B cell repertoire in patients with a novel BTK mutation: expanding the spectrum of atypical X-linked agammaglobulinemia

Ori Toker, Arnon Broides, Atar Lev, Amos J. Simon, Orli Megged, Oded Shamriz, Yuval Tal, Raz Somech, Yu Nee Lee, Amit Nahum

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


X-linked agammaglobulinemia (XLA) is caused by mutations in the Bruton tyrosine kinase) BTK) gene. Affected patients have severely reduced amounts of circulating B cells. Patients with atypical XLA may have residual circulating B cells, and there are few studies exploring these cells’ repertoire. We aimed to study the B cell repertoire of a novel hypomorphic mutation in the BTK gene, using the next generation sequencing (NGS) technology. Clinical data was collected from our clinical records. Real-time PCR was used to determine KREC copies, and NGS was used to determine the immunoglobulin (Ig) heavy chain (IgH) repertoire diversity. Both patients had a relatively mild clinical and laboratory phenotype, residual BTK protein expression, and the same novel mutation in the BTK gene, c.1841 T > C, p. L614P. Signal-joint kappa-deleting recombination excision circles (sj-KREC) for both patients were completely absent reflecting lack of naïve B cells. The intron RSS-Kde coding joints (cj) were significantly reduced, reflecting residual replicating B cells. NGS displayed restricted IgH repertoire with highly uneven distribution of clones, especially for Pt2. We report a novel BTK mutation, c.1841 T > C (p. L614P) that is associated with a relatively mild phenotype. We conclude that the IgH repertoire in atypical XLA is restricted with highly uneven distribution of clones. This phenomenon may be explained by extremely reduced to non-existent levels of BTK in B cells. This report sheds further light on atypical cases of XLA.

Original languageEnglish
Pages (from-to)216-223
Number of pages8
JournalImmunologic Research
Issue number2
StatePublished - Apr 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.


  • Agammaglobulinemia
  • BTK
  • IgH repertoire diversity
  • KREC
  • XLA


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