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Clinical application of exome sequencing in undiagnosed genetic conditions.

Publication ,  Journal Article
Need, AC; Shashi, V; Hitomi, Y; Schoch, K; Shianna, KV; McDonald, MT; Meisler, MH; Goldstein, DB
Published in: J Med Genet
June 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.

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Published In

J Med Genet

DOI

EISSN

1468-6244

Publication Date

June 2012

Volume

49

Issue

6

Start / End Page

353 / 361

Location

England

Related Subject Headings

  • Transcription Factors
  • Transcription Factor 4
  • Smad4 Protein
  • Sequence Analysis, DNA
  • Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
  • NAV1.2 Voltage-Gated Sodium Channel
  • Mutation
  • Molecular Diagnostic Techniques
  • Models, Genetic
  • Male
 

Citation

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Need, A. C., Shashi, V., Hitomi, Y., Schoch, K., Shianna, K. V., McDonald, M. T., … Goldstein, D. B. (2012). Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet, 49(6), 353–361. https://doi.org/10.1136/jmedgenet-2012-100819
Need, Anna C., Vandana Shashi, Yuki Hitomi, Kelly Schoch, Kevin V. Shianna, Marie T. McDonald, Miriam H. Meisler, and David B. Goldstein. “Clinical application of exome sequencing in undiagnosed genetic conditions.J Med Genet 49, no. 6 (June 2012): 353–61. https://doi.org/10.1136/jmedgenet-2012-100819.
Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012 Jun;49(6):353–61.
Need, Anna C., et al. “Clinical application of exome sequencing in undiagnosed genetic conditions.J Med Genet, vol. 49, no. 6, June 2012, pp. 353–61. Pubmed, doi:10.1136/jmedgenet-2012-100819.
Need AC, Shashi V, Hitomi Y, Schoch K, Shianna KV, McDonald MT, Meisler MH, Goldstein DB. Clinical application of exome sequencing in undiagnosed genetic conditions. J Med Genet. 2012 Jun;49(6):353–361.

Published In

J Med Genet

DOI

EISSN

1468-6244

Publication Date

June 2012

Volume

49

Issue

6

Start / End Page

353 / 361

Location

England

Related Subject Headings

  • Transcription Factors
  • Transcription Factor 4
  • Smad4 Protein
  • Sequence Analysis, DNA
  • Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
  • NAV1.2 Voltage-Gated Sodium Channel
  • Mutation
  • Molecular Diagnostic Techniques
  • Models, Genetic
  • Male