Heterozygous Variants in DOCK2 Leading to Susceptibility to Viral Illnesses

Background Inborn errors of immunity (IEIs) are classically identified in infants and young children with severe or recurrent infections. However, hypomorphic variants with a partial loss-of-function can remain unrecognized until later in life and may underlie clinically significant susceptibility to infections in previously healthy individuals. We investigated how three novel heterozygous variants in DOCK2 contribute to impaired antiviral immunity, extending the understanding of DOCK2 deficiency beyond an autosomal recessive disease. Methods After identifying the first heterozygous DOCK2 variant in a family with 4 individuals with warts and T cell lymphopenia, we screened 1,109 exomes from three cohorts of patients with a history of at least one severe infection. We assessed the biologic impact of each variant via functional and transcriptional assays of the patients’ primary peripheral blood mononuclear cells and in cell-based overexpression systems. Results Six individuals from three unrelated families, aged 3 months to 50 years, carried one of three heterozygous DOCK2 variants and experienced severe infections with human papillomavirus, respiratory syncytial virus, or SARS-CoV-2. All variants resided within the DOCK2 domain that binds and stabilizes ELMO1. Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2 function, as shown by diminished Rac1 activation and selective defects in Toll-like receptor signaling. Weekly IFN-alpha therapy led to complete resolution of severe, refractory warts in one patient, highlighting a potential therapeutic approach for DOCK2-associated immunodeficiency. Conclusions These findings expand the spectrum of DOCK2-related disease by showing that heterozygous pathogenic variants disrupting DOCK2–ELMO1 interactions impair protein stability and antiviral immunity, revealing a previously unrecognized IEI affecting otherwise healthy individuals.