Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease

Background Caspase activation and recruitment domain 11 ( CARD11) encodes a scaffold proteinin lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic targetof rapamycincomplex 1. Germline CARD11mutations cause several distinct primary immune disordersin human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11mutations discovered by using whole-exome sequencing. Objectives We sought to determine the molecular actions of an extended allelic series of CARD11and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11loss-of-function alleles. Methods Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11variants. Results Here we report on an expanded cohort of patients harboring novel heterozygous CARD11mutations that extend beyond atopyto include other immunologic phenotypes not previously associated with CARD11mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indelmutations in CARD11presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked–like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coildomains of the CARD11protein. Conclusion These results illuminate a broader phenotypic spectrum associated with CARD11mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.