Genetic Familial Interstitial Lung Disease

Introduction

Interstitial lung diseases (ILDs) are a heterogenous group of progressive chronic lung disorders. There are many systems that have been used to classify them, but most practically we can divide them into those that have known causes and those without known causes. Those with a known cause include inorganic and organic exposures and tobacco related ILD, and ILDs associated with autoimmune diseases, while sarcoidosis, idiopathic pulmonary fibrosis (IPF) and the other idiopathic interstitial pneumonias¹ do not have known causal exposures. It has long-been recognized that cases of idiopathic interstitial lung disease can cluster in families, with case reports dating back to the 1950’s when Dr. JW Peabody reported pulmonary fibrosis in twin sisters². Through the past two decades there has been considerable progress elucidating the genetic risk mechanisms that underlie heritable pulmonary fibrosis³.

There are several multisystem disorders that have pulmonary manifestations (e.g. Hermansky-Pudlak Syndrome, Lymphangioleiomyomatosis) that are reviewed in other excellent chapters in this issue (see Chapters 12, & 1 respectively for more details). Here, we focus on the fibrotic ILDs found to run in families that have an association with an identified rare variant in a single gene. We review the genes that have been linked to familial ILD, the clinical manifestations of these patients, treatment considerations, and discuss implications for relatives of FPF patients.

What is Familial Interstitial Lung Disease?

Although hundreds of manuscripts have established that interstitial lung disease can manifest in a heritable/familial form³, there is no consensus definition for familial interstitial lung disease. Differences in precise definitions likely contribute to some of the variability in terms of clinical phenotype distribution, frequencies of specific genetic risk variants, and outcomes of subjects reported across studies. The terms familial pulmonary fibrosis (FPF) and familial interstitial pneumonia (FIP) have been used by different groups to describe a syndrome of heritable interstitial lung disease. While there is broad agreement that FPF/FIP requires 2 or more bloodline relatives with interstitial lung disease, there are differences regarding the required relationship between cases, as well as the ILD phenotypes that would meet FPF/FIP criteria across US-based studies^4–8. The recent European Respiratory Society statement on FPF utilized criteria limiting the degree of relatedness to first or second-degree relatives, including non-idiopathic but excluding non-fibrotic ILD phenotypes⁹. For simplicity, and to align with the most commonly used terminology, we use the term Familial Pulmonary Fibrosis (FPF) in this review.

FPF was originally thought to be very rare¹⁰, but several more recent studies suggest ~12–20% of IIP cases are familial^11–14. A specific genetic etiology is found in only a subset of FPF cases (~25%)^6,8, thus monogenic causes of PF likely comprise ~5% of all ILD cases (Figure 1). The vast majority of studies on this topic have been restricted to individuals of European ancestry, and extrapolating these estimates to individuals from other ancestries is of uncertain validity; further study of IPF/FPF genetics in diverse populations is an urgent need.

Figure 1: Schematic of ILD Subtypes.

Interstitial lung disease includes a broad set of disorders, the majority of which present with a fibrotic phenotype (pulmonary fibrosis, PF). A subset of ILD have no known exogenous cause (Idiopathic ILD), and this group of disorders includes with fibrotic and non-fibrotic disease phenotypes. A subset of ILD cases occur in individuals with a family history of ILD. This syndrome is termed Familial Pulmonary Fibrosis (FPF), and can include individuals with idiopathic and non-idiopathic phenotypes. In a subset of FPF cases, a single-gene mutation is causal (Monogenic ILD). Such single-gene mutation can rarely be observed in ILD patients without a known family history of ILD, and can include fibrotic and non-fibrotic disease patterns.

Genetics of Pulmonary Fibrosis

There are two types of genetic factors which influence risk for any disease or syndrome, including pulmonary fibrosis: common and rare genetic variants. Common genetic variants (i.e those identified in genome-wide-association studies, GWAS) are found in at least 5% of the general population and individually exert small effects on risk for disease (i.e odds ratios of 1.2 – 1.5). Culprit variants in GWAS loci are often found in regions of the genome that do not encode a protein, and are thought to confer risk by regulating gene expression. Rare genetic variants (RVs) are sequence changes not typically found in the general population, and RVs generally alter the structure/function of a protein. Carrying an RV in a disease-causing gene can make an individual dozens to hundreds of times more likely to develop a disease than someone without a variant in that gene (i.e. monogenic disease).

Monogenic Causes of Pulmonary Fibrosis

Two large US-based FPF cohorts^6,8 have recently reported results from whole-exome/whole-genome sequencing studies that provide the best available estimates of the impact of RVs on disease risk. These results, derived from a total of more than 900 FPF kindreds from independent, geographically diverse cohorts, are remarkably concordant, reporting that pathogenic/likely pathogenic causal rare genetic variants were identified 14.9 – 25% of families (with differences largely related to classification of novel/ultra-rare missense variants). These monogenic causes fall into two major categories: 1) genes related to surfactant biology, and 2) genes related to telomere biology. A small number of FPF cases have been linked to variants in genes that do not clearly fit into these two categories^6,15, while cases also have been observed in the context of monogenic syndromes with multisystem manifestations.

It is also notable that pathogenic RVs in these same genes and pathways are found in cohorts of “sporadic” IPF/ILD cases, albeit at somewhat lower frequencies^8,16–18. It is not clear if these findings are due to incomplete ascertainment of family history, variable penetrance, or de-novo mutations. There is also evidence that similar patterns are seen in individuals with rheumatoid-arthritis-associated ILD¹⁹ and chronic hypersensitivity pneumonitis²⁰. With these observation that monogenic causes of PF can be found absent a known family history of disease and present with a range of clinical phenotypes, we suggest that rather than focusing on a distinction between “sporadic” and “familial” ILD, the time has come to recognize monogenic ILD as an entity in and of-itself (Figure 1). Below, we discuss specific monogenic causes of ILD.

Surfactant Genes

Mutations in surfactant-related genes were the first implicated in FPF, and their identification has proven crucial in advancing mechanistic understanding of ILD pathogenesis²¹. Surfactant-related mutations are rare causes of monogenic FPF, likely comprising 1–2% of all FPF kindreds^6,8. The first genetic cause of familial ILD was reported In 2001, when Nogee and colleagues identified a heterozygous mutation in the gene encoding for surfactant protein C (SFTPC) in a mother and infant with interstitial lung disease²². Soon after, a large family with highly penetrant ILD including phenotypes ranging from neonatal respiratory distress syndrome to adult presentations with UIP-like features was found to carry a different SFTPC mutation²³, and subsequently a number of reports have described a range of FPF-associated SFTPC mutations^8,13,24–34..

As appears to be the case for nearly all FPF-associated genes, carrying a single copy of an SFTPC mutation (i.e. autosomal dominant inheritance) appears to be sufficient to cause interstitial lung disease. Surfactant Protein C (SP-C) is highly hydrophobic and produced as a proprotein exclusively by type 2 alveolar epithelial (AT2) cells. Following a series of endoplasmic-reticulum and Golgi-mediated cleavage and trafficking steps, the mature form of SP-C, together with other surfactant proteins and phospholipids, comprise the secreted surfactant that reduces the surface tension of alveoli to prevent atelectasis at end expiration³⁵. Elegant studies using cell and animal models indicate FPF-associated SFTPC mutations act through toxic “gain of function” mechanisms, leading to dysregulation processing and/or trafficking of the pro-protein that results in AT2 cell dysfunction^21,36–40.

These toxic gain-of-function mutations lead to a variety of different clinical and radiologic manifestations. Some yield small stellate, peripheral, fibrotic lesions as seen in Figure 2A. Others demonstrate significant GGOs (Figure 2B) usually atypical for persistent fibrotic lung disease. Some present with interstitial changes that are peribronchovascular (Figure 2C) while others demonstrate more typical usual interstitial pneumonia distributions (Figure 2D & E). How these SFTPC mutations cause different patterns of disease remains uncertain.

Figure 2:

Representative images of CT scans of patients with SFTPC mutations.

Following the description of SFTPC mutations in FPF, several groups sought to determine whether mutations in other surfactant proteins might also be responsible for FPF cases. In 2009, Wang and colleagues reported mutations in surfactant-protein A2 (SFTPA2) in families with FPF and lung cancer⁴¹, a pattern that has since been reported in several other kindreds^6,42,43. Mutations in both SFTPA1 and SFTPA2^32,42,44,45 have been implicated as causal in FPF kindreds, while to date there has not been evidence that monoallelic SFTPB or SFTPD variants cause FPF. Bi-allelic surfactant protein B (SFTPB) mutations have been reported in neonates with alveolar proteinosis or respiratory distress syndrome^35,46 and there is one report of ILD presentation in early adulthood⁴⁷, but no carrier phenotype has been reported.

A final surfactant-related gene warrants particular discussion. There have also been reports of rare variants in the gene encoding ATP-binding cassette subfamily A member 3 (ABCA3) in a number of FPF kindreds^27,32,48,49. Biallelic ABCA3 mutations cause neonatal respiratory distress syndrome⁵⁰ and severity appears related to the degree of retained ABCA3 function⁵¹. Notably, ABCA3 haploinsufficiency appears well tolerated when assessed using in-vitro models⁵¹. As such, while ABCA3 is frequently included in gene panels used for FPF testing, we suggest the evidence is currently insufficient to consider monoallelic ABCA3 rare variants as causal for FPF.

Telomere Biology Genes

Pulmonary fibrosis has long been recognized as one feature of dyskeratosis congenita, a complex syndrome caused by loss-of-function mutations in genes related to telomere maintenance^52–54. Telomeres are a complex nucleoprotein structure made up of a repetitive DNA bound by proteins called shelterins that help to “cap” the end of the chromosome, preventing chromosome ends from being sensed as double-stranded DNA-breaks⁵⁵. Loss-of-function genetic variants in the telomerase complex and the associated telomere processing genes lead to reduced telomerase activity, accelerated telomere shortening, and persistently broken telomeres.

In 2007, two groups reported rare variants in the genes encoding for telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC/TR) in FPF kindreds^56,57.

Soon after the discovery of telomerase mutations in FPF kindreds, it was recognized that a large proportion of individuals with FPF (and IPF) have short peripheral blood telomeres (defined as <10th percentile for age)^58,59 - 30–50% of subjects, far more than have recognized TERT/TR rare variants. This led to a search for causal variants in other genes related to telomere biology. In the past decade, there have been reports of FPF/IPF-associated rare genetic variants in at least 12 genes related to telomere biology (Table 1). In general these mutations act by altering the enzymatic activity of TERT directly, reduce levels, stability or function of TR, or impair access of the telomerase enzymatic complex to telomeric DNA, or affecting ultimately leading to telomere attrition and telomere damage.

Table 1.

Genes implicated in familial interstitial lung disease

Gene	Gene Product	Clinical Features and Manifestations	Function	References
Surfactant-related genes
SFTPC	Surfactant Protein C	Neonatal Respiratory Distress Syndrome Childhood ILD Adult ILD	Surfactant in Alveoli, causes Unfolded Protein Response	22,24,25,27–30,123
SFTPA1/ SFTPA2	Surfactant Protein A1/A2	Adult ILD Lung cancer	Surfactant in Alveoli, causes Unfolded Protein Response	32,33,41,43
ABCA3*	ATP Binding Cassette Subfamily A Member 3	Neonatal respiratory distress syndrome Childhood ILD	Processing of Surfactant	27,32,48–50,124
Telomere-related genes
TERT	Telomerase Reverse Transcriptase	Pulmonary Fibrosis, Cirrhosis, Aplastic Anemia, GI Enteropathy, Dyskeratosis Congenita, Hoyeraal-Hreidarsson syndrome	Telomerase enzyme leading to telomere elongation	56,57,102,125
TERC	Telomerase RNA Template	Pulmonary Fibrosis, Cirrhosis, Aplastic Anemia, GI Enteropathy	Telomeric template for TERT	57,60,102,126,127
DKC1	Dyskerin	Pulmonary Fibrosis, Cirrhosis, Aplastic Anemia, GI Enteropathy	Stability of TERC 128	129,130
TINF2	TINF2	Pulmonary Fibrosis, Cirrhosis, Aplastic Anemia, GI Enteropathy	Telomere Capping, Telomerase Localization	131–133
ACD	TPP1	Aplastic Anemia, Pulmonary Fibrosis, Hereditary Melanoma, Hoyeraal-Hreidarsson syndrome	Telomere Capping, Telomerase Localization	134–137
POT1	POT1	Pulmonary Fibrosis, Chronic Lymphocytic Leukemia, Familial Melanoma	Telomere Capping	138
RTEL1	RTEL1	Pulmonary Fibrosis, Dyskeratosis Congenita, Hoyeraal-Hreidarsson syndrome	Telomere Replication, 3' G-overhang regulation, Telomere Length	5,16,18,34,60,139,140
NAF1	NHP2	Pulmonary Fibrosis, Myelodysplastic Syndrome	TERC stability	141
PARN	PARN	Pulmonary Fibrosis, Dyskeratosis Congenita, Hoyeraal-Hreidarsson syndrome, Myelodsyplastic syndrome	TERC stability	60,139,142,143
ZCCHC8	ZCCHC8	Pulmonary Fibrosis	TERC stability	144
RPA1	RPA1	Pulmonary Fibrosis, Dyskeratosis Conegenita	Telomere replication, single stranded DNA binding factor	145
Genes associated multisystem disorders including ILD
NKX2–1	NKX2–1	Brain-Lung-Thyroid Syndrome Neuroendocrine Hyperplasia of Infancy Childhood ILD Adult ILD	Lung epithelial specification	67–70
COPA	COPA	Alveolar hemorrhage Interstitial lung disease Inflammatory arthritis Nephritic Syndrome High-titer autoantibodies	ER-Golgi trafficking	71–75
TMEM173	STING	Skin vasculitis Raynaud’s phenomenon Adenopathy Childhood ILD Adult ILD	ER-Golgi trafficking	79,81,82,146

^*biallelic (recessive) inheritance

TERT variants appear to be the most common (10–15% of families), followed by RTEL1 (5–7% of families), and other genes in <2% of kindreds^6,8. As is the case for surfactant-related genes, autosomal dominant inheritance is observed with high penetrance, although in this case the mechanism through which these mutations cause disease is through haploinsufficiency.

In general, these variants are found in individuals with clinical and/or laboratory evidence of a short-telomere syndrome, including a personal or family history of premature greying, cryptogenic cirrhosis, macrocytosis, myelodysplasia and other bone marrow dyscrasias, and short peripheral blood telomeres. Compared to other individuals with ILD or FPF, individuals with monogenic PF caused by a telomere-related gene mutation may be younger at the time of diagnosis, and a spectrum of clinical phenotypes can be seen within the same family^60–63 (Table 1).

The mechanism through which telomere shortening and damage causes pulmonary fibrosis remains incompletely understood. The prevailing hypothesis is that telomere dysfunction (either by shortening or becoming recognized as DNA damage) leads to senescence in AT2 cells and loss of capacity of these cells to serve as facultative progenitors during lung epithelial homeostasis and injury-repair^64–66, although questions remain as to the complex interplay between the lung epithelium, the immune system, and the fibroblasts involved in normal lung regeneration. How telomere genes affect each one of these cell types remains an active area of investigation that will uncover new therapeutic avenues to improve lung regeneration.

Other Monogenic Syndromes Associated with ILD

Several other rare multisystem disorders that may include interstitial lung disease have recently been identified as having specific genetic etiologies (Table 1). Mutations in the gene encoding for the transcription factor NKX2-1, required for lung epithelial specification, have also been described in a small number of families with ILD. NKX2-1 mutations, first described in “brain-lung-thryoid” syndrome⁶⁷ and also reported in families with neuroendocrine hyperplasia of infancy⁶⁸, are now recognized to present with a range of pulmonary phenotypes⁶⁹ including adult UIP-like patterns⁷⁰.

“COPA Syndrome” is a multisystem autoinflammatory disorder that was first described in 2015 and is caused by mutation in the gene encoding for coatomer subunit alpha (COPA)⁷¹. The primary manifestations of this syndrome include inflammatory arthritis, high-titers of multiple autoantibodies, and interstitial lung disease. The earliest reports described this syndrome primarily in childhood or early adulthood, although with increased awareness and testing it has become clear that later adult ILD-predominant presentations can be observed^71–76. COPA syndrome follows an autosomal dominant inheritance pattern, wherein a single copy of a disease-associated rare-variant is sufficient to cause disease. Available evidence suggests that COPA mutations impair ER-Golgi trafficking and can activate the unfolded protein response to promote TH17-cell polarization⁷¹. There are no specific studies of treatments for COPA-syndrome, but case-reports and case-series suggest that Janus-kinase (JAK) inhibitors may in some circumstances be effective^77,78.

STING-Associated Vasculopathy in Infancy (SAVI) is another autoinflammatory syndrome originally described in children⁷⁹ that has also been increasingly recognized to exhibit phenotypic heterogeneity including presentation as adult onset pulmonary fibrosis^80–82. SAVI, caused by mutations in TMEM173, leads to skin eruption, fever, and pulmonary manifestations that range from alveolar hemorrhage to fibrotic interstitial lung disease. Intriguingly, a connection between COPA and SAVI has recently been identified, as STING (encoded by TMEM173) is among substrates trafficked by COPA^83,84; COPA mutations lead to STING activation. Similar to treatment of COPA syndrome, there are limited trial data to guide therapy, however as an “interferonopathy,” successful use of JAK inhibitors as the primary means of immunosuppression has been reported in case series⁸⁵ and small trials⁸⁶.

Common genetic variation and risk of Pulmonary Fibrosis

In addition to rare/ultra-rare genetic variants, common genetic variants also influence risk for PF in families. More than 20 common genetic variants, including a highly prevalent polymorphism in the gene encoding for Mucin 5B (MUC5B) have been linked to IPF risk by GWAS^87–90, and limited available data suggest that these variants have similar frequencies in FPF^89,91. Currently there is no role in testing or evaluating for these genetic variants among individuals with or at risk for pulmonary fibrosis⁹², however in the future polygenic risk scores and/or other approaches may be utilized for diagnostic and/or risk-stratification^93–95.

Diagnosing Familial Pulmonary Fibrosis

Making a diagnosis of FPF requires taking a detailed family history. Oftentimes, details as to the medical history of relatives from past generations are sparse and/or limited to non-specific observations (“breathing problems”, “wore oxygen”), and there was likely misdiagnosis/underdiagnosis of interstitial lung diseases prior to widespread availability of CT imaging. With this in mind, we suggest that asking broad, open-ended questions with specific follow-up queries can increase the likelihood of uncovering associated respiratory symptoms or other associated pathologies (cirrhosis, bone marrow failure) that could suggest a familial/monogenic etiology. We also encourage periodic reassessment for changes in family history, as in our experience as many as half of all FPF patients do not have another known family history of ILD at the time of their initial evaluation but subsequently relatives with ILD are newly diagnosed or identified.

Referring Patients & Family Members for Genetic Evaluation

US and European-based groups have released guidance regarding the role of genetic testing in pulmonary fibrosis^9,92, and the same general principle underlies the recommended approach. Testing should be considered when personal or family history, together with physical exam findings, imaging features and/or laboratory studies suggest a high likelihood of identifying a causal rare genetic variant. Any genetic testing should be performed in collaboration with a genetic counsellor experienced in pulmonary fibrosis genetics, as such tests have implications not only for patients with FPF but also their family members. If genetic testing is to be pursued, most groups recommend starting with an affected member of the family^9,92.

Testing results are classified into categories based on criteria from the American College of Medical Genetics (ACMG)⁹⁶. If a result is “positive”, in consultation with genetic counselors, testing may then be offered to other relatives. In contrast, a “negative” test is not informative - such a result does not exclude the possibility of a heritable cause, but simply indicates no such variant was identified among the genes sequenced using that particular method. VUS present a challenge, as novel missense variants will, by definition, always be classified as a VUS. Over time, most VUS are reclassified as benign, but a subset are likely causal for a given individual/family. Efforts are ongoing to develop tools for helping clinicians navigate the complexities of VUS.

Treatment of Patients with Monogenic Familial Interstitial Lung Disease

Patients diagnosed with monogenic FPF should be screened for gastroesophageal reflux disease, obstructive sleep apnea, and exertional hypoxemia and these conditions treated similarly to other ILD patients⁹⁷, and where appropriate, pulmonary rehabilitation should be offered. Concomitant treatment of lung disease and other extrapulmonary disease requires a multi-disciplinary collaboration across medical subspecialties that can include medical genetics, hematology/oncology, rheumatology, gastroenterology, dermatology and others. While prospective randomized control trials have not been performed in monogenic ILD populations, there are several pharmacotherapeutic considerations that warrant discussion.

Antifibrotics

There have been no prospective studies of current antifibrotic treatments for patients with known monogenic forms of FPF. (Results of studies of pirfenidone/nintedanib in Hermansky-Pudlak Syndrome are discussed in Chapter 12). For FPF patients who meet criteria for IPF or Progressive Pulmonary Fibrosis⁹⁸, antifibrotic therapy with pirfenidone⁹⁹ or nintedanib^100,101 should be offered commensurate with the diagnosis. Available data suggest that these treatments have comparable efficacy, safety and tolerability among subjects with short telomeres compared to sporadic IPF patients^17,102. While these medications often have significant side effects which can limit their tolerability, they remain the mainstay of treatment to help patients preserve lung function with progressive forms of pulmonary fibrosis.

Immunosuppression

The PANTHER trial convincingly demonstrated that combination immunosuppression with prednisone and azathioprine is ineffective and potentially harmful for patients with IPF¹⁰³, and subsequent work has suggested the signal for harm was driven largely by patients with short telomeres¹⁰⁴. Thus, while immunosuppression is no longer used to treat patients who meet IPF clinical criteria, these results and follow-up studies¹⁰⁵ have raised questions as to how to approach immunosuppressive treatments of other ILD phenotypes which can be observed in FPF kindreds with short telomeres/telomerase mutations (i.e. chronic hypersensitivity pneumonitis, CTD-ILD). Prospective studies will likely be required to resolve these questions, and in the interim these findings suggest caution and close monitoring of FPF patients with short telomeres if immunosuppressive treatments are considered.

For other monogenic forms of ILD, available data are limited to case reports and case series. There are anecdotal reports of steroid-responsive SFTPC patients and other immunomodulators have been used in small numbers of these patients^31,106; currently there is not sufficient evidence to recommend for or against the use of steroids and/or other immunomodulators in surfactant-related ILD patients. COPA and STING-related autoinflammatory syndromes require immunosuppression, and case-series/small trials suggest JAK-inhibitors^77,78,85,86 may have a particular role in these syndromes; these patients generally benefit from co-management including pulmonary, rheumatology and/or immunology specialists.

Danazol

Danazol is a weak androgen that was discovered to lengthen telomeres of patients with aplastic anemia¹⁰⁷. This observation has prompted questions as to whether danazol might be efficacious for the treatment for pulmonary fibrosis associated with short telomeres/telomerase mutations. While at least one trial is ongoing¹⁰⁸, registry-based observational data¹⁰⁹ have not suggested an impact on pulmonary function tests, and one clinical trial which has been reported in abstract form suggested poor tolerability¹¹⁰. Based on these data, there is not sufficient evidence to recommend androgen-based treatment of short-telomere associated pulmonary fibrosis outside of a clinical trial.

Lung Cancer Screening

CT-based screening for lung-cancer has been shown to reduce mortality among current/former tobacco users at increased risk for lung cancer¹¹¹. While there are currently no prospective studies evaluating lung cancer screening among ILD patients with SFTPA1/SFTPA2 mutations, in light of the high reported prevalence of lung cancer in these individuals, we suggest CT-based lung cancer screening should be considered for these individuals in addition to other monogenic FPF patients who meet local criteria.

Lung Transplant

While current antifibrotic therapies slow disease progression, most FPF patients ultimately progress to respiratory failure and for certain patients, lung transplantation offers the potential for improved survival and quality of life. In general, when ILD has progressed to a significant point requiring continuous oxygen, discussion of and referral for lung transplantation evaluation is appropriate for FPF patients without prohibitive comorbidities. While IPF/FPF patients with short telomeres may be at increased risk of complications including acute kidney injury and chronic lung allograft dysfunction,^112,113 lung transplantation can be safely and effectively performed in these individuals and should not be withheld based on a genetic diagnosis. Ongoing work seeks to elucidate the best ways to manage post-transplant immunosuppression and to understand what drives this increased allograft dysfunction.

Considerations for unaffected relatives of patients with Monogenic Interstitial Lung Disease

The diagnosis of a monogenic disorder, particularly a monogenic disorder with an autosomal-dominant inheritance pattern, has implications not only for the affected individual but also their first-degree relatives. Although the precise penetrance of FPF has not been established and likely varies according to the specific gene and risk variant, first-degree relatives of FPF patients are at significantly increased risk for developing FPF compared to individuals without such a family history^4,12. This prompts the question of whether FPF family members should undergo screening and/or genetic evaluation. There has been limited study of the psychological effects of screening/genetic evaluation for FPF, however available evidence suggests this can be performed in consultation with genetic counselors¹¹⁴.

There are currently no guidelines addressing the role of screening for PF among FPF relatives, although data from multiple cohorts support a potential role for CT-based screening. Using HRCT, several cross sectional studies have identified interstitial lung abnormalities (ILA) in 15–25% of first-degree relatives of FPF patients^115–122. Limited longitudinal evaluation suggests a substantial proportion of FPF relatives with ILA have evidence of progression to clinical ILD over time^117,118,120. We suggest these findings build a compelling case for CT-based screening of FPF relatives, however the optimal timing and frequency remains uncertain. In the future, we anticipate that for families with a known culprit variant, genetic evaluation and testing may inform the approach to screening and observation, while clinical trials will be required to determine whether early detection of and treatment for interstitial lung abnormalities can impact progression to symptomatic pulmonary fibrosis.

Synopsis.

Interstitial lung diseases (ILD) are a heterogenous group of disorders leading to progressive loss of lung function. A subset of ILD cases can be linked to specific single-gene causes. These monogenic forms of ILD often run in families, exhibit specific clinical and imaging phenotypes, and are most commonly linked to autosomal dominant inheritance of rare genetic variants in genes related to telomere and surfactant biology. When clinical suspicion of a monogenic cause is high, genetic evaluation and testing can yield prognostic and treatment-modifying results and impact the screening and test of unaffected relatives. The available evidence suggests that known genetic etiologies should influence pharmacotherapy decisions for ILD patients, particularly when immunosuppression is considered. There is emerging consensus supporting screening of unaffected relatives of familial ILD patients to enhance early disease detection, while future studies exploring primary and secondary prevention of ILD in high-risk individuals offer hope of preventing the life-limited complications of these disorders.

Key Points:

• Familial interstitial lung disease is common and may represent up to 1 in 5 idiopathic ILD cases

• A specific genetic cause of ILD can be identified in ~25% of familial pulmonary fibrosis cases, and genetic testing should be considered when a personal or family history is suggestive of a genetic etiology

• Close monitoring of unaffected relatives in families with pulmonary fibrosis presents an opportunity for early disease detection and early treatment

Clinic Care Points.

• Approximately 1 in 5 ILD cases are familial, and careful family history is crucial to identify individuals with high likelihood of a specific genetic cause

• Monogenic forms of ILD can present with a range of clinical phenotypes (even within the same family)

• For individuals with personal or family histories suggestive of a genetic etiology, genetic testing should be offered in consultation with genetic counseling as a positive test may impact their treatment and care of family members