Most cases of idiopathic pulmonary fibrosis (IPF) — a progressive form of interstitial lung disease (ILD) — are considered sporadic or by chance. However, approximately 10% of patients with IPF have a first-degree relative with ILD, which indicates pulmonary fibrosis has a strong hereditary element.
Research published in BMC Pulmonary Medicine offers new insight into familial IPF, specifically the role of telomere-related gene mutations in ILD.
In the case study, researchers performed genomic testing on a 72-year-old woman who had familial IPF with a usual interstitial pneumonia (UIP) pattern. She also had a multigenerational family history of lung disease as well as multiple relatives with premature hair greying — both indicators of a likely telomere biology disorder.
Based on analysis, the scientists identified a previously unreported heterozygous nonsense mutation in the RTEL1 gene. The case report, “A Novel RTEL1 Nonsense Variant in a Case of Familial Pulmonary Fibrosis: Clinical Description and Genetic Implications,” details complete findings.
The surprising discovery broadens scientific knowledge of how genetic mutations contribute to familial IPF. The most associated mutations occur in the TERT, TERC, PARN and RTEL1 telomere-related genes (TRGs) — a group of genes that stabilize chromosomes during cell division.
“Genetic analysis provided crucial insights into disease etiology, reinforcing the importance of integrating genomic tools into diagnostic workup of familial ILD,” the authors wrote. “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.”
The case study describes how the single-nucleotide mutation of RTEL1 creates a premature stop codon, which is believed to cause disfunction in the encoded DNA helicase. This impacts telomere maintenance, genome stability and DNA repair and leads to early cellular aging and weakened epithelial repair.
Researchers noted that while IPF is the most common expression of RTEL1 mutations, patients may also develop sarcoidosis, pneumoconiosis, chronic hypersensitivity pneumonitis or unclassifiable ILD.
Incorporating genetic testing into the diagnostic process can identify familial IPF early and help guide prognosis and treatment strategies. This is especially critical, they said, because TRG mutation carriers are known to react differently to immunosuppressive therapies and can put people at higher risk of hematologic complications following lung transplant surgery.
