Clonal hematopoiesis in telomere biology disorders

Telomere biology disorders (TBDs) are a group of genetic conditions of varying severity caused by defects in telomere maintenance. Patients with TBDs can experience dysfunction in nearly all organ systems, including the bone marrow, with increased risk for bone marrow failure and myeloid neoplasms. Over the past decade, several groups have identified higher rates and earlier onset of clonal hematopoiesis (CH) in TBDs patients, with a distinct profile of somatic variants compared to the general population. While TBDs patients sometimes develop variants seen in age-related CH, these are proportionally much less prevalent in TBDs. Instead, TBDs patients develop recurrent gene variants that overcome cell growth constraints caused by telomere shortening or dysfunction. These variants include those that enhance telomere maintenance through reversion of the underlying TBD-causing germline variant or through compensatory mutations in other telomere maintenance machinery, mutations in spliceosome genes, and mutations that disrupt components of the DNA damage response. Early links between specific types of variants and subsequent progression to myeloid malignancies have been reported. In this manuscript, we critically review the existing literature, highlighting open questions in the field, and discuss clinical tools for detecting and monitoring CH in patients with TBDs.