Idiopathic pulmonary fibrosis (IPF) is a form of lung disease that causes progressive fibrosing interstitial pneumonia, leading to progressive dyspnea and poor lung function. IPF typically occurs in older adults and in most cases, the cause is unknown and prognosis is poor. In less than 5% of cases, this condition affects two or more close relatives and is termed Familial Pulmonary Fibrosis (FPF). While the clinical features and lung histology in patients with FPF and IPF are generally indistinguishable, FPF tends to develop at an earlier age (Raghu et al., 2011).

A diagnosis of IPF requires first excluding more common causes of lung disease such as environmental exposures and drug toxicity. The preferred method of diagnosing IPF is with volumetric scanning of the chest with high resolution computed tomography. A usual interstitial pneumonia pattern is the radiographic hallmark of IPF. Histological examination of lung biopsy may also provide evidence of this disease, though biopsy is not always required for diagnosis (Thomson et al., 2019).

Familial Pulmonary Fibrosis (FPF) should be suspected when two or more close relatives are affected with IPF. The four most common genes that have been associated with FPF include TERT, TERC, SFTPC, and SFTPA2. Other rare variants in additional genes have been implicated as well, including ABCA3, DKC1, NKX2-1, TINF2, RTELI, and PARN, as well as polymorphisms in the MUC5B promoter (Kaur et al., 2017; Courtwright and El-Chemaly, 2019). Most of these genes exhibit autosomal dominant inheritance with reduced penetrance. Pathogenic variants in ABCA3 are expressed in an autosomal recessive manner (Coghlan et al., 2014). There are also some genes that have been implicated in the development of IPF without a familial component, as they have modest effect sizes or polygenic interactions. These genes include MUC5B, DSP, and AKAP13 (Barros et al., 2019). 

TERC and TERT are genes involved in telomerase activity, in which pathogenic variants may also cause phenotypes such as dyskeratosis congenita, aplastic anemia or acute leukemia, cryptogenic cirrhosis, myelodysplastic syndrome, and coronary artery disease (Savage and Niewisch, 2009). Pathogenic/likely pathogenic (P/LP) variants in TERT and TERC result in telomere shortening, which ultimately causes apoptosis of cells. Apoptosis of the alveolar epithelial cells leads to the manifestations of lung disease observed in IPF (Raghu et al., 2011). Among patients with IPF, up to 15-20% of familial cases and up to 5% of sporadic cases carry a heterozygous TERC or TERT P/LP variant (Calado 2014; Garcia, 2011). Recent evidence suggests that evaluation of telomere length via flow FISH may provide prognostic information for affected individuals, and it can also help clarify the significance of novel variants in these genes. However, telomere length studies should be integrated with clinical and genetic findings, as neither test is 100% sensitive or specific (Alder et al., 2018; Newton et al., 2022).

Pathogenic variants in SFTPA1, SFTPA2, SFTPB, ABCA3, and SFTPC are associated with surfactant dysfunction. Familial Pulmonary Fibrosis (FPF) cases related to these gene variants can range in onset from infancy to adulthood, with significant variability in severity (Nathan et al., 2018). Phenotypes associated with surfactant-associated FPF include respiratory distress syndrome in preterm infants, infantile-onset respiratory insufficiency, chronic pediatric idiopathic lung disease, and pulmonary alveolar proteinosis. Cases of FPF caused by pathogenic SFTPA2 variants show higher rates of lung adenocarcinoma and bronchoalveolar cell carcinoma (BAC) (Coghlan et al., 2014).

The NKX2-1 gene encodes the thyroid transcription factor I, which is expressed in the thyroid gland, brain and lungs. Pathogenic variants can result in neurologic abnormalities, hypothyroidism, recurrent infections, and neonatal respiratory distress syndrome. Adult-onset pulmonary fibrosis has also been reported (Hamvas et al., 2013).

Treatment of IPF is primarily symptom-based. Antifibrotic treatments such as pirfenidone and nintedanib have been shown to decrease the rate of lung function decline in patients with IPF and FPF (Bennett et al., 2019). While it has been suggested that telomere-specific therapies may be beneficial for FPF patients with TERT or TERC P/LP variants, there are no current therapies that are targeted to specific genotypes (Kaur et al., 2017). Clinical trials looking at androgen therapies are ongoing (Antoniou et al. 2021). Lung transplantation may be beneficial in some cases (Raghu et al., 2011).

Among adults with IPF, genetic testing for inherited causes may have utility when a familial form is suspected (IPF present in two or more first degree relatives) in order to predict risks to other family members (Newton et al., 2022). Identification of a P/LP gene variant may help to predict associated complications in both the patient and their family members. Depending on the patient’s phenotype, targeted testing may be possible. For example, premature graying of the hair and dysplastic nails are features of dyskeratosis congenita that may direct testing to the TERT and TERC genes.

Childhood Interstitial Lung Disease (chILD)

Interstitial lung disease in children (chILD) is an umbrella term that encompasses any chronic respiratory disorders with early age of onset. These include cystic fibrosis, immunodeficiencies, pulmonary infections, congenital heart disease, and bronchopulmonary dysplasia. In many cases, the cause of chILD remains unknown, but inherited pathogenic variants in genes related to surfactant proteins are estimated to cause about 20% of cases (Nathan et al., 2018). Term infants with respiratory distress that is not explained by history and does not improve after the first week of life, or infants who died of lung disease of unclear etiology, should be suspected of having a heritable disorder (Polin et al 2011).

In February 2013, the American Thoracic Society (ATS) convened a special committee to develop guidelines to inform clinicians, patients, and organizations regarding the classification, evaluation, and management of chILD. Once common diseases are ruled out as the cause, the ATS strongly recommends genetic testing of SFTPB, ABCA3, and SFTPC for all infants with chILD who have severe and progressive disease, or a family history of ILD in an adult or child. Given the association of NKX2-1 pathogenic variants with thyroid and brain disorders as well, targeted testing of this gene is strongly recommended if congenital hypothyroidism and/or neurological symptoms are also present (Kurland et al., 2013). Additionally, testing of FOXF1, which is associated with alveolar capillary dysplasia, may also be indicated in infants with chILD (Vece and Young, 2016). In neonates who are identified to have an underlying heritable surfactant deficiency, it is recommended to continue oxygen administration by nasal cannula and avoid a lung biopsy (Kurland et al., 2013). However, results from lung biopsy are often available faster than genetic testing panels; thus, lung biopsy may be the best initial assessment for newborns with quickly-progressing disease (Nogee, 2017).