Abstract
Inborn errors of immunity (IEIs) are caused by deleterious variants in immune-related genes. ASXL1 is an epigenetic modifier not previously linked to an IEI. Clonal hematopoiesis and hematologic neoplasms often feature somatic ASXL1 variants, and Bohring-Opitz syndrome, a neurodevelopmental disorder, is caused by heterozygous truncating ASXL1 variants. We present an IEI caused by biallelic germline missense variants in ASXL1. The patient had a history of hematologic abnormalities and viral-associated complications, including chronic macrocytosis, persistent vaccine-strain rubella granulomas, and EBV-associated Hodgkin lymphoma. Immunophenotyping revealed loss of B cells, hypogammaglobulinemia, and impairments in cytotoxic T and NK cell populations. T cells exhibited skewing toward an exhausted memory phenotype, global DNA methylation loss, and increased epigenetic aging. These aberrations were ameliorated by wild-type ASXL1 transduction, confirming the patient variants’ pathogenicity. This study defines a novel human IEI caused by ASXL1 deficiency, a diagnosis that should be considered in individuals with chronic viral infections, viral-associated malignancies, and combined immune deficiency.
Citation
Fu M, Sharma M*, Merrill S, Yousefi P, Tan R, Modi B, Del Bel K, Deyell R, Rozmus J, Rehmus W, Hildebrand K, James E, Blanchard-Rohner G, Lin S, Junker A, Shopsowitz K, Setiadi A, Terry J, Lee A, Drögemöller B, Matthews A, Tarailo-Graovac M, Sauvé L, Mitchell H, Prendiville J, MacIsaac J, Dever K, Lin D, Ross C, Dobson S, Vercauteren S, Wasserman W, van Karnebeek C, McKinnon M, Kobor M, Turvey S, Biggs C, “ASXL1 deficiency causes epigenetic dysfunction, combined immunodeficiency, and EBV-associated lymphoma,” J Exp Med 222, 10(2025): e20240945, doi: 10.1084/jem.20240945