Germ line 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 germ line disruptive alleles for CLL have been identified. We performed whole-exome sequencing of 66 CLL families, identifying 4 families where loss-of-function mutations in protection of telomeres 1 (<i>POT1</i>) 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 adrenocortical dysplasia homolog (ACD), which is a part of the telomere-capping shelterin complex. We also identified mutations in <i>ACD</i> (c.752-2A>C) and another shelterin component, telomeric repeat binding factor 2, interacting protein (p.Ala104Pro and p.Arg133Gln), in 3 CLL families. In a complementary analysis of 1083 cases and 5854 controls, the <i>POT1</i> p.Gln376Arg variant, which has a global minor allele frequency of 0.0005, conferred a 3.61-fold increased risk of CLL (<i>P</i> = .009). This study further highlights telomere dysregulation as a key process in CLL development.