Long-Read Amplicon Sequencing for the Detection of TERT Promoter Variant Clonal Hematopoiesis in Patients with Telomere Biology Disorders

Acquired TERT promoter (TERTp) variants are found in the blood of patients with telomere biology disorders (TBDs) and carry diagnostic and prognostic significance. Detection of these variants is challenging due to low variant allele frequencies (VAFs) and high GC content. We tested the sensitivity of long-read amplicon sequencing with deepSNV analysis, referred to as LR-deep AmpSeq, for TERTp variant detection. Among 47 patients with TBD features, we achieved an average depth of coverage of 7,943x and detected seven TERTp variants in six individuals (13%) with VAFs ranging from 0.006-0.33.