DNA replication-associated inborn errors of immunity

J Allergy Clin Immunol. 2022 Nov 14;S0091-6749(22)01514-7. doi: 10.1016/j.jaci.2022.11.003. Online ahead of print.


Inborn errors of immunity are a heterogenous group of monogenic immunological disorders caused by mutations in genes with critical roles in the development, maintenance or function of the immune system. The genetic basis is frequently a mutation in a gene with restricted expression and/or function in immune cells, leading to an immune disorder. Several classes of inborn errors of immunity, however, result from mutation in genes that are ubiquitously expressed. Despite the genes participating in cellular processes conserved between cell types, immune cells are disproportionally affected, leading to inborn errors of immunity. Mutations in DNA replication, DNA repair or DNA damage response factors can result in monogenic human disease, some of which are classified as inborn error of immunity. Genetic defects in the DNA repair machinery are a well-known cause of T-B-NK+ severe combined immunodeficiency. An emerging class of inborn errors of immunity is those caused by mutations in DNA replication factors. Considerable heterogeneity exists within the DNA replication-associated inborn errors of immunity, with diverse immunological defects and clinical manifestations observed. These differences are suggestive for differential sensitivity of certain leukocyte subsets to deficiencies in specific DNA replication factors. Here, we provide an overview of DNA replication-associated inborn errors of immunity and discuss the emerging mechanistic insights that can explain the observed immunological heterogeneity.

Keywords: DNA replication; developmental delay; developmental syndromes; genetics; inborn errors of immunity; leukocytes; perturbed growth; primary immunodeficiency.