A novel CARD11 heterozygous missense variant in a CADINS patient

Background: CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) is developed as a result of heterozygous loss-of-function variants in CARD11 that function as strong dominant-negative alleles. In lymphocytes, CARD11 encodes a scaffold protein that links activation of the antigen receptor with downstream signaling. Patients with CADINS generally experience severe atopic dermatitis, asthma, recurrent pneumonia and other upper respiratory tract infections, skin infections, and allergies to a variety of dietary and environmental antigens. Additionally, patients experience elevated levels of serum IgE, but low to normal levels of other immunoglobulin types. Objective: We performed genetic diagnosis of a patient of nonconsanguineous descent presenting at 11 years of age with severe atopic dermatitis, asthma, food allergy, skin and recurrent infections, and an extremely elevated level of serum IgE. Methods: We performed whole genome sequencing of samples obtained from the patient and his entire family. Results: Clinical, laboratory, genetic, and functional findings suggested CADINS. Genetic evaluation revealed a novel heterozygous missense variant (c.2913C>G, p.Cys971Trp) in the CARD11 gene as the potential underlying defect. Expression of CARD11 variant–stimulated constitutive NF-κB activity in T-cell lines demonstrated both loss-of-function and dominant-negative activity. Conclusion: A novel germline heterozygous missense variant (c.2913C>G) in CARD11 potentially leads to CADINS.