Sequence-based molecular diagnosis of X-linked agammaglobulinemia in South African individuals

[摘要] ENGLISH SUMMARY: Background: Primary immunodeficiency disorders (PID) disrupt the proper functioning of the immunesystem. The prototypic PID is X-linked Agammaglobulinemia (XLA). This disorder is caused by mutationsin the Bruton tyrosine kinase (Btk) gene and results in an arrest in B cell development which leads to aprofound reduction of all classes of serum immunoglobulins (i.e antibodies). Patients with a lack ofantibodies experience recurring bacterial infections during early childhood that can be fatal if not treated.Intravenous gammaglobulin replacement therapy (IVIg) is the standard treatment for XLA. It providespassive immunity thereby reducing the number and severity of infections as well as limiting many of theinfectious complications. Early detection and treatment of XLA allows affected individuals to live arelatively normal life.Objective: The purpose of this study was to determine the molecular basis of XLA in South Africa using adirect sequence-based method to detect abnormalities in the Btk gene to aid clinical diagnosis of thedisease.Methods : Male patients with a clinical diagnosis of XLA were included in this study. Genetic analysiswas used to explore the exonic region of the Btk gene of 5 unrelated male patients and compared to 10healthy controls. Family members were followed up to determine carrier status, where possible.Results: Mutational analysis revealed Btk abnormalities in 4 of the 5 patients leading to a definitivediagnosis of XLA. Two of the three mutations found in this study have been previously described whileone mutation appears to be novel. The novel mutation is a one base pair deletion in exon 16 which leads tothe truncation of the Btk protein. Despite the clinical findings suggestive of XLA, no mutation wasidentified in the exonic region of the Btk gene of the remaining patient, indicating that this patient mighthave a different form of PID. Maternal follow-up confirmed the maternal inheritance pattern as all mothersscreened were carriers of the Btk mutation present in the affected individual.Discussion :Using a direct sequence-based method abnormalities were identified in the Btk gene of three patients.Molecular diagnosis coupled to clinical history of the patient provides a definitive XLA diagnosis. Thisstudy supports the use of molecular techniques in the diagnosis of PID and underlines the synergy thatcould be possible in a clinical setting.

[发布机构] Stellenbosch University