Genetics: Mendelian inheritance of immunodeficiency disorders

Primary immunodeficiency disorders (PIDs) are conditions in which the immune system is compromised due to genetic defects. PIDs are typically characterized by the person’s inability to make sufficient amounts of immune cells or by the production of immune cells that are mutated such that they cannot function properly. Since most PIDs have a genetic basis, most are heritable, although type of immune cell deficiency and the mode of inheritance varies widely between disorders.

Bruton syndrome, or X-linked agammaglobulinemia (XLA), is a rare genetic disorder caused by mutations in the gene encoding a cytoplasmic protein tyrosine kinase, Bruton’s tyrosine kinase (Btk), a signal transduction molecule downstream of pre-B cell receptor (Pre-BCR). In a healthy person, the enzyme is activated by the pre-B cell receptor and delivers biochemical signals that prompt the B cells to divide or mature. Figure 1 shows the pedigree of a family with members who suffer from XLA.

Figure 1 Pedigree of family with cases of Bruton’s syndrome

Hyper-IgE syndrome (HIES), also known as Job's syndrome, is another rare PID characterized by elevated levels of immunoglobulin E (IgE), resulting in improper neutrophil chemotaxis and recurrent bacterial infections. It is primarily a genetic disorder, and there are two main types: autosomal dominant hyper-IgE syndrome (AD-HIES) caused by mutations in the STAT3 (signal transducer and activator of transcription 3) gene, a critical component in the JAK-STAT signaling pathway; and autosomal recessive hyper-IgE syndrome (AR-HIES), many of which are caused by mutations in the DOCK8 gene, involved in the regulation of the cytoskeleton and immune cell function. Figure 2 shows the pedigree of another family with members who exhibit hyper-IgE syndrome.

Figure 2 Pedigree of family with cases of hyper-IgE syndrome