A landscape of genetic heterogeneity in germline predisposition to familial chronic lymphocytic leukemia

This study provides a comprehensive analysis of the germline landscape in 81 families with chronic lymphocytic leukemia (CLL). We uncovered key genetic pathways associated with CLL predisposition, including telomere maintenance, DNA double-strand break (DSB) repair, and immune regulation. Notably, pathogenic variants were found in POT1 and TINF2 , suggesting defects in telomere stability, while variants in CHEK2 , MRE11 , CDKN1B , RAD51D , ERCC2 and RAD50 indicate defects in DSB repair mechanisms. Variants in immune-related genes such as RUNX1 and TNFRSF13B were also identified, with TNFRSF13B mutations occurring in 4 different families and 4 of the 57 (7%) investigated sporadic cases, further highlighting their potential role in disease susceptibility. Other novel candidates included RASA2 , involved in MAPK/ERK signaling, and NCOR2, a nuclear co-repressor involved in regulation of B cell development and maintenance of genomic integrity. These findings expand the understanding of genetic heterogeneity in familial CLL, supporting a model in which low-penetrance tumor suppressor genes and complex genetic interactions drive disease development. Our results underscore the importance of integrating genetic studies to unravel the hereditary basis of CLL and to further characterize the mechanisms that drive the development of the disease.