Abstract for presentation at 11th International Congress of Human Genetics

Identification of a new Bruton’s tyrosine kinase (BTK) mutation associated with an unusual phenotype in a patient with X-linked agammaglobulinemia (XLA)

  • Gigliola Di Matteo, Italy
  • Andrea Finocchi, Division of Immunology and Infectious Diseases, Children's Hospital Bambino Gesu, Department of Paediatrics, University of Rome, Italy
  • Simona Graziani, Division of Immunology and Infectious Diseases, Children's Hospital Bambino Gesu, Department of Paediatrics, University of Rome, Italy
  • Antonio Filareto, Department of Biopathology and Diagnosting Imaging, Human Genetics Section, University of Rome Tor Vergata, Rome, Italy., Italy
  • Maria Chiriaco, Division of Immunology and Infectious Diseases, Children's Hospital Bambino Gesu, Department of Paediatrics, University of Rome, Italy
  • Federica Sangiuiolo, Department of Biopathology and Diagnosting Imaging, Human Genetics Section, University of Rome Tor Vergata, Rome, Italy., Italy
  • Paolo Rossi, Division of Immunology and Infectious Diseases, Children's Hospital Bambino Gesu, Department of Paediatrics, University of Rome, Italy
  • Viviana Moschese, Division of Immunology and Infectious Diseases, Children's Hospital Bambino Gesu, Department of Paediatrics, University of Rome, Italy

    • X-linked (recessive) agammaglobulinemia (XLA; OMIN:307200) is caused by mutations in the Bruton’s tyrosine kinase (BTK) gene, which result in a precursor B-cell differentiation arrest in the bone marrow and the absence of or strongly reduced B lymphocytes (CD19+) in blood. The defect results in a pronounced reduction in serum immunoglobulins (Igs) of all classes, and the affected individuals therefore, suffer from recurrent bacterial and enteroviral infections.
    We recently characterized a new mutation in BTK gene segregating in XLA family. The proband is a 29-old patient with a positive family history of recurrent respiratory infections (two uncles died from infections). Nevertheless, immunological investigation showed a selective IgM deficiency with normal value of IgG and IgA and mild decreased number of CD19+ cells. Not all XLA cases are conform to the classic phenotype and has been showed that B-cell lymphocyte maturation and immunoglobulin production are possible, despite the absence of BTK expression. Interestingly the mother of the patient and her two sisters suffered from chronic lung disease due to recurrent respiratory infections. For this reason the molecular analysis was performed also on his relatives.
    The mutation is a missense substitution (1108 a>g) that cause the change of the threonine 316 in alanin in SH2 domain of the tyrosine kinase. The mother and her two sisters of the affected boys were heterozygotes.
    Although genotype-phenotype correlations have not been established in XLA, female carriers usually, have no clinical sign of the genetic defect. The symptomatic phenotype of the females of this family correlates with a possible preferential selection of the normal, non-mutated X-chromosome as the active allele in hematopoietic cells. A methylation analysis is in progress for testing this hypothesis.

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