TY - JOUR
T1 - ASXL1 deficiency causes epigenetic dysfunction, combined immunodeficiency, and EBV-associated lymphoma
AU - Fu, Maggie P.
AU - Sharma, Mehul
AU - Yousefi, Pariya
AU - Merrill, Sarah M.
AU - Tan, Ryan
AU - Samra, Simran
AU - Setiadi, Audi
AU - Golding, Liam
AU - Modi, Bhavi P.
AU - del Bel, Kate L.
AU - Deyell, Rebecca J.
AU - Rozmus, Jacob
AU - Rehmus, Wingfield
AU - Hildebrand, Kyla J.
AU - James, Elliot
AU - Blanchard-Rohner, G. raldine
AU - Lin, Susan
AU - Shopsowitz, Kevin E.
AU - Terry, Jefferson
AU - Lee, Anna F.
AU - Drögemöller, Britt I.
AU - Matthews, Allison
AU - Tarailo-Graovac, Maja
AU - Sauvé, Laura
AU - Mitchell, Hana
AU - Prendiville, Julie S.
AU - MacIsaac, Julia L.
AU - Dever, Kristy
AU - Lin, David T. S.
AU - Meijer, Mandy
AU - Ross, Colin J. D.
AU - Dobson, Simon R. M.
AU - Vercauteren, Suzanne M.
AU - Wasserman, Wyeth W.
AU - van Karnebeek, Clara D. M.
AU - McKinnon, Margaret L.
AU - Kobor, Michael S.
AU - Turvey, Stuart E.
AU - Biggs, Catherine M.
N1 - Publisher Copyright:
© 2025 Fu et al.
PY - 2025/10/6
Y1 - 2025/10/6
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/105012789560
U2 - 10.1084/jem.20240945
DO - 10.1084/jem.20240945
M3 - Article
C2 - 40742536
SN - 0022-1007
VL - 222
JO - Journal of experimental medicine
JF - Journal of experimental medicine
IS - 10
ER -
