A Novel STAT3 Splice-Site Variant in A Kindred with Autosomal Dominant Hyper IgE Syndrome

Background: Dominant negative STAT3 loss-of-function is the most common genetic cause of hyper-IgE syndrome (HIES). Patients may present with a host of both immune and non-immune manifestations, including connective tissue abnormalities, recurrent infections, malignant predisposition, and biochemical evidence of elevated serum IgE or eosinophilia. Aim: To describe a novel splice-site variant in STAT3 resulting in HIES. Methods: Case report of two family members with HIES. Results: A proband and his son presented with neonatal-onset pustular rash, recurrent skin and sinopulmonary infections and elevated serum IgE and were diagnosed with AD-HIES. They were identified to harbor a novel splice-site variant in the DNA-binding domain (DBD) of STAT3: c.1110-3C>G, predicted to result in defective splicing in exon 12. Interestingly, a number of other patients with AD-HIES with mutations affecting the same splice-site, suggesting this may be a hot-spot for mutagenesis. Conclusion: Splice-site mutations in the DBD of STAT3 are increasingly identified as a cause of AD-HIES. Future work is required to delineate whether patients with splice site mutations have unique clinical characteristics, supporting efforts for genotype-phenotype correlation in this disease.