X-Linked Agammagobulinemia in a Large Series of North African Patients: Frequency, Clinical Features and Novel BTK Mutations

J Clin Immunol. 2016 Apr;36(3):187-94. doi: 10.1007/s10875-016-0251-z. Epub 2016 Mar 1.


Purpose: X-linked agammagobulinemia (XLA) is a primary immunodeficiency caused by Bruton's tyrosine kinase (BTK) gene defect. XLA patients have absent or reduced number of peripheral B cells and a profound deficiency in all immunoglobulin isotypes. This multicenter study reports the clinical, immunological and molecular features of Bruton's disease in 40 North African male patients.

Methods: Fifty male out of 63 (male and female) patients diagnosed with serum agammaglobulinemia and non detectable to less than 2% peripheral B cells were enrolled. The search for BTK gene mutations was performed for all of them by genomic DNA amplification and Sanger sequencing.

Results: We identified 33 different mutations in the BTK gene in 40 patients including 12 missense mutations, 6 nonsense mutations, 6 splice-site mutations, 5 frameshift, 2 large deletions, one complex mutation and one in-frame deletion. Seventeen of these mutations are novel. This large series shows a lower frequency of XLA among male patients from North Africa with agammaglobulinemia and absent to low B cells compared with other international studies (63.5% vs. 85%). No strong evidence for genotype-phenotype correlation was observed.

Conclusions: This study adds to other reports from highly consanguineous North African populations, showing lower frequency of X-linked forms as compared to AR forms of the same primary immunodeficiency. Furthermore, a large number of novel BTK mutations were identified and could further help identify carriers for genetic counseling.

Keywords: BTK; XLA; north african population; novel mutations.

Publication types

  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Agammaglobulinaemia Tyrosine Kinase
  • Agammaglobulinemia / complications
  • Agammaglobulinemia / diagnosis
  • Agammaglobulinemia / genetics*
  • Agammaglobulinemia / immunology
  • Age of Onset
  • Algeria
  • Alleles
  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology
  • Child
  • Child, Preschool
  • Gene Expression*
  • Gene Frequency*
  • Genetic Association Studies
  • Genetic Counseling
  • Genetic Diseases, X-Linked / complications
  • Genetic Diseases, X-Linked / diagnosis
  • Genetic Diseases, X-Linked / genetics*
  • Genetic Diseases, X-Linked / immunology
  • Heterozygote
  • Humans
  • Infant
  • Male
  • Morocco
  • Mutation*
  • Opportunistic Infections / complications
  • Opportunistic Infections / diagnosis
  • Opportunistic Infections / genetics*
  • Opportunistic Infections / immunology
  • Protein-Tyrosine Kinases / genetics*
  • Protein-Tyrosine Kinases / immunology
  • Sequence Analysis, DNA
  • Tunisia


  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human

Supplementary concepts

  • Bruton type agammaglobulinemia