Missense mutation in Btk Exon 15 results in variant X-linked agammaglobulinemia (XLA) with mild clinical phenotype

Abstract

Rationale Classic XLA is characterized by recurrent viral and bacterial infections, paucity or absence of peripheral lymphoid tissue, absence of circulating B cells, marked depression of serum IgG, IgA, and IgM; absent specific antibody production and mutations in the Btk gene. We report a variant form of XLA with partial B cell function resulting from a mutation in Exon 15 of the Btk gene. Methods Phenotyping was performed by standard flow cytometry. Immunoglobulin and specific antibody levels were performed in CLIA certified laboratories. Btk expression was screened by flow cytometry on platelets and mutation analysis was performed using dye termination sequencing of cDNA and gDNA. Results The proband presented at 7 yo with pneumonia, a history of croup at 18 mo and mild cellulitis at 6 yo but no other serious infections. He had normal growth and development and immunizations were current. At presentation his IgG, A, and M were 671, 192, 5.1 mg/dl respectively with normal IgG subclasses. Diphtheria and tetanus antibody levels were normal. Flow studies showed <1% B cells, normal T and NK cells, and normal in vitro proliferation to mitogens and antigens. Platelets expressed no Btk protein and Btk sequencing showed a point mutation G1571T resulting in amino acid substitution gly480val near the kinase domain. A 1 yo asymptomatic brother had similar lab findings with 2% B cells, mildly decreased IgG, falling IgM levels and normal antibody to protein vaccines. Conclusions This report extends the spectrum of XLA and provides insight into the role of Btk protein in humoral immunity.