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Case-only exome sequencing and complex disease susceptibility gene discovery: study design considerations
  1. Lang Wu1,2,
  2. Daniel J Schaid1,
  3. Hugues Sicotte1,
  4. Eric D Wieben3,
  5. Hu Li4,
  6. Gloria M Petersen1
  1. 1Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  2. 2Center for Clinical and Translational Science, Mayo Clinic, Rochester, Minnesota, USA
  3. 3Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
  4. 4Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
  1. Correspondence to Dr Gloria M Petersen, Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA; Petersen.Gloria{at}


Whole exome sequencing (WES) provides an unprecedented opportunity to identify the potential aetiological role of rare functional variants in human complex diseases. Large-scale collaborations have generated germline WES data on patients with a number of diseases, especially cancer, but less often on healthy controls under the same sequencing procedures. These data can be a valuable resource for identifying new disease susceptibility loci if study designs are appropriately applied. This review describes suggested strategies and technical considerations when focusing on case-only study designs that use WES data in complex disease scenarios. These include variant filtering based on frequency and functionality, gene prioritisation, interrogation of different data types and targeted sequencing validation. We propose that if case-only WES designs were applied in an appropriate manner, new susceptibility genes containing rare variants for human complex diseases can be detected.

  • Complex traits
  • Genetic epidemiology
  • Genetics
  • Molecular genetics

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