A novel SPI1 variant (c.566T > C (p.Ile189Thr)) possibly associated with autosomal dominant agammaglobulinemia in a Chinese girl

Agammaglobulinemia is a rare primary immunodeficiency disorder characterized by deficient B lymphocyte development and reduced serum immunoglobulin levels, leading to recurrent infections. Autosomal dominant agammaglobulinemia (AD-AGM) related to SPI1 gene mutations is extremely rare, with limited reported cases worldwide. A 13-year-old Chinese girl was admitted with recurrent respiratory infections for over 6 years and acute cough/fever lasting 1 week. Laboratory tests showed significantly decreased IgG (3.94 g/L) and IgA (0 g/L) levels, with a B lymphocyte ratio (CD3−CD19+)/ lymphocytes) of 0.03% and absolute B cell count of 1 cell/µL. Whole-exome sequencing identified a heterozygous SPI1 variant (c.566T > C (p.Ile189Thr)) inherited from her asymptomatic mother; her father and younger brother did not carry the variant. The variant is annotated as “of uncertain significance (VUS)” according to ACMG criteria, supporting a potential diagnosis of AD-AGM associated with the SPI1 variant. Literature review indicated that the c.566T > C mutation in the SPI1 gene had not been previously reported. Additionally, we summarized the clinical and genetic characteristics of patients from different continents. The patient received anti-infection therapy, intravenous gamma globulin infusion, bronchoalveolar lavage, and symptomatic treatment (e.g., antipyretic, antitussive, expectorant, and nutritional support), with significant clinical improvement. Long-term follow-up (12 months) showed no severe recurrent infections with monthly gamma globulin maintenance. This report describes a novel SPI1 variant (c.566T > C, p.Ile189Thr) in a Chinese girl with clinical features of AD-AGM. The variant has not been recorded in the Genome Aggregation Database (gnomAD) or Chinese reference databases. The novel SPI1 variant expands the genotypic spectrum of agammaglobulinemia and provides a potential candidate for further functional and therapeutic research. Whole-exome sequencing may facilitate early identification of such rare variants in patients with suspected immunodeficiency.