ASXL1 deficiency causes epigenetic dysfunction, combined immunodeficiency, and EBV-associated lymphoma

Area of Science:

• Immunology
• Genetics
• Epigenetics

Background:

• Inborn errors of immunity (IEIs) result from genetic defects in immune system genes.
• ASXL1, an epigenetic modifier, is known for roles in clonal hematopoiesis and Bohring-Opitz syndrome, but not previously linked to IEIs.

Purpose of the Study:

• To identify and characterize a novel IEI caused by germline variants in the ASXL1 gene.
• To investigate the immunological and epigenetic consequences of ASXL1 deficiency.

Main Methods:

• Genetic analysis to identify biallelic germline missense variants in ASXL1.
• Comprehensive immunophenotyping of patient immune cells (B cells, T cells, NK cells).
• Assessment of T cell phenotype, DNA methylation, and epigenetic aging; functional validation using gene transduction.

Main Results:

• A patient presented with hematologic abnormalities, chronic viral infections (rubella, EBV), and EBV-associated Hodgkin lymphoma.
• Immunophenotyping showed B cell deficiency, hypogammaglobulinemia, impaired cytotoxic T and NK cells, and T cell exhaustion.
• Evidence of global DNA hypomethylation and accelerated epigenetic aging was observed, which were reversed by ASXL1 reintroduction.

Conclusions:

• This study defines a new human IEI due to ASXL1 deficiency.
• ASXL1 deficiency leads to combined immune deficiency with susceptibility to viral infections and malignancies.
• Diagnosis should be considered in patients with combined immune deficiency, chronic viral infections, and viral-associated cancers.