Abstract Introduction Telomeres are essential for genome maintenance. Rare variants disrupting telomere maintenance genes cause a spectrum of short telomere syndromes, with idiopathic pulmonary fibrosis (IPF) as the most common phenotype. Variants in the shelterin component TIN2 typically cause severe pediatric dyskeratosis congenita (DC) and bone marrow failure. However, a subset of patients with germline TINF2 variants presents with less severe, adult-onset disease, including IPF, suggesting the presence of modifying factors. Methods We identified three patients with pathogenic germline TINF2 hotspot variants evaluated at the University of Pittsburgh Medical Center for lung transplantation. Two had a family history of DC; one had a sporadic presentation. Clinical genetic testing and deep exome sequencing was used to identify somatic variants. We validated the function of somatic variants in vitro using CRISPR/Cas9-mediated genome editing in multiple cell lines and in patient-derived induced pluripotent stem cells (iPSCs). Results All three patients had somatic variants in the DNA-binding domain of POT1 where tumor-specific variants have been previously reported. Edited cells showed no signs of DNA damage, genomic instability, or altered growth kinetics. Telomeres progressively lengthened in all edited lines. iPSCs reprogrammed from patient PBMCs, which harbored both the germline TINF2 and somatic POT1 variants, also demonstrated gradual telomere lengthening, verifying the POT1 variants are functional and sufficient for telomere elongation, even in the context of the pathogenic TINF2 variant. Conclusions Somatic POT1 variants appear to rescue hematopoietic function and cause telomere lengthening in vitro. POT1 editing is efficient and does not appear to influence genome stability. We propose that genetically modifying POT1 may be an effective therapy to rescue the bone marrow of patients with short telomeres. This abstract is funded by: NA
Jiang et al. (2026) studied this question.