Mutations in histone lysine methyltransferase genes are associated with autoimmune cytopenias: a single-center study

Epigenetic dysregulation is increasingly recognized as a contributor to autoimmunity and autoimmune cytopenias (AIC). Histone lysine methyltransferases (MTs) are key regulators of gene expression through epigenetic modification. Germline MT mutations are associated with immunodeficiency syndromes such as Kabuki syndrome, which frequently co-occurs with AIC, while somatic KMT2D mutations have been reported in cold agglutinin disease. This study aimed to (1) determine the frequency of mutations in histone methyltransferase genes (KMT2D, KMT2A, KMT2C, and KDM6A) among patients with AIC, and (2) compare clinical, laboratory, and immunologic characteristics, as well as treatment responses, between patients with and without MT mutations. We retrospectively analyzed 534 patients who underwent comprehensive next-generation sequencing of bone marrow or peripheral blood; 80 had a diagnosis of AIC. Patients were categorized as MT-positive (MT⁺) or MT-negative (MT⁻) based on the presence of mutations in the specified genes. MT⁺ patients were significantly more likely to develop AIC compared with MT⁻ patients (25/90 vs 55/444). MT⁺ patients with AIC exhibited significantly lower serum immunoglobulin G levels, and those with autoimmune hemolytic anemia were more likely to demonstrate complement involvement on the direct antiglobulin test. MT variants identified in the AIC cohort were absent from the 1000 Genomes database and were predicted to be among the top 1% of the most deleterious variants based on Phred scores. These findings suggest that mutations in histone methyltransferase genes may play a role in the development of AIC. Prospective studies are warranted to validate these associations and to elucidate the epigenetic mechanisms underlying autoimmunity, which may ultimately support biomarker discovery and personalized approaches to disease management.