https://orcid.org/0000-0003-1740-5939
Key point:
Histone lysine methyltransferase mutations are associated with the development of autoimmune cytopenias
Rare variants in histone lysine methyltransferase gene are associated with autoimmune cytopenias and lower IgG levels
Abstract
Epigenetic dysregulation is associated with autoimmunity and autoimmune cytopenia (AIC). (Surace et al Front lmmunol. 2019) Histone lysine methyltransferase (MT) plays an important role in epigenetic modification, restricting gene expression. Germline MT mutations are associated with immunodeficiencies, including Kabuki syndrome (KS), which is associated with autoimmune cytopenias. Somatic mutations in the KMT2D gene have also been observed in patients with Cold Agglutinin Disease. (Malecka et al Br J Haematol. 2018). The aims of this study are: 1) to identify the frequency of mutations in histone methyltransferase genes (MT) KMT2D, KMT2A, KMT2C, and KDM6A in patients with autoimmune cytopenias, and 2) to compare clinical, laboratory and immunological characteristics, and response to therapy in patients with or without mutation in MT and autoimmune cytopenias (AIC). We retrospectively analyzed the prevalence of MT gene mutations in 534 patients who had comprehensive next generation sequencing performed on bone marrow or peripheral blood. Among these, 80 had a diagnosis of AIC. Patients with AIC were categorized into two groups based on the presence or absence of mutations in the MT genes (MT+, MT-). MT- patients served as control group. Patients with MT mutations were more likely to develop autoimmune cytopenia (25/90 vs 55/444, p=0.00025). MT-mutated patients with autoimmune cytopenias had lower IgG level (p=0.001). Patients with AIHA were more likely to have complement involvement on the Direct Coombs test (p=0.03). Mutations in the MT genes identified in the AIC cohort were compared against data from the 1000 Genome Project to assess their frequency in the general population. These MT variants were not observed in the broader population dataset, suggesting they may be unique to individuals within the AIC cohort. Furthermore, based on Phred scores, the majority of these mutations are predicted to be among the top 1% of the most deleterious variants. MT mutations may play a role in the development of AIC, though further prospective studies are needed to clarify their significance. Investigating the epigenetic mechanisms underlying autoimmune diseases could help identify potential biomarkers and improve understanding of disease pathways. This knowledge may ultimately support more personalized approaches to diagnosing and managing the variable clinical presentations and outcomes seen across autoimmune conditions.
