Receiving an intermediate allele or reduced penetrance genetic test result also known as a 'grey area' result can be confusing.


This qualitative study, led by Jenny De Souza and Cardiff University looks at the psychosocial implications of receiving an intermediate allele or reduced penetrance allele predictive genetic test result for Huntington's disease.

Study information

13 people took part in the study and data was collected in an interview format via Zoom.

Recruitment took place between November 2021 and February 2022 via the Huntington's Disease Association website and Specialist Advisers.

Participants were asked:

Participants were asked a number of questions relating to family experience, predictive testing, psychosocial experience and genetic counselling such as:

  • How/when did you learn of your own risk and how did you feel about your risk?
  • Prior to receiving your test result, were you aware of the possibility of intermediate allele/reduced penetrance results?
  • How has your predictive test result influenced your life, if at all?
  • What follow-up, if any at all, did you receive from a genetic counsellor following your test result?

Participant criteria:

  • Over 18
  • Has capacity to consent
  • Able to verbally confirm they have a CAG repeat length between 27 and 39 repeats 


Study breakdown

Choosing to undergo predictive testing for Huntington’s disease is a very personal and emotional decision. People choose to undergo predictive testing for a number of different reasons, but the most common reasons cited, include: to reduce uncertainty, for future planning, to provide information to relatives, or for reproductive decision-making and hope for future treatments. Therefore, at the end of the predictive testing process, people are looking for a clear answer as to whether they will or will not develop Huntington’s disease. 

Although, the majority of people do get a black or white result, a small proportion fall into one of two less clear-cut categories: an intermediate or a reduced penetrance range. 

CAG repeats and what they mean

Huntington’s disease is caused by a genetic mutation that increases the number of CAG repeats in the huntingtin (HTT) gene on chromosome 4. Everyone has two copies of the HTT gene; one inherited from their mother and one from their father. Huntington’s is what’s known as an autosomal dominant disorder, this means that having just one copy of the gene not working properly is sufficient to cause the condition. Huntington’s disease genetic testing involves measuring the number of CAG repeats in both copies of an individual’s HTT gene. There are four different possible outcomes of a Huntington’s genetic test, depending on the number of CAG repeats.

A normal / mutation negative test result (26 or fewer CAG repeats):

If both copies of the HTT gene have 26 or fewer CAG repeats, then that person will not develop Huntington's disease in their lifetime. Their children will also not develop Huntington’s disease.

An intermediate allele (27-35 CAG repeats):

Individuals with a CAG repeat length of between 27 and 35 CAGs in one of their HTT genes have what is known as an intermediate allele. Someone with a result in this range will not develop Huntington’s disease themselves. However, the CAG repeat expansion is unstable. Therefore, although a similar repeat length may be passed from parent to child, it may also increase further in length. Therefore, there is a very small risk of their children developing Huntington’s if the number of CAG repeats increases into the penetrance range when the HTT gene is inherited.

A reduced penetrance allele (36-39 CAG repeats):

A CAG repeat length of between 36 and 39 CAG repeats is known as the reduced penetrance range. Someone with a reduced penetrance result may or may not develop Huntington's disease in their lifetime. Although it is not possible to determine who will and who won’t develop Huntington's disease, for those that do develop symptoms, onset is usually in older age and with a slower progression of disease. Children of an individual with an HTT gene in the reduced penetrance range have a 50% chance of inheriting this expanded copy of the gene. It is also possible for this CAG repeat to expand into the full penetrance range when passed from parent to child. 

  

A full penetrance/mutation positive test result (40 or more CAG repeats):

If one copy of the HTT gene has 40 or more CAG repeats, then that person will develop Huntington's disease in their lifetime. Each of their children will have a 50% risk of inheriting the expanded copy of the gene.

CAG repeats

Qualitative study

Consequently, many uncertainties remain for individuals who receive an intermediate allele or reduced penetrance result. A recent qualitative study was carried out by an MSc student at Cardiff University to better understand the psychosocial implications of receiving an intermediate allele or reduced penetrance predictive test result for Huntington's disease.

Thirteen participants (two with an intermediate allele and 11 with a reduced penetrance predictive test result) were recruited via the Huntington's Disease Association. In-depth semi-structured interviews on topics including family experience, predictive testing, psychosocial experience and genetic counselling were conducted over Zoom. The interviews were transcribed and analysed using a type of analysis called reflexive thematic analysis (using the researcher's subjectivity to understand the patterns behind the results).

The analysis identified five main themes within the dataset: interpretation of the result, living with the unknown, unmet support needs, communication challenges and coping mechanisms. 

Interpretation of the result

Intermediate allele and reduced penetrance predictive test results were found to be interpreted in one of three ways: may or may not develop Huntington's disease, will definitely develop Huntington's disease or an intermediate allele and reduced penetrance result leads to a different disease presentation. Some participants were unaware prior to receiving their results that there was a possibility of an intermediate allele or reduced penetrance result, as one individual stated:

We'd never even heard of the grey area before then you know, that there’s this weird nebulous area where you don't have Huntington's disease but you might have Huntington's disease.

Those with a reduced penetrance result often assumed that they would have a similar experience of Huntington's disease to relatives with a result also in that range:

My mum's 38 (CAG repeats) and she's definitely got symptoms you know, she's had them for 15 years, so my personal experience of someone with a 38 is not what they're saying, it doesn't match up.

Living with the unknown

Many of the study participants had undergone predictive testing to help plan for the future because knowing either way was better for them than living with the unknown. Receiving a grey area result meant that predictive testing hadn’t given them a straightforward answer and consequently, some participants struggled to cope with their result and experienced some psychological difficulties. 

I think anxiety is more the fact that you don’t know if or when it’s gonna happen, if it’s gonna happen.

Several participants reported that the uncertainty around whether they would or wouldn’t develop Huntington's disease impacted their ability to make important decisions and plan for the future. They reported feeling unsure what to invest in and felt less motivated about pursuing a potentially stressful career. Others struggled with decisions around family planning and health anxiety associated with symptom checking was frequently reported. These participants reported that a full expansion result would possibly have been preferable to a reduced penetrance one. 

I think it was possibly more difficult than being told outright you’ve got it, you’re going to get symptoms (…) I went there wanting to know yes or no and I think that I found out maybe.

However, others were able to view the reduced penetrance result in a more positive light with the hope that if they were to develop symptoms of Huntington's disease, this would be in later life.

I didn't know there was a positive with hope.

Unmet support needs

The lack of professional support offered to participants following their intermediate allele or reduced penetrance result was repeated throughout the participant interviews; only 1 out of the 13 participants was happy with their follow-up support. 

You know if I'd been positive, they would have been offering me lots and lots and lots [of follow-up] and yes, in the end all that happened was one phone call several, several, several weeks later, I'd almost thought they'd forgotten about me actually.

As a result, participants felt abandoned and left to do their own research and found there was little information available on their specific result. In addition, some participants had unanswered questions related to practical aspects of their reduced penetrance result.

I think if there was ever anything that needed a medical questionnaire attached to it, I think then it [reduced penetrance result] would possibly be a negative influence because would I not have to declare it? I feel like I’ll possibly have to declare something but I don’t know for sure.

Communication challenges

Some participants described how their result was scientifically complex for them to understand, let alone to try and explain to others. Some felt their friends/family dismissed their worries about Huntington's disease by focusing on the fact they had a reduced penetrance result and might not develop any symptoms. Others found their grey area result as a barrier to joining support groups.

I'd feel a bit of a fraud talking in front of them, saying well, I might get it and it might come as a later onset, but I don't know, I might feel a bit bad talking about it, if in front of somebody who’d definitely got it if that makes sense.

Both participants with an intermediate allele had most likely inherited it from the so-called unaffected side of the family. This led to problematic family communication as this inheritance was not always believed and the information was dismissed by family members. 

Coping strategies

Despite the emotional difficulties participants faced following their predictive test result, the majority of the participants were able to describe changes they had subsequently made to their lifestyle and outlook on life following their results.

Examples included engaging in regular exercise, healthy eating and giving up alcohol, which participants felt benefited their mental and physical health. The result had also influenced their lives by giving them the push they needed to make changes to their lives such as moving house, retiring early and spending more time with family and friends. The majority of participants explained how taking part in research was very important to them as a way of feeling like they were helping make a difference. It also provided them with some support they didn’t feel they otherwise had. 

They always sort of ask, you know, ask you how you’re feeling or whatever when you, when you do the study so, um, I suppose if there was anything I needed to say then I could say it at those things.