A Three-Year-Old Male with an Intronic BTK Variant of Uncertain Significance

A three-year-old male presented to the allergy and immunology clinic after a recent admission for pneumococcal sepsis. His infectious history was significant for several episodes of acute otitis media, and he was fully immunized. Evaluation demonstrated pan-hypogammaglobulinemia (immunoglobulin [Ig]G—230 mg/dL, IgA—<5 mg/dL, and IgM—<5 mg/dL), absent pneumococcal, tetanus, and diphtheria titers. Lymphocyte enumeration showed near-absent CD19+ B cells (20 cells/μL, 0%), mildly elevated CD3+ T cells (5763 cells/μL), and normal NK cells (267 cells/μL). Further inquiry into family history was notable for a 5-year-old brother with several episodes of community-acquired pneumonia and acute otitis media. Immunophenotyping in the sibling revealed pan-hypogammaglobulinemia (IgG—336 mg/dL, IgA—<5 mg/dL, and IgM—33 mg/dL) and near absent CD19+ B cells (4 cells/μL, 0%) as well. Intracellular BTK protein expression via flow cytometry in the index patient was decreased in monocytes (mean fluorescent intensity [MFI] 1.06) as compared with a healthy control (MFI 5.91). Given these findings, genetic testing was pursued. Single-gene sequencing (to 20 flanking intronic nucleotides) of BTK by Laboratory Corporation of America (labcorp®) demonstrated a synonymous variant, c.1899C>T, which was interpreted as benign. An inborn errors of immunity/primary immunodeficiency panel was then sent to Prevention Genetics notable for a hemizygous intronic variant of uncertain significance in BTK, c.1567-23A>C. This variant was not reported in ClinVar and was not predicted to significantly impact splicing of the BTK gene based on available prediction programs. However, it was absent in gnomAD and is mentioned in one previously published patient in a cohort of those with X-linked agammaglobulinemia. Genetic testing in the older sibling is still pending. With the addition of phenotypic and functional data, the suggested reclassification of the BTK variant is likely pathogenic. XLA typically presents in the first year of life with recurrent infections, low to absent immunoglobulins, and B cells. We describe two siblings with pan-hypogammaglobulinemia, near-absent B cells, and abnormal BTK expression. Initial single-gene sequencing failed to detect the likely culprit BTK intronic variant, which was later noted on repeat testing.