A rare TERT p.Ala880Thr variant associated with familial pulmonary fibrosis and multisystem involvement: Intrafamilial heterogeneity in a Vietnamese kindred – A case series

Abstract

Short telomere syndromes (STS) are rare telomere biology disorders caused by germline variants affecting telomere maintenance and may present with organ-limited disease (e.g., pulmonary fibrosis) or multisystem involvement. We report a Vietnamese family carrying a heterozygous TERT p. Ala880Thr variant. The proband was a 42-year-old man with cryptogenic cirrhosis who was incidentally found to have a probable usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) and later developed progressive interstitial lung disease (ILD). He also had marked premature graying, platypnea, digital clubbing, and hepatopulmonary syndrome. Cascade evaluation identified two monozygotic twin sisters (41 years) who also had ILD with discrepant severity: one symptomatic with probable UIP and FVC 47% predicted, while the other was asymptomatic with mild probable UIP changes and FVC 84% predicted. Further pedigree assessment identified maternal cryptogenic cirrhosis and two siblings who died in early childhood with transfusion-dependent anemia, suggesting additional hepatic and hematologic manifestations within the family. Panel-based targeted NGS identified the heterozygous TERT p. Ala880Thr variant in the proband and one affected twin sister, and targeted Sanger sequencing confirmed the familial variant in additional relatives. This case series provides detailed clinical and segregation data from a Vietnamese kindred carrying the previously reported TERT p. Ala880Thr variant. It also highlights the need to suspect telomere-related disease when ILD presents at a young age or is accompanied by extrapulmonary features such as cryptogenic liver disease, premature graying, or a suggestive family history. Early genetic testing and cascade counseling may improve recognition and longitudinal surveillance of at-risk relatives.