Frontiers in immunology · 2025
Dual variants of uncertain significance in a case of hyper-IgM syndrome: implications for diagnosis and management.
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Agrebi Nourhen, Mackeh Rafah, Alsabbagh Mohamed, Elmi Asha, Al-Marri Amnah A, Hubrack Satanay Z, Purayil Saleema C, Karim Mohammed Yousuf, Hassan Amel, Lo Bernice
Аннотация
BACKGROUND: Hyper-IgM syndrome (HIGM) is a genetic immunodeficiency characterized by elevated to normal IgM levels and decreased IgG, IgA, and IgE. The overlapping clinical presentations of different gene mutations complicate diagnosis and management.
OBJECTIVE: This study aims to elucidate the clinical implications of concurrent AICDA and IKBKB homozygous variants in a pediatric patient diagnosed with hyper-IgM syndrome.
METHODS: We present immunological and genetic analysis of a Tunisian patient with two homozygous variants of uncertain significance (VUSs) in the IKBKB and AICDA genes, suspected of causing hyper-IgM and immune deficiency. We conducted functional tests to ascertain the pathogenicity of IKBKB and AICDA mutations and to provide a definitive diagnosis and appropriate management.
RESULTS: Genetic analysis identified two homozygous variants: AICDA (p.W80S) and IKBKB (p.R77Q). Immunophenotyping and functional studies found greatly reduced class-switched memory B cells and somatic hypermutations but normal T cell responses and NFkB activation.
CONCLUSION: The simultaneous presence of multiple homozygous VUSs emphasizes a major challenge in the genetic diagnosis of highly consanguinous patients. Functional workup as well as familial segregation studies are needed to clarify variant pathogenicity and provide a definitive diagnosis and tailored treatment strategies for these patients. Our studies suggest that the AICDA p.W80S variant is pathogenic, while the IKBKB p.R77Q variant is likely benign.
OBJECTIVE: This study aims to elucidate the clinical implications of concurrent AICDA and IKBKB homozygous variants in a pediatric patient diagnosed with hyper-IgM syndrome.
METHODS: We present immunological and genetic analysis of a Tunisian patient with two homozygous variants of uncertain significance (VUSs) in the IKBKB and AICDA genes, suspected of causing hyper-IgM and immune deficiency. We conducted functional tests to ascertain the pathogenicity of IKBKB and AICDA mutations and to provide a definitive diagnosis and appropriate management.
RESULTS: Genetic analysis identified two homozygous variants: AICDA (p.W80S) and IKBKB (p.R77Q). Immunophenotyping and functional studies found greatly reduced class-switched memory B cells and somatic hypermutations but normal T cell responses and NFkB activation.
CONCLUSION: The simultaneous presence of multiple homozygous VUSs emphasizes a major challenge in the genetic diagnosis of highly consanguinous patients. Functional workup as well as familial segregation studies are needed to clarify variant pathogenicity and provide a definitive diagnosis and tailored treatment strategies for these patients. Our studies suggest that the AICDA p.W80S variant is pathogenic, while the IKBKB p.R77Q variant is likely benign.