Improved tests could boost diagnosis of a rare lung disease

Southampton researchers are making advances in genetic testing to help diagnose Primary Ciliary Dyskinesia (PCD).

PCD is a rare genetic lung disease that currently has no cure. It affects one in 7,500 people in the UK.

Early diagnosis of PCD improves patient outcomes. However, this can be challenging due to the lack of a single, definitive test to diagnose it.

PhD student Lee Baker is driving new research to improve genetic diagnosis rates at the NIHR Southampton Biomedical Research Centre (BRC). His work is supervised by Professor Jane Lucas.

The research forms part of the NIHR Southampton BRC’s Data, Health and Society theme.

What is PCD?

PCD affects small, hair-like structures called motile cilia. Responsible for fluid movement, these are found in the airways, reproductive system and parts of the brain.

In people with PCD, the motile cilia can’t clear enough mucus away from the lungs, nose, and ears. It builds up, causing inflammation and chronic lung, ear and sinus infections.

PCD can cause other symptoms throughout the body, including hearing problems and infertility.

Half of those diagnosed with this disease also have a complication called ‘situs inversus’. This means the organs in their chest and abdomen are on the wrong side of the body.

Difficult to diagnose

Early diagnosis of PCD is important to start treatments that can delay permanent lung damage.

Guidelines suggest that clinicians should use a combination of functional tests, imaging and genetic tests for diagnosis.

Researchers have so far identified over 60 genes that cause PCD. However, between 20-30% of patients are still unable to get a firm genetic diagnosis.

Standard genetic testing often identifies ‘variants of unknown significance’. The effect they have on causing disease is not yet known. This prevents a confident genetic diagnosis from being made.

Advanced genetic testing

Researchers are now investigating if techniques like RNA sequencing can support genetic diagnosis when standard tests are inconclusive.

RNA sequencing provides deeper insights into how genes are activated (gene expression). It can also show if parts of a gene have been joined together in an unusual way (alternative splicing).

Clinicians take cell samples from the nose using a tiny brush and send them off for sequencing.

The research team then receive data for processing and analysis. They compare it to samples from healthy volunteers to determine any genomic changes that may be contributing to the disease.

“RNA sequencing provides additional evidence,” Lee explained. “It has helped resolve challenging PCD patient cases where the DNA-level information was inconclusive.

“By refining our analytical approach, we have enabled faster generation of RNA results. Delivering this information to clinicians more rapidly helps shorten the patient’s diagnostic journey. This allows earlier access to appropriate support.”

Lee added: “We hope to explore the application of machine learning models in predicting patient disease outcome and identifying novel insights relating to PCD. This will help better characterise this rare disease and contribute to a higher sensitivity in PCD diagnosis.”