Impact of Germline DNA Repair Mutations on Clonal Hematopoiesis and Myeloid Neoplasm Development

Clonal hematopoiesis (CH) arises from the expansion of a single hematopoietic stem cell harboring somatic mutations that confer growth advantage. Recent studies highlight a substantial heritable component to CH, implicating germline mutations in DNA damage repair (DDR) genes. These genes are essential for maintaining genomic integrity and pathogenic variants in key DDR genes are well-established genetic underpinnings of several hereditary cancer syndromes. This review synthesizes current data linking germline DDR mutations – including ATM, CHEK2, TP53, PPM1D, BRCA1/2, and PARP1 – to CH and the development of myeloid malignancies.

Emerging evidence suggests that germline perturbations in DDR pathway contribute to CH, though mechanisms remain incompletely defined. Large scale genome-wide association studies (GWAS) have identified strong associations between ATM and CHEK2 variants and CH. Assessing prevalence and CH risk in individuals with germline TP53 variants presents unique challenges, as distinguishing between somatic and constitutional lesions is often complex and requires careful tissue evaluation. The link between germline BRCA1/2 and CH remains inconclusive, confounded by concurrent diagnosis of solid malignancy and prior exposure to chemoradiation therapy in studied patient populations. Although germline mutations in PPM1D and PARP1 are rare, a potential germline predisposition to CH cannot be excluded.

The totality of current evidence suggests that germline DDR pathway mutations not only predispose to well-established solid malignancy syndromes but also to CH, which independently increases the risk of hematologic malignancies. Recognizing germline contributions to CH has broad implications for risk assessment, surveillance strategies, and development of preventive strategies in myeloid neoplasia.