Abstract
SASH3 is a lymphoid-specific adaptor protein. In a recent study, SASH3 deficiency was described as a novel X-linked combined immunodeficiency with immune dysregulation, associated with impaired TCR signaling and thymocyte survival in humans. The small number of patients reported to date showed recurrent sinopulmonary, cutaneous and mucosal infections, and autoimmune cytopenia. Here we describe an adult patient previously diagnosed with common variable immunodeficiency (CVID) due to low IgG and IgM levels and recurrent upper tract infections. Two separate, severe viral infections drew our attention and pointed to an underlying T cell defect: severe varicella zoster virus (VZV) infection at the age of 4 years and bilateral pneumonia due type A influenza infection at the age of 38. Genetic testing using an NGS-based custom-targeted gene panel revealed a novel hemizygous loss-of-function variant in the SASH3 gene (c.505C>T/p.Gln169*). The patient’s immunological phenotype included marked B cell lymphopenia with reduced pre-switch and switch memory B cells, decreased CD4 + and CD8 + naïve T cells, elevated CD4 + and CD8 + T EMRA cells, and abnormal T cell activation and proliferation. The patient showed a suboptimal response to Streptococcus pneumoniae (polysaccharide) vaccine, and a normal response to Haemophilus influenzae type B (conjugate) vaccine and SARS-CoV-2 (RNA) vaccine. In summary, our patient has a combined immunodeficiency, although he presented with a phenotype resembling CVID. Two severe episodes of viral infection alerted us to a possible T-cell defect, and genetic testing led to SASH3 deficiency. Our patient displays a milder phenotype than has been reported previously in these patients, thus expanding the clinical spectrum of this recently identified inborn error of immunity.
Keywords: SASH3 deficiency; combined immunodeficiency; common variable immunodeficiency; genetics; inborn errors of immunity; mutation; primary immunodeficiencies.
【저자키워드】 Mutation, genetics, inborn errors of immunity, common variable immunodeficiency, SASH3 deficiency, combined immunodeficiency, primary immunodeficiencies., 【초록키워드】 SARS-CoV-2, viral infection, Vaccine, Mutation, Immunity, T cells, Influenza, variant, Infection, immunodeficiency, memory B cells, virus, CD4, CD8, viral infections, genetics, RNA, lymphopenia, B cell, Protein, T cell, infections, survival, cells, humans, Genetic testing, Patient, phenotype, age, Autoimmune, T-cell, polysaccharide, TCR, CVID, patients, T cell activation, common variable immunodeficiency, Signaling, mucosal, Haemophilus influenzae, Streptococcus pneumoniae, combined immunodeficiency, immune dysregulation, IgG and IgM, proliferation, dysregulation, deficiency, Inborn errors, influenza infection, bilateral pneumonia, immunological phenotype, loss-of-function, Haemophilus influenzae type b, naïve T cells, varicella, Varicella zoster virus, X-linked, SASH3, described, reported, diagnosed, elevated, reduced, 【제목키워드】 common variable immunodeficiency, variable, common,