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.