A novel case of autosomal recessive CARD11 loss‐of‐function underlying impaired antiviral immunity and a review of literature

Objectives Germline CARD11 variants lead to a spectrum of disease depending on the effect of signalling augmentation or impairment. Autosomal recessive (AR) CARD11 loss‐of‐function (LOF) is rare with only 12 cases reported to date. Methods Clinical and immunological information was collated for a patient with a homozygous CARD11 p.(Arg379Pro) variant. Results The patient (P1, aged 5, female) has a history of developmental delay and growth failure, severe early‐onset asthma, impaired clearance of naturally acquired viruses and probable susceptibility to live attenuated vaccines (LAV). Genetic testing revealed that P1 has a hypomorphic homozygous novel missense variant in the coiled‐coil (CC) domain of CARD11, leading to LOF. She has combined immunodeficiency with significant T and B cell defects, and impaired nuclear factor kappa B (NF‐κB) activity in lymphocytes. Conclusion We expand the phenotypic spectrum of CARD11‐opathies by describing a patient homozygous for a novel AR LOF CARD11 variant, demonstrating susceptibility to Japanese encephalitis and varicella LAV and impaired clearance of multiple naturally acquired respiratory viral infections. Inborn errors of immunity affecting the CARD11‐BCL10‐MALT1 (CBM) complex should be considered in individuals with LAV vaccine susceptibility and recurrent or persistent viral infections.