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Updated: May 10, 2025
Novel Sequence Discovery by Subtractive Genomics
Published on: January 25, 2019
A novel CARD11 heterozygous missense variant in a CADINS patient
Randa S AlYafie1,2, Mehdi Adeli3,4, Dinesh Velayutham1
1College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
Insights
CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) is caused by a novel CARD11 gene variant. This genetic defect leads to severe atopic dermatitis, asthma, and recurrent infections in affected individuals.
Area of Science:
- Immunology
- Genetics
- Molecular Biology
Background:
- CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) results from heterozygous loss-of-function variants in the CARD11 gene.
- CARD11 protein acts as a crucial scaffold in lymphocytes, linking antigen receptor activation to downstream signaling pathways.
- Patients with CADINS exhibit severe atopic dermatitis, asthma, recurrent infections, allergies, and elevated serum IgE levels.
Purpose of the Study:
- To genetically diagnose a patient presenting with severe atopic dermatitis, asthma, food allergy, and recurrent infections.
- To identify the underlying genetic cause of CADINS in the patient and their family.
Main Methods:
- Whole genome sequencing was performed on the patient and their family members.
- Clinical, laboratory, genetic, and functional analyses were conducted.
Main Results:
- A novel heterozygous missense variant (c.2913C>G, p.Cys971Trp) in the CARD11 gene was identified as the potential cause.
- Functional studies in T-cell lines confirmed loss-of-function and dominant-negative activity of the CARD11 variant.
- Findings were consistent with a diagnosis of CADINS.
Conclusions:
- A novel germline heterozygous missense variant in the CARD11 gene is implicated in the development of CADINS.
- This variant disrupts CARD11 function, leading to the observed clinical phenotype.
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.
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