CDC45 haploinsufficiency as a novel cause of natural killer cell deficiency

Natural killer cell deficiency (NKD) is a primary immunodeficiency where natural killer cells are the primary lineage affected. Individuals with NKD present with malignancies and susceptibility to viral infection, especially from the Herpesviridae family. Though NKD is rare, four genes that are involved in the CDC45-MCM-GINS (CMG) helicase have been described to result in NKD, including MCM4, GINS1, MCM10, and GINS4. The CMG helicase is critical for eukaryotic replication and plays a critical role in maintaining genomic stability. To our knowledge, CDC45 has never been described as a monogenic cause of NKD. However, here we describe a single damaging heterozygous variant in CDC45 in an individual with consistent defects in the NK cell compartment. This individual has a disruption in the ratio of CD56bright to CD56dim cells, severely decreased frequency of adaptive NK cells, and decreased NK cell cytotoxic function. As previously reported for other helicase variants that cause NKD, we found cell cycle defects, increased DNA damage, and impaired DNA damage repair signaling in patient lymphocytes. The description of CDC45 as a cause of NKD contributes to our understanding of the role of the CMG helicase in NK cell maturation, function, and biology.