The recognition and understanding of inherited forms of interstitial lung disease (ILD), including familial pulmonary fibrosis, have grown considerably in recent years, experts said. Genetic predisposition in individuals and their families suggests familial ILD is a distinct entity, separate from idiopathic disease and other cases associated with occupational and environmental exposures, connective tissue disease, and other known causes.

Genetics may not only illuminate predisposition and verify ILD in about 1 in 5 symptomatic people with ILD but can also explain disease progression. Even so, challenges remain, including identifying the drivers behind a majority of idiopathic cases, counseling asymptomatic individuals and families about ILD risk, and encouraging those predisposed to ILD to adopt behaviors that could reduce their risk.

Family history is now recognized as the strongest risk factor for ILD, and candidate gene-based, linkage, and next generation sequence-based strategies have identified changes in more than 10 genes driving disease in families with ILD.

From Sporadic to Genetic

“The entire disease entity of pulmonary fibrosis has undergone a very rapid transformation in the last 10-15 years,” said Suhail Raoof, MD, chief of pulmonology at Northwell’s Lenox Hill Hospital in New York City. Before the recent genetic discoveries, “it was all kept under one bucket of scarring and fibrosis in the lungs, resulting in specific physiological deficits, and it followed an inexorable downhill course.”

Historically, ILD cases that could not be explained by known causes were considered idiopathic. That was before researchers discovered that a substantial minority of ILD diagnoses are familial. They implicated a common genetic change, the MUC5B promoter polymorphism, that signals early ILD, as well as pathogenic variants in surfactant and telomere genes.

Despite these discoveries, widespread genetic testing for ILD is not recommended as a first-line approach to diagnosis. Instead, guidelines from the American Thoracic Society and other societies recommend high resolution CT scans for early detection of idiopathic pulmonary fibrosis. These 2022 guidelines also address progression of pulmonary fibrosis in patients with ILDs other than idiopathic pulmonary fibrosis.

A family history of pulmonary fibrosis is found in an estimated 20%-25% of people with idiopathic pulmonary fibrosis, for example. In addition, another study found 31% of relatives of an affected individual also had ILD, reinforcing a strong genetic basis in some cases.

When Is Genetic Testing Warranted?

“Pulmonology is one of those specialties where genetic testing for heritable disorders is the least known,” said Shweta U. Dhar, MD, medical director of Adult Genetics at Baylor College of Medicine in Houston. “There are a lot of confounding factors and so the heritability of a lot of these pulmonary disorders is not clearly known.”

The Pulmonary Fibrosis Foundation provides a patient-friendly online genetic testing primer with definitions of familial pulmonary fibrosis, genes, variants, and who in general should get tested.

Commercially available genetic testing panels can also help. They can identify the presence of a known pathogenic variant(s) in an individual and their family, but some people who test positive for genetic risk never develop ILD. And others who test negative can go on to become symptomatic. Therefore, although genetic testing is becoming more clinically relevant, it is not yet recommended for screening large populations.

A Mayo Clinic study selected 54 people with a family history of pulmonary fibrosis, development of fibrosis at or before age 60, progressive fibrotic disease, or clinical signs of surfactant protein or telomere biology disorders. The researchers found that positive genetic findings guided patient management in more than 50% of cases.

Therefore, targeted testing remains essential for some patients and their families. For example, an individual with two or more affected first- or second-degree relatives should prompt genetic testing for familial pulmonary fibrosis.

“I think the most important message is to not let genetic testing replace clinical judgment. Obtaining accurate family history remains one of our most powerful tools, especially since genetic testing is not universally available,” said Tejaswini Kulkarni, MD, associate professor of medicine and director of the Interstitial Lung Disease Program with The University of Alabama at Birmingham.

Dhar puts the age cutoff at 50 years. If someone develops pulmonary fibrosis after age 50, occupational or environmental factors are more likely due to longer lifetime exposure. In contrast, genetic drivers become more common with pulmonary fibrosis in younger individuals. This age cutoff applies beyond lung disease to the many disorders Dhar sees with both genetic and sporadic patterns.

Idiopathic pulmonary fibrosis is generally seen in men, in individuals with a smoking history, and in individuals older than the age of 60 or 65, Raoof noted.

In addition to a younger age, women and nonsmokers who develop fibrosis may also be more likely to carry genetic than environmental risk, Raoof said. Furthermore, a rapid or unexplained disease progression or a poor treatment response raises the bar for considering a genetic etiology.

Telomere Changes: Not Just for Aging Anymore

Premature gray hair, bone marrow failure or cytopenia, and liver disease of unknown etiology are all signs of telomere biology disorder. These presentations can increase the consideration of genetic testing for ILD, Dhar, Raoof, and Kulkarni said.

Telomeres are six-nucleotide repeats at the end of each chromosome that act like a cap, Dhar explained. They provide stability. Telomere length tends to shorten with age, but a pathogenic variant can accelerate the shortening to the point of “uncapping.” This in turn triggers a DNA repair mechanism and apoptosis or cell death in the alveolar epithelium, for example. The ensuing inflammation causes pulmonary fibrosis and irreversible damage, she added.

When the length of the telomere drops below the 10th percentile for age, it strengthens the argument for genetic testing, Raoof said. “These patients may show more rapid progression of the disease and very, very importantly, they may not respond to certain medications” to slow progression.

Tying Results to Clinical Management

Physicians can order commercial testing themselves, or if they need further direction, definitely refer to a genetics professional for either initial testing or follow-up, Dhar said. “We are the experts in figuring out all of this.”

Finding a pathogenic variant can help explain why disease is occurring, identify relatives who may be at risk, and potentially influence how to monitor and manage the patient, Kulkarni said. “However, it is important to distinguish between genetic susceptibility and a genetic diagnosis.” Discussion about family history covering at least three generations remains the key and guides toward further testing and patient counseling, she added.

It is also important to note, Kulkarni said, that there is no genotype-specific treatment yet. However, knowledge from genetic testing can influence the timing of treatment initiation and lung transplant evaluation.

Counseling Remains Imperative

Although idiopathic pulmonary fibrosis is the most common ILD subtype, familial pulmonary fibrosis can include other forms such as hypersensitivity pneumonitis or ILD related to systemic autoimmune rheumatic disease. Also counsel patients that there are different types of genetic findings and that the impact of each of these may be different, Kulkarni said. “I would also tell patients that a negative genetic panel does not mean that the family does not have a genetic predisposition.”

“I would also emphasize that genetic testing is not the same as genetic counseling,” she added. She recommended a multidisciplinary approach involving ILD specialists, genetic counselors, geneticists, and other relevant specialists to accurately interpret genetic results and their appropriate application to clinical care.

“This is where counseling becomes particularly important,” Kulkarni said. “A positive pathogenic variant does not mean that the person currently has ILD or is guaranteed to develop ILD. There is currently no evidence to support giving antifibrotic therapy simply because an asymptomatic person carries a pathogenic variant.”

For a patient who has watched a parent, sibling, or other family member develop pulmonary fibrosis, genetic testing and the following monitoring plan may be reassuring, Kulkarni said. “However, this can also be associated with anxiety. Knowing this, in my opinion, it is crucial to refer for genetic counseling before obtaining genetic testing for the patient and their family members.”

Dhar typically provides family letters explaining the genetic finding in the individual patient “because we obviously can’t reach out to every family member who is not our patient.”

One strategy all physicians can take is to address modifiable risk factors, Raoof said. “For instance, if my father has pulmonary fibrosis, and he’s found to have a genetic mutation for it, I could be more likely to develop pulmonary fibrosis. Then I am the individual who would benefit from medical advice: If you are smoking, absolutely stop smoking. If you develop shortness of breath on exertion, seek medical attention quickly so that we can get the appropriate testing.”

Other high risk situations include an occupation where someone is coming in contact with mineral dust, such as a construction worker, or exposed to higher levels of particulate matter, such as individuals living close to a highway.

Some Unknowns Remain

Not all pathogenic variants driving ILD are known, Dhar said. Therefore, more work is needed to get a more complete picture of heritable etiology. “We can get there. Technology is better today than it was 5 years ago and will be better 5 years from now.”

At this stage, genetics is an area that is advancing from genetic discovery to early clinical implementation in the management of ILD, Kulkarni said. “Our understanding on the role of genetics, particularly in familial pulmonary fibrosis, and its impact on diagnosis, treatment, and prognosis is evolving although we are not quite yet at the point of precision medicine for most patients with ILD.”

“I would frame the field as promising but not yet fully mature,” Kulkarni added. “We have made remarkable advances in identifying genetic pathways that contribute to ILD, but significant gaps remain in understanding how to translate these findings into individualized risk prediction, prevention, and genotype-specific treatment.”

Dhar reported receiving royalties from Elsevier as an editor and writer for a handbook on clinical adult genetics and genomics. Raoof and Kulkarni had no relevant disclosures.