X-linked agammaglobulinemia (XLA) is a congenital humoral immunodefici
ency caused by a defect in a B-cell-specific signaling molecule, Btk.
There has been little concordance of phenotype with genotype in this d
isorder, and defects in Btk cause immunodeficiencies that range from m
ild impairment to complete inability to produce antibodies. The factor
s modifying the phenotype of XLA are not understood. The current study
is the first description of two male siblings with identical T-134-->
C mutations in the translation initiation ATG of Btk who have differen
t clinical phenotypes as well as different laboratory phenotypes. The
proband lacks immunoglobulins and B cells and has recurrent infections
, while the elder, affected brother has normal levels of IgG and IgM a
nd very few infections. Both have undetectable levels of Btk kinase ac
tivity in circulating mononuclear cells. Complete sequencing of Btk ge
ne transcripts in both brothers revealed no additional mutations to ac
count for the discordant phenotypes. This description provides unequiv
ocal evidence that the phenotype of XLA is influenced by factors addit
ional to the Btk gene.