Gene hunting in the genomic era: approaches to diagnostic dilemmas in patients with primary immunodeficiencies

J Allergy Clin Immunol. 2014 Aug;134(2):262-8. doi: 10.1016/j.jaci.2013.08.021. Epub 2013 Oct 5.


There are more than 180 different genetic causes of primary immunodeficiencies identified to date. Approaches for identifying causative mutations can be broadly classified into 3 strategies: (1) educated guesses based on known signaling pathways essential for immune cell development and function, (2) similarity of clinical phenotypes to mouse models, and (3) unbiased genetic approaches. Next-generation DNA sequencing permits efficient sequencing of whole genomes or exomes but also requires strategies for filtering vast amounts of data. Recent studies have identified ways to solve difficult cases, such as diseases with autosomal dominant inheritance, incomplete penetrance, or mutations in noncoding regions. This review focuses on recently identified primary immunodeficiencies to illustrate the strategies, technologies, and potential pitfalls in finding novel causes of these diseases.

Keywords: Primary immunodeficiencies; homozygosity mapping; linkage analysis; whole-exome sequencing; whole-genome sequencing.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Exome
  • Gene Expression Regulation
  • Genetic Counseling
  • Genetic Linkage
  • Genomics / methods*
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunologic Deficiency Syndromes / diagnosis*
  • Immunologic Deficiency Syndromes / genetics*
  • Immunologic Deficiency Syndromes / pathology
  • Mice
  • Pedigree
  • Phenotype
  • Signal Transduction