J Med Genet 49:353-361 doi:10.1136/jmedgenet-2012-100819
  • New disease loci
  • Original article

Clinical application of exome sequencing in undiagnosed genetic conditions

Open AccessEditor's Choice
  1. David B Goldstein1,4
  1. 1Center for Human Genome Variation and Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA
  2. 2Department of Pediatrics, Section of Medical Genetics, Duke University, Durham, North Carolina, USA
  3. 3Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA
  4. 4Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA
  1. Correspondence to Dr David Goldstein, Center for Human Genome Variation, Duke University School of Medicine, Box 91009, Durham, NC 27708, USA; d.goldstein{at}
  1. Contributors AN: study design, data analysis and interpretation and manuscript writing. VS: patient recruitment and counselling, clinical follow-up, study design, data interpretation and manuscript writing. YH: laboratory follow-up of candidate variants, data interpretation, manuscript writing and figures. KSchoch: patient recruitment and counselling, clinical follow-up, data interpretation and manuscript writing. KShianna: sample preparation, genotyping and genotyping quality control and manuscript writing. MHM: data interpretation, figures and writing. DBG: study design, data interpretation and manuscript writing. MTM: patient selection.

  • Received 10 February 2012
  • Revised 14 March 2012
  • Accepted 2 April 2012
  • Published Online First 11 May 2012


Background There is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations.

Methods The authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met.

Results This undertaking resulted in a likely genetic diagnosis in 6 of the 12 probands, including the identification of apparently causal mutations in four genes known to cause Mendelian disease (TCF4, EFTUD2, SCN2A and SMAD4) and one gene related to known Mendelian disease genes (NGLY1). Of particular interest is that at the time of this study, EFTUD2 was not yet known as a Mendelian disease gene but was nominated as a likely cause based on the observation of de novo mutations in two unrelated probands. In a seventh case with multiple disparate clinical features, the authors were able to identify homozygous mutations in EFEMP1 as a likely cause for macular degeneration (though likely not for other features).

Conclusions This study provides evidence that next-generation sequencing can have high success rates in a clinical setting, but also highlights key challenges. It further suggests that the presentation of known Mendelian conditions may be considerably broader than currently recognised.


  • AN and VS contributed equally to this work.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was granted by the Duke University Institutional Review Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Inquiries from scientists/clinicians about specific variants, variants in specific genes, or putatively pathogenic groups of variants (eg, rare recessive) should be addressed to the corresponding author and information will be provided in compliance with the signed consents of the participating families.

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits use, distribution, and reproduction in any medium, provided the original work is properly cited, the use is non commercial and is otherwise in compliance with the license. See: and