Inconclusive diagnosis: life on the edge

Feature -

Amy has cystic fibrosis (CF) and her daughter Evie, aged two and a half, has an inconclusive diagnosis. This means that she has some of the symptoms of CF, but tests cannot prove that she definitely has the condition. The Cystic Fibrosis Trust met with Amy to talk about Evie's inconclusive diagnosis and what the experience has been like for her family.

Amy and Evie

In our spring issue of CF Life we interviewed parents with CF about what it is like juggling the condition and the challenges of parenthood. One of the parents we spoke to was Amy, who has CF herself and is mother to two-and-a-half-year-old Evie, who has an inconclusive diagnosis or 'non-classical CF'.

Holly Davis-Bollard from the Trust met up with Amy to hear her story and find out what the experience of receiving an inconclusive diagnosis has been like for her. Listen to her story and find out more about inconclusive diagnosis by reading the expert information provided by Professor Kevin Southern below.

Professor Kevin Southern

Hear from Professor Kevin Southern

My name is Kevin Southern, and I am a Paediatric Consultant at the University of Liverpool. I am leading on CF START, a UK-wide clinical trial assessing the benefits of prescribing antibiotics for infants with CF as a preventative measure. I also specialise in newborn screening and diagnostic issues and was a founding member of the European Cystic Fibrosis Society (ECFS) Diagnostic Network.

Amy and Evie’s story is unusual and Evie’s case has clearly been challenging. Inconclusive diagnosis affects many individuals and families across the UK, and this story highlights the issues that those families can face.

The following information expands on some of the issues raised in the podcast.

What is cystic fibrosis?

Cystic fibrosis is caused by a mutation of one of the genes in our body, so it is a condition you are born with and have all your life. The CF gene makes a protein that is important for the movement of molecules (salts) across cells. When the CF gene is mutated it causes the salt to move abnormally across cells, resulting in the features we associate with CF, namely a lot of salt in the sweat, thicker mucus, a predisposition to airway infection and pancreatic damage (which affects the digestion of food).

What are gene changes and ‘mutations’?

Human genes have a fairly constant structure but if you look carefully in the laboratory, you can find many variations in each of our genes. These are called variants. Some variants have absolutely no impact on how our genes work, and are called normal variants (this is what Amy describes as a polymorphism in the interview, and is what normal variants were previously called). Some variants do change the way a gene works, stopping the gene from making a protein or causing it to produce a protein that doesn’t work properly. These variants are called mutations.

How is the CF gene handed down from generation to generation?

We have many thousands of genes, and each does a specific job. We inherit two copies of each gene, one set of genes from our mother and one from our father. Both sets of CF genes need to be affected for a child to have cystic fibrosis. If one gene is affected by a mutation but the other gene is OK, then the person is a healthy carrier (and may never know it!). For a baby to have CF, they must have two mutated CF genes, one inherited from their mother and one from their father.

How many CF-causing mutations are there?

Over 2,000 CF gene mutations have been identified and hundreds of these have been clearly characterised as CF-causing. However, many of the CF gene variants are quite rare (sometimes only occurring in one or two people) and it can be difficult to be certain that they are CF-causing. There are some variants that are very difficult to characterise and we cannot be sure of the consequence of these variants. Some variants have been shown to have no negative effects on the function of the CF gene and are called normal variants.

How likely is it that a person with CF will have a baby with the condition?

People with CF have an increased risk of having a child with CF as they will automatically pass on an abnormal CF gene, while a ‘carrier’ has a one in two chance of passing on their abnormal CF gene. In both scenarios, their partner must also have an abnormal CF gene for a child to have cystic fibrosis.

Evie’s parents have taken measures to reduce the risk of passing on CF to their child. They knew that Evie’s father does not carry one of the more common CF-causing gene abnormalities, but it transpired that he does carry an unusual CF gene change.

Why do some people receive an inconclusive CF diagnosis?

Some mutations affect the function of the CF gene, but not in a severe way. These mutations are called ‘mutations of varying clinical consequence’. People with mutations like this may have some features that suggest CF but not all the characteristic presentations. For example, they may have apparently normal pancreatic function and a low amount of salt in their sweat. 

Is it correct to use the term CF for people with an inconclusive diagnosis?

There has been a lot of debate as to the best way to describe people with features of CF who do not fulfil the exact criteria that we use to diagnose cystic fibrosis. Most physicians in the UK would describe these people as having atypical CF and take a pragmatic approach, including providing treatment to keep them well.

What is CFTR-related disorder?

CFTR-related disorder is used to describe someone with a condition that is not CF but is caused by some abnormality of the CF gene. These disorders are very significant to those diagnosed with them, but are not CF and have a different outlook when it comes to life expectancy, standards of living and treatments.

Can people with atypical CF develop severe disease?

As a group, people with atypical CF have generally better respiratory condition and nutrition than people with cystic fibrosis. However, they are at risk of developing significant airway infection and in some cases this can be quite debilitating. People with atypical (or non-classical) CF can sometimes have their health compromised by exposure to difficult bugs and Evie’s case may illustrate this, as her mother mentions.

Why was Evie’s newborn CF screening test negative?

Newborn screening is very sensitive and should recognise infants with inconclusive diagnosis, some of whom will go on to develop features of cystic fibrosis. However, newborn screening is not perfect and cases of CF will be missed occasionally. If Evie had a positive newborn screening test she would have been designated as “CF Screen Positive, Inconclusive Diagnosis (CFSPID)”, because she has two mutations of her CF gene, one of which has unclear consequences. This term describes infants who have had a positive screening test and are otherwise healthy, but have some features that may suggest a CF diagnosis, such as a slightly raised salt level in their sweat. The majority of infants with CFSPID remain well, but some will develop features consistent with cystic fibrosis.

Did Evie have CFSPID when she was born?

Evie had a negative newborn screening test, so she did not have CFSPID, however given her subsequent clinical condition it is very appropriate to describe her as having atypical CF, or non-classical CF as her CF team have diagnosed her.

In summary, this case highlights some of the issues we face making a diagnosis of CF and the challenges of managing an inconclusive diagnosis. With the treatments that Evie is receiving, it is reasonable to be hopeful that she will maintain good health and wellbeing as she grows.

Confused by any of the terms presented in this feature? Take a look at our glossary at the bottom of this page.

This article supplements a feature in our latest edition of CF Life magazine, which is packed full of stories and articles about life with cystic fibrosis. If you don’t already receive the magazine and would like to in future, please email


Normal variant

A gene change that has no negative effects on the function of the gene, previously known as a polymorphism.


When a gene mutation causes a person to exhibit the features of cystic fibrosis. This person would then be classified as having CF.


When a gene change affects the gene in a way that stops it from working, such as by stopping the gene from making a protein or causing it to produce a protein that doesn’t work properly.

CFSPID (CF Screen Positive, Inconclusive Diagnosis)

A diagnosis given to infants who have had a positive screening test and are healthy, but have some features that may suggest a CF diagnosis, such as a slightly raised salt level in their sweat.

CF-related disorder

A condition that is not CF but is caused by some abnormality of the CF gene.

Inconclusive diagnosis/grey-area CF/non-classical CF/atypical CF

The terms used to describe a person whose diagnosis cannot be classified as CF but has some of the symptoms of the condition.

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