The first article citing Bertrand's genetic condition was just published in the Journal of Medical Genetics! Our family (Bertrand, Cristina, and Matt) comprises Trio 2. This article (PDF) was published under the Creative Commons License, so please spread the word about this fantastic study. :)
Clinical application of exome sequencing in undiagnosed genetic conditions
- Anna C Need1,
- Vandana Shashi2,
- Yuki Hitomi1,
- Kelly Schoch2,
- Kevin V Shianna1,
- Marie T McDonald2,
- Miriam H Meisler3,
- David B Goldstein1,4
+Author Affiliations
- Correspondence toDr David Goldstein, Center for Human Genome Variation, Duke University School of Medicine, Box 91009, Durham, NC 27708, USA; d.goldstein@duke.edu
- 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
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.
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: http://creativecommons.org/licenses/by-nc/2.0/ andhttp://creativecommons.org/licenses/by-nc/2.0/legalcode.
We will tell our neurologist! Congratulations Bertrand and family! Kisses from Argentina, Iara.
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