Clonal Hematopoiesis in Telomere Biology Disorders Associates with the Underlying Germline Defect and Somatic Mutations in POT1, PPM1D, and TERT promoter

Introduction: Telomere biology (TBD) disorders are caused by pathogenic germline variants in genes related to telomere maintenance. In TBD, clonal hematopoiesis (CH) has been hypothesized to compensate for restricted cell fitness and to lead to development of myelodysplastic syndromes and acute myeloid leukemia (MDS/AML). We sought to characterize the clonal landscape and dynamics by deep sequencing of a large cohort of TBD patients with a broad spectrum of phenotypes and ages. Methods: We screened 120 TBD patients (median age=29) from the National Institutes of Health and the University of Sao Paulo for somatic mutations in genes related to myeloid malignancies and telomere diseases using an error-correcting DNA sequencing panel (minimum allele frequency [VAF] of 0.5%). Patients had either a pathogenic germline variant in telomere-related genes or short telomeres in blood and a strong clinical suspicion for TBD. Relatives were included if they harbored the proband's germline mutation. Single-cell DNA sequencing was performed in marrow samples from two TBD patients with MDS (TBD-MDS) to elucidate clonal trajectories Results: Fifty-eight TBD patients (48%) had somatic mutations in peripheral blood (median age and range, 42 years; 9-57), most frequently in PPM1D (all exon 6 truncated; n=18) , TERTp (-57, -124, and -146; n=14), POT1 (n=12), U2AF1 (n=12), and other MDS-associated genes. Clinically, these patients had dyskeratosis congenita (DC; n=12/27), aplastic anemia (AA; n=11/27), isolated cytopenias (n=7/10), MDS/AML (n=7/8), pulmonary or liver fibrosis (n=4/8), and multi-organ disease (n=19/26). In this series, no relatives had somatic mutations (n=14). CH frequency increased with age and was significantly more frequently observed than in healthy controls, regardless of age (p