Germline mutations in shelterin complex genes are associated with familial chronic lymphocytic leukemia.

Abstract

Chronic lymphocytic leukemia (CLL) can be familial, however thus far no rare germline disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying four families where loss-of-function mutations in POT1 co-segregated with CLL. The p.Tyr36Cys mutation is predicted to disrupt the interaction between POT1 and the telomeric overhang. The c.1164-1G>A splice-site, p.Gln358SerfsTer13 frameshift and p.Gln376Arg missense mutations are likely to impact the interaction between POT1 and ACD, part of the telomere-capping shelterin complex. We also identified mutations in ACD (c.752-2A>C) and another shelterin component, TERF2IP (p.Ala104Pro and p.Arg133Gln), in three CLL families. In a complementary analysis of 1,083 cases and 5,854 controls, the POT1 p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (P=0.009). This study further highlights telomere dysregulation as a key process in CLL development.