title: Clinical application of exome sequencing in undiagnosed genetic conditions.
abstract: 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.
authors.affiliation: Center for Human Genome Variation, Duke University School of Medicine, Box 91009, Durham, NC 27708, USA. d.goldstein@duke.edu
authors.forename: Anna C
authors.initials: AC
authors.lastname: Need
authors.forename: Vandana
authors.initials: V
authors.lastname: Shashi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Hitomi
authors.forename: Kelly
authors.initials: K
authors.lastname: Schoch
authors.forename: Kevin V
authors.initials: KV
authors.lastname: Shianna
authors.forename: Marie T
authors.initials: MT
authors.lastname: McDonald
authors.forename: Miriam H
authors.initials: MH
authors.lastname: Meisler
authors.forename: David B
authors.initials: DB
authors.lastname: Goldstein
mesh_terms: D000293:Adolescent; D000328:Adult; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D059472:Exome; D005260:Female; D030342:Genetic Diseases, Inborn / Q000175:diagnosis* / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008957:Models, Genetic; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D009154:Mutation; D062551:NAV1.2 Voltage-Gated Sodium Channel / Q000235:genetics; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods*; D051901:Smad4 Protein / Q000235:genetics; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D062551:NAV1.2 Voltage-Gated Sodium Channel; C568251:SCN2A protein, human; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D043524:Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase