Researchers have made significant breakthroughs in understanding the genetic factors underlying the rare disorder primary ciliary dyskinesia (PCD): August 2024. Image PCD affects motile cilia - small, hair-like structures lining the airways, brain ventricles and reproductive tracts that help create fluid flow. It is thought to affect one in 7,500 births. Patients born with the condition experience various debilitating symptoms including a life-long progressive decline in lung function, potential brain fluid accumulation, hearing loss and abnormally positioned organs. To date, mutations in over 50 genes have been implicated in causing PCD, but even after genetic testing, about 30% of patients still lack a genetic diagnosis. A genetic diagnosis allows for appropriate clinical management of patients, helping to predict how their disease may progress and what type of symptoms they may have. More recently, patients will need a genetic diagnosis to be eligible for novel and much needed genetic therapies that have just started in early clinical trials for PCD. A new study, led by researchers at the Institute of Genetics and Cancer and the Institute for Regeneration and Repair (CIR), undertook whole generation sequencing (WGS) of eight PCD patients lacking genetic diagnoses. In seven out of eight cases, researchers identified two copies of pathogenic changes in the patient’s DNA in known PCD genes encoding the molecular motors which drive cilia beat or cytoplasmic chaperones, which help motors fold properly. In several cases, these were large structural variants with sizeable pieces of the DNA missing. These types of mutations are more difficult to detect using traditional panel-based approaches. The team found that WGS was most powerful for detecting de novo mutations - mutations found only in the patient and not in their parents, in a novel PCD gene, the beta-tubulin subunit TUBB4B. The researchers showed how WGS uplifted genetic diagnosis of PCD by identifying structural variants and revealing novel modes of inheritance in new candidate genes, enabling them to solve all eight cases (100% diagnostic rate) in this small study. We believe that next-generation sequencing will become an important component of our PCD diagnostic toolkit, helping us increase genetic diagnostic rates above the current 50% ceiling. From a basic science perspective, WGS will help also reveal exciting and unexpected insights into fundamental biology including how the non-coding genome controls airway health. Professor Pleasantine MillMRC Human Genetics Unit Read the study in Pediatric Pulmonology: https://doi.org/10.1002/ppul.27200 Publication date 09 Aug, 2024
