Not too little, not too much: the impact of mutation types in Wiskott-Aldrich syndrome and RAC2 patients.

ABSTRACT

Primary immune deficiencies (PIDs) are genetic disorders impacting the appropriate development or functioning of any portion of the immune system. The broad adoption of high-throughput sequencing has driven discovery of new genes as well as expanded phenotypes associated with known genes. Beginning with the identification of WAS mutations in patients with severe Wiskott-Aldrich Syndrome, recognition of WAS mutations in additional patients has revealed phenotypes including isolated thrombocytopenia and X-linked neutropenia. Likewise RAC2 patients present with vastly different phenotypes depending on the mutation-ranging from reticular dysgenesis or severe neutrophil dysfunction with neonatal presentation to later onset common variable immune deficiency. This review examines genotype-phenotype correlations in patients with WAS (Wiskott-Aldrich Syndrome) and RAC2 mutations, highlighting functional protein domains, how mutations alter protein interactions, and how specific mutations can affect isolated functions of the protein leading to disparate phenotypes.