Tu160 - Clinical Outcome of Dominant Negative Mutation in Caspase Activation and Recruitment Domain Family Member 11 (CARD11)

Laura Abrego Fuentes, MD – Division of Immunology and Allergy, Department of Paediatrics – The Hospital for Sick Children; Myra Pereira, MN – Division of Immunology and Allergy, Department of Paediatrics – The Hospital for Sick Children; Linda Vong, PhD – Division of Immunology and Allergy, Department of Paediatrics – The Hospital for Sick Children; Chaim Roifman, CM, MD, FRCP, FCACB – Division of Immunology and Allergy, Department of Paediatrics – The Hospital for Sick Children

Abstract Text: Caspase activation and recruitment domain family member 11 (CARD11) is a scaffold protein belonging to a family of membrane-associated guanylate kinases required for B-cell receptor and T-cell receptor signalling and subsequent activation of the nuclear factor κβ (NF-κβ) pathway. Aberrations in CARD11 have been shown to impact lymphocyte differentiation, proliferation, and survival, resulting in combined immunodeficiency.
We previously reported a multi-generation kindred with novel heterozygous c.C887T variant in CARD11, resulting in amino acid change R30W. The variant lead to loss-of-function of CARD11 while exerting a dominant negative effect. Functional studies identified defects in canonical NF-κβ pathway signalling resulting in dampened IFN- and IL-2 secretion. In addition to combined immunodeficiency, these individuals presented with marked multi-organ atopy and autoimmunity.

Objective: Describe the clinical progress of a kindred with CARD11 R30W 5 years after established diagnosis.

Methods: A comprehensive retrospective chart review was performed.

Results: During the follow-up period, 2 of the individuals (proband and daughter) exhibited worsening autoimmunity and atopy. The other 3 cases had well controlled asthma, eczema and food allergy. From an infectious standpoint, all 5 family members remained relatively well and did not develop any severe or recurrent infections. Three experienced mild COVID-19 and recovered without complication. In contrast, the proband developed colitis flare post-COVID-19 while her daughter developed severe atopic dermatitis not responding to conventional therapy.

Conclusion: CARD11 R30W results in susceptibility to infection but with more prominent multi-organ atopy and autoimmunity symptoms. Longitudinal follow-up revealed worsening autoimmunity and atopy in 2 of the 5 affected individuals.