A110-19 Telomere Biology Disorder With a Novel Nhp2 Variant: A Case Series of Familial Pulmonary Fibrosis

Abstract Introduction Telomeres are repetitive DNA sequences that preserve chromosomal integrity. Telomere Biology Disorders (TBDs) arise when telomere length is markedly shorter than expected for age, resulting in multi-organ dysfunction. In the respiratory system, TBDs are increasingly recognized as a cause of familial pulmonary fibrosis (FPF). We describe two siblings with FPF secondary to a novel NHP2 variant, expanding the known mutational spectrum of short telomere syndromes. Case Presentations A 60-year-old woman presented to our Interstitial Lung Disease (ILD) clinic for progressive dyspnea and dry cough over one year. She required 3 L/min of supplemental oxygen and reported sicca symptoms. Her past medical and surgical history was unremarkable. Family history was notable for fibrotic lung disease in her 57-year-old brother. Pulmonary function testing (PFT) revealed severe restriction with a marked reduction in diffusing capacity. Chest Computed Tomography (CT) demonstrated a non-specific interstitial pneumonia (NSIP) pattern (figure 1). Autoimmune serology was positive for anti-SS-A antibody and low-titer Anti-Nuclear Antibody (ANA) 1: 80. Given her family history, telomere length testing was performed and revealed values below the 1st percentile in lymphocytes and granulocytes. She underwent successful bilateral lung transplantation for rapidly progressive ILD. Her 57-year-old brother was later evaluated during hospitalization for coronary artery bypass surgery. He had a prior diagnosis of pulmonary fibrosis in the setting of short telomere syndrome made six years earlier but had declined antifibrotic therapy. Repeat assessment confirmed telomere length below the 1st percentile. PFT demonstrated preserved lung volumes but severe reduction in diffusing capacity. CT chest showed a usual interstitial pneumonia (UIP) pattern (figure 2). His autoimmune serologies were unremarkable. He is currently undergoing lung transplantat evaluation. Genetic testing in both siblings identified a novel NHP2 c. 459₄60del (p. 154Argext29) frameshift variant. This variant has not been previously reported and was classified as a variant of uncertain significance, though strongly correlated with their short telomere phenotype. Both siblings had premature hair greying but no hepatic or hematologic involvement. Conclusion This case series describes the first known familial cases of short telomere syndrome due to NHP2 c. 459₄60del. NHP2 encodes a core H/ACA ribonucleoprotein critical for telomerase RNA stability. Biallelic pathogenic variants in the NHP2 gene represent a rare but important cause of short telomere syndromes, including dyskeratosis congenita and related phenotypes. Loss-of-function variants impair telomerase assembly, causing critically short telomeres. Identification of this variant broadens the NHP2 mutational landscape and reinforces the role of telomere testing in familial pulmonary fibrosis. This abstract is funded by: None