Primary Immunodeficiency: Complex Genetic Disorders?

Classical primary immunodeficiencies (PIDs) are usually monogenic (Mendelian) disorders affecting host defenses. More than 200 clinical phenotypes of PID have been described, and about 100 of them now have a well-defined molecular genetic basis (1). The classical example is X-linked agammaglobulinemia, in which disease-causing variants in the gene ( BTK , Bruton agammaglobulinemia tyrosine kinase) coding for Bruton’s tyrosine kinase lead to arrest of B-cell development at the pre-B-cell stage (2). Identification and characterization of such monogenic diseases are not only helpful for diagnosis and genetic counseling but will be valuable in development of mechanism-based therapies or gene therapy. Gene therapy has been used to insert a functional gene in hematopoietic stem cells in children with severe combined immunodeficiency, and it is hoped that this procedure will supplement or even replace allogeneic bone marrow transplantations as a treatment option in many diseases in the …