BACKGROUND: The 17q12 deletion syndrome (17q12DS) is a heterozygous deletion of a 1.4 megabase‒spanning DNA sequence on chromosome 17. The clinical characteristics of 17q12DS include neurodevelopmental disorders, kidney and urinary tract abnormalities. In our cohort of 37 subjects with 17q12DS, we observed increased atopic disorders and recurrent sinopulmonary infections, raising the possibility of immune dysregulation in 17q12DS, a feature that has not been previously reported. We tested the hypothesis that individuals with 17q12DS have altered T-cell function, contributing to recurrent infections and atopy. METHODS: Alteration of CD4 FINDINGS: We found that individuals with 17q12DS had a substantially decreased frequency of CD4 INTERPRETATION: Our study is the first to demonstrate immune alterations in 17q12DS characterized by decreased T-bet and its downstream effector cytokines such as IFN-γ. These findings warrant further investigation into underlying mechanisms, which would inform precision therapy for individuals with 17q12DS. FUNDING: National Institutes of HealthKL2 TR001862 to JJS, T35DK104689 to AG, 5T32AR007107 to JPY and LO, 1R01AG056728 to IK, and 1R21AI161838 to IK and JJS.