Genetic ghosts in the lung : post- COVID fibrosis unveils CTC1 mutation

Abstract

Background: Familial pulmonary fibrosis (FPF) accounts for 10%-20% of idiopathic pulmonary fibrosis cases and is associated with mutations in telomere-related genes, including TERT, TERC, RTEL1, PARN, and, more recently, CTC1. Telomere dysfunction predisposes to progressive fibrotic interstitial lung disease (ILD) and may increase susceptibility to environmental triggers. Emerging evidence suggests that COVID-19 pneumonitis may unmask or accelerate fibrosis in genetically predisposed individuals, though a causal relationship has not been established. We report a case of genetically confirmed FPF due to a likely pathogenic CTC1 mutation presenting with progressive post-COVID pulmonary fibrosis.

Case Presentation: A 59-year-old woman with post-COVID pulmonary fibrosis presented with progressive dyspnea, orthopnea, and functional decline over 6 months. She required long-term oxygen therapy (5 l/min). Family history was significant for two first-degree relatives with usual interstitial pneumonia. Pulmonary function tests showed severe restriction (FVC 48%, diffusing capacity 19%). Imaging evolved from organizing pneumonia during acute COVID-19 to established bilateral fibrotic ILD with traction bronchiectasis and features suggestive of pulmonary hypertension (grade 3), confirmed on right heart catheterization (mean PAP 38 mmHg). Autoimmune workup was largely negative aside from anti-nuclear antibody positivity. Pirfenidone was discontinued due to hepatotoxicity. Genetic testing identified a heterozygous CTC1 variant (c.2518C>T; p.Arg840Trp), classified as likely pathogenic. She was commenced on nintedanib and referred for lung transplantation.

Conclusion: This case highlights the interplay between telomere-related genetic predisposition and viral injury in FPF. COVID-19 may have unmasked or accelerated fibrotic progression in susceptible individuals, though this association remains observational. Early genetic testing, multidisciplinary management, and timely transplant referral are crucial, with careful monitoring for treatment-related and post-transplant complications.