Characterizing A Novel Variant in ABCB1 in a Family with Activated PI3K Delta Syndrome-like Presentation

Activated PI3K delta syndrome (APDS) is a rare inborn error of immunity (IEI) due to a heterozygous gain-of-function mutation in the PIK3CD or PIK3R1 genes. APDS patients have high variability in clinical manifestations including recurrent sinopulmonary infections, lymphoproliferation, and susceptibility to CMV and/or EBV viremia. APDS is characterized by a block in B-cell development to follicular stage. Therefore, increase in transitional compartment is almost exclusively seen in untreated APDS patients. We describe a family that present with APDS-like clinical and laboratory findings, while harboring a novel variant in ATP binding cassette subfamily B member 1 (ABCB1), which is involved in adenosine salvage and mTORC1 pathways. Retrospective chart review was performed for clinical and laboratory data. Extensive immune phenotyping was obtained. Genetic evaluation included targeted immune panel and whole exome sequencing. Mitotracker-green detection by flow cytometry was used to determine progression to follicular B cell stage. Index case is a 14-year-old female with a complex presentation of infectious and non-infectious complications notable for lifelong hypogammaglobulinemia with poor vaccine response, multiple intubations for upper respiratory illnesses, bronchiectasis, and short stature. Patient had 3 other siblings who also had similar presentation with varied severity, including features of short stature, recurrent infections, alopecia universalis and immune dysregulation. Three siblings required immunoglobulin replacement therapy. Extensive immune-phenotyping revealed significant expansion of CD24hiCD38hi transitional and CD19hiCD21lo B-cells, with decrease in follicular and memory B-cell compartment in all. Although clinical and lab findings prompted APDS diagnosis, repeated targeted genetic panel testing did not show variants in PIK3CD or PIK3R1. Consequent whole exome sequencing revealed a candidate variant in ABCB1 p.Ala1187Thr that was shared among all. Interestingly, surface expression of ABCB1 was significantly elevated in patients compared to healthy controls. Initial functional testing showed disruption in mitochondrial efflux, further supporting the block from transitional to follicular stage. Determining diagnostic approaches in APDS-like disorders liked to ABCB1 variant is challenging, especially when pathogenesis is yet to be determined. Although further functional testing of ABCB1 and its potential role in PI3K signaling is needed, ABCB1 gene may play an important role in APDS pathology.