Heterozygous variants in DOCK2 leading to susceptibility to viral illnesses

Inborn errors of immunity 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 sought to investigate how 3 novel heterozygous variants in dedicator of cytokinesis 2 (DOCK2) contribute to impaired antiviral immunity, extending the understanding of DOCK2 deficiency beyond an autosomal-recessive disease.

After identifying the first DOCK2 variant, we screened 1109 exomes from 3 cohorts of patients with a history of at least 1 severe respiratory, blood-borne, or soft-tissue infection. We assessed the biologic impact of each variant via functional and transcriptional assays of the patients' primary PBMCs and in cell-based overexpression systems.

Six individuals from 3 unrelated families, aged 3 months to 50 years, carried 1 of 3 heterozygous variants in DOCK2 and experienced severe infections with human papilloma virus, respiratory syncytial virus, or severe acute respiratory syndrome coronavirus 2. All variants reside 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-α therapy led to complete resolution of refractory warts in 1 patient, highlighting a potential therapeutic approach for DOCK2-associated immunodeficiency.

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 inborn error of immunity affecting otherwise healthy individuals.