development.
A further test at the chromosome level is called a karyotype test. A person’s full chromosome pattern is known as their karyotype. This test can detect if there’s a whole chromosome (or one or more larger sections) missing or extra. It can also detect if any of the chromosomes are rearranged, such as two being joined together, or sections that have swapped places.
Whole exome sequencing (WES) looks at all the genes which actively code for proteins. This testing is more complex and reads all 20,000 genes (or ‘books’ in the library): this is the 'exome'.
Whole genome sequencing (WGS) looks at all the genes that actively code for proteins, but also looks at all the DNA between genes: this is our full 'genome'. Most of our DNA is in ‘joining-up’ sections between genes which do not code for proteins but may play a role in regulating other genes. Another way to think of this is like reading all 20,000 ‘books’ (genes) but also all the ‘scrap paper’ (DNA) between each book for useful bits of information.
The complexity of WES and WGS means that they’re only just starting to be offered routinely. These tests may be considered if someone has a more complex medical picture, with deafness in combination with other signs or symptoms. Currently, a family is more likely to be seen in a clinical genetics service before these tests are considered.
A huge amount of DNA code is produced through WGS, so the laboratory often applies ‘virtual gene panels’ to give a manageable amount of data. This could be thought of as a computer having scanned and stored all the letters on all the paperwork in the ‘library’, but then only looking at a selected proportion of the books and paperwork. The selected genes are those that are known to be potential causes of that person’s medical picture. For example, a virtual gene panel for learning difficulties can include over a thousand genes. The fact that all the code has been scanned and stored means that it’s possible to go back and look at someone’s DNA data in the future, as more genes are identified, without having to retest the DNA sample. Your consent would be needed for any re-examination of your child’s DNA data, and a health professional would discuss this with you.
Because so much information is analysed in WES and WGS, there is a greater chance of finding variants of uncertain significance (VUS). To help the analysis, parents are often asked to give blood samples to compare their genetic code with their child’s.
With WES and WGS, there’s also a chance of finding a variant in a gene unrelated to the main reason for testing. For example, it’s possible that a variant is found in a gene that increases the risk of certain types of cancer. These possible outcomes would be discussed with you before any testing.
The timescale for results can vary, and WGS results can currently take a year or more, but this is likely to become quicker.
Until recently, the 100,000 Genomes Project was the main way WGS could be offered to families in England. Other research studies across the UK also used WGS technology. These large research studies aimed to identify genetic causes of rare conditions, including deafness. Results from this research have taken a long time, often years, to be completed because of the complexity of the testing. Now, WGS and WES are part of NHS testing options.
The shift from single gene testing to looking at more genes, or even the full genome, is why it’s sometimes described as 'genomic testing' now, rather than 'genetic testing'.
Genetic testing may not be appropriate or recommended for all families. Some types of deafness may be more likely to have a genetic cause than others. For example, deafness in both ears (bilateral deafness) is more likely to have a genetic cause than if it’s one ear only (unilateral deafness). There’s also a higher chance genetic testing could find a cause of deafness if there’s a family history of deafness or signs that could fit with a syndromic type of deafness.
For these reasons, there are National Genomic Test Directory guidelines in England that give health professionals in audiology information about who can be offered testing. Professionals in Scotland, Northern Ireland and Wales refer to the same published evidence, and genetic services across all four nations within the UK communicate closely around genomic testing developments.
Newborn hearing screening means that deafness from birth can be identified much younger, on average, than it was in the past. This means that tests to explore a possible cause can also be offered earlier.
The genetic panel test can be carried out from any age. Of course, if your child has only recently been diagnosed with deafness, there’s likely to be a huge amount of information and many decisions that you’re considering. Genetic testing and other aetiological investigations are generally not urgent and are something that you can consider later, if you prefer.
If you want to know more about the cause of your child’s deafness, your child’s audiology clinician will discuss and arrange tests for possible causes (both genetic and non-genetic) in the first instance. This clinician may be a paediatrician or audiological physician or, less commonly, an ear, nose and throat (ENT) doctor or an audiologist (who is not a doctor).
If there’s a likely cause for your child’s deafness already suspected, for example, problems during their birth or a known infection such as cytomegalovirus (CMV), the clinician will consider whether all the other tests are necessary, based on their clinical judgement. The most appropriate genetic tests may vary depending on what’s already known about your child’s deafness and family history.
If your child has a combination of different health problems together with deafness, your clinician may want to refer you to the clinical genetics service for expert opinion and possible additional testing. They may still arrange some of the more standard genetic testing before they refer you.
The clinician organising the genetic tests will document your consent to going ahead. Your consent should be ‘fully informed’, meaning you have been given enough information in advance to be clear about the possible results and implications. This should include:
- what test is being done
- what the results could show
- what will happen to the remaining DNA sample
- whether you are willing to share the results of the test with other family members (this can be done anonymously, if necessary).