Newly Identified RTEL1 Variant Could Broaden Genetic Landscape of Familial PF

A newly reported case study has documented a novel nonsense variant in the RTEL1 gene in a patient with familial pulmonary fibrosis (PF), adding to an expanding understanding of how telomere-related gene mutations contribute to interstitial lung disease (ILD).¹

The case, details of which were published in BMC Pulmonary Medicine, highlights how genetic testing is becoming an essential component of evaluating suspected inherited pulmonary fibrosis, especially in families where lung disease spans multiple generations, describe the researchers.

“Genetic analysis provided crucial insights into disease etiology, reinforcing the importance of integrating genomic tools into the diagnostic workup of familial ILD,” wrote the researchers. “Further studies and family-based segregation analysis are warranted to confirm the pathogenicity of this variant and to better understand the phenotypic spectrum of RTEL1-associated pulmonary fibrosis.”

Idiopathic PF (IPF) is a progressive form of ILD marked by scarring of the lung tissue, causing stiffness of the lungs and subsequent difficulty in brreathing.² While IPF is generally considered sporadic, approximately 10% of patients have a first-degree relative with interstitial lung disease (ILD), pointing to a strong hereditary component. Among the genes most frequently implicated are the telomere-related genes (TRGs), a group of genes responsible for maintaining chromosomal stability during cell division. Mutations in TERT, TERC, RTEL1, and PARN are among the most common contributors to familial PF (FPF).

The current study details the case of a 72-year-old woman diagnosed with familial IPF with a usual interstitial pneumonia (UIP) pattern. The patient had multiple family members affected by PF, along with premature hair greying in multiple relatives—both important clues pointing toward a telomere biology disorder. After she initially declining antifibrotic treatment, radiologic progression 1 year later prompted initiation of pirfenidone, which was well tolerated, with lung function remaining stable over a 5-year follow-up period.

Given the strong familial aggregation, the patient received genomic testing, which identified a previously unreported heterozygous nonsense mutation in RTEL1.

This single-nucleotide change introduces a premature stop codon predicted to result in loss of function of the encoded DNA helicase, an enzyme essential for telomere maintenance, genome stability, and DNA repair. Because telomere dysfunction leads to premature cellular aging and impaired epithelial repair, such mutations are a recognized driver of PF.

The variant was absent from all major population databases, including gnomAD, ClinVar, and dbSNP, and was classified as “likely pathogenic” using ACMG criteria. Although segregation analysis of additional family members has not yet been performed, the clustering of pulmonary fibrosis in first- and second-degree relatives strongly supports its clinical significance. The possibility of somatic mosaicism remains, but the hereditary pattern suggests a germline variant.

Research cited within the case report showed that RTEL1 mutations account for roughly 5% to 10% of FPF cases and are associated with a wide range of ILD phenotypes. While IPF is the most common manifestation, carriers may also develop chronic hypersensitivity pneumonitis, sarcoidosis, pneumoconiosis, or unclassifiable ILD. Notably, extrapulmonary features, such as bone marrow failure or liver disease, are less commonly seen in RTEL1 mutation carriers compared with those with TERT or TERC mutations, although telomere biology disorders can involve multiple organs.

Histologic and imaging studies confirmed that RTEL1 dysfunction primarily affects alveolar epithelial cells and macrophages, supporting the idea that epithelial injury, rather than fibroblast activation alone, is central to disease initiation. This aligns with current mechanistic theories that place epithelial vulnerability at the core of pulmonary fibrosis pathogenesis.

This new case therefore expands the known mutational spectrum of RTEL1-associated disease, wrote the researchers. It underscores how genetic analysis can refine diagnostic accuracy, guide prognosis, and shape treatment decisions in familial pulmonary fibrosis. TRG mutation carriers are known to respond differently to immunosuppressive treatments and may face higher risks of hematologic complications after lung transplantation, making early identification clinically meaningful.

References

1. Franco G, Bertola F, Aloisi F, et al. A novel RTEL1 nonsense variant in a case of familial pulmonary fibrosis: clinical description and genetic implications. BMC Pulm Med. Published online November 7, 2025. doi:10.1186/s12890-025-03976-4

2. Idiopathic pulmonary fibrosis (IPF). American Lung Association. Accessed November 13, 2025. https://www.lung.org/lung-health-diseases/lung-disease-lookup/idiopathic-pulmonary-fibrosis