Functional DBF4 deficiency as novel DNA replication-associated inborn error of immunity

DNA replication-associated inborn errors of immunity are caused by mutations in DNA replication factors and often present with a convergent phenotype of perturbed growth, developmental delay and immunodeficiency. The current inborn errors of immunity classification lists 8 clinical entities associated with variants in 9 DNA replication factor-encoding genes.

In this thesis, I aimed to characterize a patient with severe congenital neutropenia and syndromic features without a genetic diagnosis. I identified a homozygous missense variant in DBF4, the regulatory subunit of the CDC7 kinase. The DBF4-CDC7 complex is essential for DNA replication initiation. The variant allele demonstrated impaired ability to bind CDC7, resulting in decreased downstream phosphorylation, defective S phase entry and progression and impaired differentiation of granulocytes associated with activation of the p53-p21 pathway. The introduction of WT DBF4 into patient CD34+ cells rescued the promyelocyte differentiation arrest, confirming a genotype-phenotype relationship.

Hypomorphic DBF4 mutation causes autosomal recessive severe congenital neutropenia with syndromic features. Thus, this thesis identifies ‘’functional DBF4 deficiency’’ as a novel DNA replication-associated inborn error of immunity.