STAT3 dominant negative Hyper-IgE syndrome: A patient report with actionable genomic findings

Over the last two decades, diagnostic genetic testing for inborn errors of immunity has primarily relied on gene panel-based approaches organized by phenotype. In this report, we describe a patient with a clinical and molecular diagnosis of STAT3 dominant negative hyper-IgE syndrome referred to the National Institutes of Health for further evaluation including genome sequencing. Genome sequencing analysis included primary, secondary, and pharmacogenomic findings. This analysis confirmed the primary molecular diagnosis of STAT3 dominant negative hyper-IgE syndrome and found a pathogenic variant in the LDLR gene associated with familial hypercholesterolemia, which led to the identification of borderline high LDL-C levels in the patient. Additionally, this analysis identified pharmacogenomic genotypes associated with suboptimal therapeutic effects for the frontline treatments of the patient's conditions. Specifically, the patient was found to be a rapid metabolizer of voriconazole, a treatment for severe fungal infections, and to have an increased risk for myopathy induced by taking statins, the most common treatment for familial hypercholesterolemia. This case underscores the potential clinical utility of comprehensive genomic evaluation for patients with rare diseases. The untargeted nature of genome sequencing and broad range of potential findings can inform treatment decisions, shorten the diagnostic odyssey, and enable a more personalized approach to patient care.