Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11).

Combined immunodeficiency (CID) is a T-cell defect frequently presenting with recurrent infections, as well as associated immune dysregulation manifesting as autoimmunity or allergic inflammation. We sought to identify the genetic aberration in 4 related patients with CID, early-onset asthma, eczema, and food allergies, as well as autoimmunity. We performed whole-exome sequencing, followed by Sanger confirmation, assessment of the genetic variant effect on cell signaling, and evaluation of the resultant immune function. A heterozygous novel c.C88T 1-bp substitution resulting in amino acid change R30W in caspase activation and recruitment domain family member 11 (CARD11) was identified by using whole-exome sequencing and segregated perfectly to family members with severe atopy only but was not found in healthy subjects. We demonstrate that the R30W mutation results in loss of function while also exerting a dominant negative effect on wild-type CARD11. The CARD11 defect altered the classical nuclear factor κB pathway, resulting in poor in vitro T-cell responses to mitogens and antigens caused by reduced secretion of IFN-γ and IL-2. Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity.