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Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios

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Title: Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios
Authors: Zhu, X
Petrovski, S
Xie, P
Ruzzo, EK
Lu, Y-F
McSweeney, KM
Ben-Zeev, B
Nissenkorn, A
Anikster, Y
Oz-Levi, D
Dhindsa, RS
Hitomi, Y
Schoch, K
Spillmann, RC
Heimer, G
Marek-Yagel, D
Tzadok, M
Han, Y
Worley, G
Goldstein, J
Jiang, Y-H
Lancet, D
Pras, E
Shashi, V
McHale, D
Need, AC
Goldstein, DB
Item Type: Journal Article
Abstract: Purpose: Despite the recognized clinical value of exome-based diagnostics, methods for comprehensive genomic interpretation remain immature. Diagnoses are based on known or presumed pathogenic variants in genes already associated with a similar phenotype. Here, we extend this paradigm by evaluating novel bioinformatics approaches to aid identification of new gene–disease associations. Methods: We analyzed 119 trios to identify both diagnostic genotypes in known genes and candidate genotypes in novel genes. We considered qualifying genotypes based on their population frequency and in silico predicted effects we also characterized the patterns of genotypes enriched among this collection of patients. Results: We obtained a genetic diagnosis for 29 (24%) of our patients. We showed that patients carried an excess of damaging de novo mutations in intolerant genes, particularly those shown to be essential in mice (P = 3.4 × 10−8). This enrichment is only partially explained by mutations found in known disease-causing genes. Conclusion: This work indicates that the application of appropriate bioinformatics analyses to clinical sequence data can also help implicate novel disease genes and suggest expanded phenotypes for known disease genes. These analyses further suggest that some cases resolved by whole-exome sequencing will have direct therapeutic implications.
Issue Date: 15-Jan-2015
Date of Acceptance: 19-Nov-2014
URI: http://hdl.handle.net/10044/1/38939
DOI: https://dx.doi.org/10.1038/gim.2014.191
ISSN: 1530-0366
Publisher: Nature Publishing Group
Start Page: 774
End Page: 781
Journal / Book Title: Genetics in Medicine
Volume: 17
Issue: 10
Copyright Statement: © 2014 The Authors. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
Keywords: Science & Technology
Life Sciences & Biomedicine
Genetics & Heredity
genic intolerance
rare disease
whole-exome sequencing
Computational Biology
Genetic Association Studies
Genetic Diseases, Inborn
High-Throughput Nucleotide Sequencing
0604 Genetics
1103 Clinical Sciences
Publication Status: Published
Appears in Collections:Department of Medicine (up to 2019)