Dadi H et al. – In this study, 4 related patients with combined immunodeficiency, early onset asthma, eczema, food allergies, and autoimmunity were investigated for genetic aberration. There was a less profound but prominent susceptibility to infections and multi–organ atopy and autoimmunity in patients with R30W defect, unlike patients with biallelic mutations in caspase recruitment domain–containing protein (CARD)11, who showed severe combined immunodeficiency.

Methods

• Whole exome sequencing (WES) was performed followed by Sanger confirmation, assessment of the genetic variant impact on cell signaling, and evaluation of the resultant immune function.

Results

• WES identified a new heterozygous c.C88T one base pair substitution, resulting in amino acid change R30W in CARD11, which segregated perfectly to family members with severe atopy only, but not in healthy individuals.
• R30W mutation resulted in a loss of function and exerted a dominant negative effect on wild–type CARD11.
• This altered classical nuclear factor–?B pathway resulting in poor in vitro T–cell responses to mitogens and antigens caused by reduced secretion of interferon gamma and interleukin–2.