Discovery of single-gene inborn errors of immunity by next generation sequencing

• Next generation sequencing has resulted in an explosion of new immunodeficiency genes (85).
• Some clinical heterogeneity is explained by gain versus loss of function mutations (82).
• The same mutation in the same gene may be associated with very different phenotypes (83).
• A surprising number of newly defined disorders are the result of de novo mutations (83).
• Mutant genes can result in different phenotypes in mice versus humans (69).

Many patients with clinical and laboratory evidence of primary immunodeficiency do not have a gene specific diagnosis. The use of next generation sequencing, particularly whole exome sequencing, has given us an extraordinarily powerful tool to identify the disease-causing genes in some of these patients. At least 34 new gene defects have been identified in the last 4 years. These findings document the striking heterogeneity of the phenotype in patients with mutations in the same gene. In some cases this can be attributed to loss-of-function mutations in some patients, but gain-of-function mutations in others. In addition, the surprisingly high frequency of autosomal dominant immunodeficiencies with variable penetrance, and de novo mutations in disorders with a severe phenotype has been unmasked.