CO16 - Impact of underlying genetic cause on clinical characteristics and survival in familial pulmonary fibrosis
Joanne J. van der Vis (Netherlands)1; Aernoud A. van Batenburg (Netherlands)1; Jan C. Grutters (Netherlands)1 2; Coline H.M. van Moorsel (Netherlands)1;
1 - ILD Center of Excellence, member of European Reference Network-Lung, St Antonius Hospital, Nieuwegein, the Netherlands; 2 - Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands;
Keywords: familial pulmonary fibrosis; telomere; MUC5B rs35705950;
Select the theme: Fibrotic Pulmonary Interstitial Fibrosis
Type: Original Papers
Presentation: Oral Communication

Introduction: Familial pulmonary fibrosis (FPF), defined as fibrotic interstitial lung disease affecting at least two blood relatives, is a heterogeneous condition with variable clinical course. Although causal variants in telomere-related genes (FPF-TRG) are identified in a substantial subset of patients, many FPF-cases remain genetically unexplained. Clinical features of this group are poorly characterized, limiting risk stratification and management.

Objectives: To characterize FPF-patients without an identifiable genetic cause and to compare their clinical features and prognosis with FPF-TRG.

Materials and Methods: This retrospective study included 516 FPF-patients from families analyzed with a comprehensive adult PF gene panel. Of these, 322 FPF-patients (217 families) were gene panel negative (FPF-gpn), and 194 patients (122 families) had FPF-TRG. Data on baseline characteristics, MUC5B rs35705950 genotype, telomere length (TL), and transplant-free survival were collected.

Results: FPF-gpn patients were significantly older at diagnosis (70.3 vs 63.7y), more often had a smoking history (81% vs 69%), and were less frequently diagnosed with idiopathic pulmonary fibrosis than FPF-TRG patients (71% vs 81%). MUC5B rs35705950 T-allele carriage was significantly more common in FPF-gpn (66% vs 43%) and associated with older age at diagnosis in both groups. Aging was significantly associated with shorter telomeres in FPF-gpn, indicating age-related telomere attrition. This relationship was absent in FPF-TRG, suggesting TL is predominantly genetically determined rather than aging. Median survival was longer in FPF-gpn than in FPF-TRG patients (4.5 vs 3.0 years, p<0.001). Age and pulmonary function were independently associated with mortality in both cohorts, while MUC5B T-allele carriage was only associated with decreased hazard for mortality in FPF-gpn and shorter TL with an increased hazard for mortality in FPF-TRG.

Conclusions: FPF‑gpn respresent a distinct clinical subgroup characterized by older age at diagnosis, more frequent MUC5B T‑allele carriage, age‑related telomere shortening, and better survival than FPF‑TRG highlighting divergent telomere dynamics, and prognostic markers relevant for personalized risk stratification and management.