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 a 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; however, the type of immune cell deficiency and the mode of inheritance varies widely between disorders.

Bruton's 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) and autosomal recessive hyper-IgE syndrome (AR-HIES). AD-HIES is caused by mutations in the STAT3 (signal transducer and activator of transcription 3) gene, a critical component in the JAK-STAT signaling pathway. AR-HIES is often caused by mutations in the DOCK8 gene, which is 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