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Clinical application of exome sequencing in undiagnosed genetic conditions

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Title: Clinical application of exome sequencing in undiagnosed genetic conditions
Authors: Need, AC
Shashi, V
Hitomi, Y
Schoch, K
Shianna, KV
McDonald, MT
Meisler, MH
Goldstein, DB
Item Type: Journal Article
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.
Issue Date: 11-May-2012
Date of Acceptance: 2-Apr-2012
URI: http://hdl.handle.net/10044/1/41671
DOI: http://dx.doi.org/10.1136/jmedgenet-2012-100819
ISSN: 1468-6244
Publisher: BMJ Publishing Group
Start Page: 353
End Page: 361
Journal / Book Title: Journal of Medical Genetics
Volume: 49
Issue: 6
Copyright Statement: 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.
Keywords: Adolescent
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Child, Preschool
Genetic Diseases, Inborn
Models, Genetic
Molecular Diagnostic Techniques
NAV1.2 Voltage-Gated Sodium Channel
Peptide-N4-(N-acetyl-beta-glucosaminyl) Asparagine Amidase
Sequence Analysis, DNA
Smad4 Protein
Transcription Factors
Genetics & Heredity
06 Biological Sciences
11 Medical And Health Sciences
Publication Status: Published
Appears in Collections:Department of Medicine (up to 2019)