Genetics’ impact on PCD
About 20 years ago, only two genes were linked to PCD, a largely autosomal recessive disorder that results from abnormalities in the cilia and subsequently improper airway clearance. Today, said Dr. Ferkol, there are over 50 known genes that, if defective, can lead to PCD.
“Based on our latest estimates, I’d say we can diagnose people using genetics about 70%, maybe 80%, of the time,” Dr. Ferkol said. Genetic testing has become a first-line diagnostic tool for PCD in North America – a significant development given that a definitive diagnosis has long been challenging, he said.
A genetics-based diagnosis of PCD is sometimes challenged by the finding of variants of unknown significance (VUSs) on genetic testing (often missense mutations) “because some of the genes involved are huge,” noted Dr. Ferkol, who coleads the NIH-funded Genetic Disorders of Mucociliary Clearance Consortium. “But many times, it’s straightforward.”
Children with PCD have repeated or persistent upper respiratory tract infections beginning early in life – like chronic rhinosinusitis or suppurative otitis media – and chronic bronchitis, leading to bronchiectasis. About half of patients have a spectrum of laterality defects, where organs are malpositioned in a mirror image of normal. Some individuals also have cardiac defects, and subfertility in both males and females can frequently occur.
Just as it has become increasingly clear that CF exists as a continuum, with milder and variant forms having been recognized since the advent of genetic testing, “we’re finding genotype-phenotype relationships in PCD,” Dr. Ferkol said. “Certain individuals have more rapid pulmonary decline, which is related in part to their genetics.”
With PCD, “I’m convinced this is a continuum. Some patients have unmistakable, clear-cut PCD, but I’m sure we’re going to find individuals who have milder variants in these PCD-associated genes that lead to milder disease,” he said.
There are no specific treatments that will correct cilia dysfunction, and current therapy options are borrowed from other diseases such as asthma and CF. However, newer treatments targeting specific genetic defects are in early clinical studies. Will the gene discoveries and more research open up new avenues for treating PCD, as happened in CF? Dr. Ferkol hopes so.
Approximately 2,000 genetic variants have been identified in the CFTR gene, though not all are pathogenic. “The newer, highly effective modulators used in CF target a particular CFTR mutation class, so some drugs will work for some people with the disease, but not all,” Dr. Ferkol said. “It’s personalized medicine.”
Modulator therapies designed to correct the malfunctioning proteins made by the CFTR gene have profoundly changed the lives of many with CF, improving lung function and everyday symptoms for patients, allowing them to lead near-normal lives. “It’s astonishing,” he said.
Dr. Garcia reported consulting for Rejuvenation Technologies and Rejuveron Telomere Therapeutics; in addition, her laboratory has received support from Boehringer Ingelheim and Astrazeneca for investigator-initiated research. Dr. Newton reported he has performed consulting for Boehringer Ingelheim. Dr. Ferkol reported involvement in a longitudinal study defining endpoints for future clinical PCD trials funded by ReCode Therapeutics and leadership of an international clinical trial for PCD supported by Parion Sciences. He has received honoraria from the Cystic Fibrosis Foundation and serves as a member of the ReCode Therapeutics PCD Clinical Steering Committee. Dr. Raby reported no relevant disclosures.