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

ME Conley, JL Casanova - Current opinion in immunology, 2014 - Elsevier
Current opinion in immunology, 2014Elsevier
Highlights•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 …
Highlights
  • 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.
Elsevier