Ending the diagnostic odyssey – providing answers for patients with rare respiratory disease

Whilst Dianne Macheta and Jean Kendrick have never met, they share a highly specific experience – suffering from frequent and serious chest infections since childhood. Both spent years waiting to understand what disease they have, both searching for a definitive diagnosis that never seemed to come.

Their journey is often known as the ‘diagnostic odyssey’ – a lifetime of unanswered questions – and they are not alone. Whilst rare diseases are by definition uncommon, there are around 7,000 of them, affecting around 3 million people in the UK.

But for Dianne and Jean the wait for a diagnosis is now over. As participants in the 100,000 Genomes Project they have finally received the answers they have been looking for.

Dianne’s story – winning the lottery

“Getting onto the genome project and being able to receive a diagnosis felt a bit like winning the lottery,” says Dianne Macheta. “It’s very hard to describe the relief at being able to put a definitive label on what I have.”

Dianne and her family.

Dianne’s relief is understandable. Her childhood was marked by regular visits to the GP owing to a persistent cough, alongside regular chest, sinus and ear infections. At 16 Dianne was diagnosed with pleurisy, which prompted three tests for cystic fibrosis, all of which proved negative.

Though unknown at the time, Dianne actually suffers from a rare condition known as primary ciliary dyskinesia (PCD). Microscopic hairs called cilia in our lungs, nose and ear move away mucus that traps dust and germs. In PCD, the cilia are either missing or don’t work properly. It has led to Dianne suffering from bronchiectasis, causing progressive and permanent scarring of her lungs, and making her more vulnerable to infection.

Still searching for a definitive diagnosis, Dianne heard a news report on Genomics England and the 100,000 Genomes Project. After speaking to her consultant, Professor Kevin Webb, at Wythenshawe Hospital in Manchester, Dianne enrolled as a participant.

The 100,000 Genomes Project proved decisive. Whilst Dianne’s condition is genetic, it isn’t found in a specific gene – which is where most genetic testing is focused. The glitch responsible for PCD is found in parts of the human genome known as the non-coding regions – something that could only be identified using the whole genome sequencing (WGS) offered by the 100,000 Genomes Project.

Using WGS, pioneering researchers at the University of Manchester discovered a defect in Dianne’s DNA that had never been previously reported as a cause of disease. Now that the glitch has been identified and mapped, Dianne’s diagnosis has been confirmed 26 years after her odyssey began.

Whilst diagnosed, Dianne’s condition is not cured – she still needs ongoing care – but the experience is a hugely positive one. “The diagnosis means the world to me in terms of wanting to have as much knowledge as possible about what I have. It’s given us a clearer picture about what choices I may have about my ongoing treatment, and also what choices my daughter and other relatives may have, as well as the prospect of new research on PCD.” 

Jean’s story – certainty and clarity

Jean and her family.

Jean Kendrick’s diagnostic odyssey also began in childhood. Illnesses and hospital visits were so frequent that she jokes, “There aren’t that many pictures of me when I was a baby”. Though Jean makes light of it, her condition was to have a serious impact for many years.

By the age of 16, ongoing problems led to referral to Abergele Chest Hospital to test for cystic fibrosis (CF) – one of the more common ‘rare’ genetic disorders that affect the lungs. Frustratingly, her results were unclear.

The test identified just one of the two gene glitches needed to confirm CF – without the second, diagnosis remained uncertain. This outcome was, understandably, very confusing and for the next three years Jean didn’t know whether she had CF or not. She says, “It wasn’t until I was 19 when I received a letter that simply said ‘because you have cystic fibrosis, you may have difficulty having children’ that I had any proper sense that this is what I had.”

A seemingly endless series of tests failed to deliver the answer she was so desperate to hear. This lead to uncertainty in both treatment options and life choices. Without diagnosis, some newer treatments for CF couldn’t be applied because they only work on patients with known types of genetic glitch. Further, in not knowing the types of glitches present, Jean and her family couldn’t know if they were carriers of the disease.

Now also under the care of Professor Webb in Manchester, Jean and her daughter joined the 100,000 Genomes Project – and results were dramatic. The Project identified a specific defect in a non-coding region of Jean’s cystic fibrosis gene, which had only ever been seen in one other patient. Once again, the unique nature of whole genome sequencing allowed scientists to detect a glitch that would have been invisible to other forms of testing.

The result has brought clarity to both to Jean and her daughter, allowing them to make informed choices about their future. Jean says, “The result provides more certainty about what current and future treatments might be effective for me, and gives us a much clearer sense of what the implications might be for future generations.”

The clinician’s story – a powerful diagnostic and treatment tool

Professor Webb is understandably pleased that his two patients have benefited from the 100,000 Genomes Project – and finally received answers.

“Whole genome sequencing is such a powerful tool for understanding more about inherited respiratory disorders. Whilst we are at the beginning of this journey, the potential for better management of people with the types of rare disorders that Dianne and Jean have is huge. WGS can dispel uncertainty, reduce the time it takes to gain a diagnosis, and open many doors to developing new and effective treatments.”