Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy

被引：117

作者：

Lupski, James R. ^{[1
,2
]}

Gonzaga-Jauregui, Claudia ^{[1
]}

Yang, Yaping ^{[3
]}

Bainbridge, Matthew N. ^{[2
]}

Jhangiani, Shalini ^{[2
]}

Buhay, Christian J. ^{[2
]}

Kovar, Christie L. ^{[2
]}

Wang, Min ^{[2
]}

Hawes, Alicia C. ^{[2
]}

Reid, Jeffrey G. ^{[2
]}

Eng, Christine ^{[3
]}

Muzny, Donna M. ^{[2
]}

Gibbs, Richard A. ^{[1
,2
]}

机构：

[1] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[2] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[3] Baylor Coll Med, Whole Genome Lab, MS NAB2015, Houston, TX 77030 USA

来源：

GENOME MEDICINE | 2013年 / 5卷

关键词：

Exome sequencing; Whole-genome sequencing; Incidental findings; SH3TC2; Personal genomes; Precision medicine; SHORT-READ; MUTATION; GENE; ADRENOLEUKODYSTROPHY; FORMAT;

D O I：

10.1186/gm461

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Background: The debate regarding the relative merits of whole genome sequencing (WGS) versus exome sequencing (ES) centers around comparative cost, average depth of coverage for each interrogated base, and their relative efficiency in the identification of medically actionable variants from the myriad of variants identified by each approach. Nevertheless, few genomes have been subjected to both WGS and ES, using multiple next generation sequencing platforms. In addition, no personal genome has been so extensively analyzed using DNA derived from peripheral blood as opposed to DNA from transformed cell lines that may either accumulate mutations during propagation or clonally expand mosaic variants during cell transformation and propagation. Methods: We investigated a genome that was studied previously by SOLiD chemistry using both ES and WGS, and now perform six independent ES assays (Illumina GAII (x2), Illumina HiSeq (x2), Life Technologies' Personal Genome Machine (PGM) and Proton), and one additional WGS (Illumina HiSeq). Results: We compared the variants identified by the different methods and provide insights into the differences among variants identified between ES runs in the same technology platform and among different sequencing technologies. We resolved the true genotypes of medically actionable variants identified in the proband through orthogonal experimental approaches. Furthermore, ES identified an additional SH3TC2 variant (p.M1?) that likely contributes to the phenotype in the proband. Conclusions: ES identified additional medically actionable variant calls and helped resolve ambiguous single nucleotide variants (SNV) documenting the power of increased depth of coverage of the captured targeted regions. Comparative analyses of WGS and ES reveal that pseudogenes and segmental duplications may explain some instances of apparent disease mutations in unaffected individuals.

引用

页数：17

共 24 条

[11] Human Genome Sequencing in Health and Disease [J].

Gonzaga-Jauregui, Claudia ;

Lupski, James R. ;

Gibbs, Richard A. .

ANNUAL REVIEW OF MEDICINE, VOL 63, 2012, 63 :35-61

[12] miRBase: tools for microRNA genomics [J].

Griffiths-Jones, Sam ;

Saini, Harpreet Kaur ;

van Dongen, Stijn ;

Enright, Anton J. .

NUCLEIC ACIDS RESEARCH, 2008, 36 :D154-D158

[13] Comparison of Three Targeted Enrichment Strategies on the SOLiD Sequencing Platform [J].

Hedges, Dale J. ;

Guettouche, Toumy ;

Yang, Shan ;

Bademci, Guney ;

Diaz, Ashley ;

Andersen, Ashley ;

Hulme, William F. ;

Linker, Sara ;

Mehta, Arpit ;

Edwards, Yvonne J. K. ;

Beecham, Gary W. ;

Martin, Eden R. ;

Pericak-Vance, Margaret A. ;

Zuchner, Stephan ;

Vance, Jeffery M. ;

Gilbert, John R. .

PLOS ONE, 2011, 6 (04)

[14] Fast and accurate short read alignment with Burrows-Wheeler transform [J].

Li, Heng ;

Durbin, Richard .

BIOINFORMATICS, 2009, 25 (14) :1754-1760

[15] Individual Genomes on the Horizon. [J].

Lifton, Richard P. .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 362 (13) :1235-1236

[16] Clan Genomics and the Complex Architecture of Human Disease [J].

Lupski, James R. ;

Belmont, John W. ;

Boerwinkle, Eric ;

Gibbs, Richard A. .

CELL, 2011, 147 (01) :32-43

[17] Whole-Genome Sequencing in a Patient with Charcot-Marie-Tooth Neuropathy. [J].

Lupski, James R. ;

Reid, Jeffrey G. ;

Gonzaga-Jauregui, Claudia ;

Deiros, David Rio ;

Chen, David C. Y. ;

Nazareth, Lynne ;

Bainbridge, Matthew ;

Dinh, Huyen ;

Jing, Chyn ;

Wheeler, David A. ;

McGuire, Amy L. ;

Zhang, Feng ;

Stankiewicz, Pawel ;

Halperin, John J. ;

Yang, Chengyong ;

Gehman, Curtis ;

Guo, Danwei ;

Irikat, Rola K. ;

Tom, Warren ;

Fantin, Nick J. ;

Muzny, Donna M. ;

Gibbs, Richard A. .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 362 (13) :1181-1191

[18] Sequence and structural variation in a human genome uncovered by short-read, massively parallel ligation sequencing using two-base encoding [J].

McKernan, Kevin Judd ;

Peckham, Heather E. ;

Costa, Gina L. ;

McLaughlin, Stephen F. ;

Fu, Yutao ;

Tsung, Eric F. ;

Clouser, Christopher R. ;

Duncan, Cisyla ;

Ichikawa, Jeffrey K. ;

Lee, Clarence C. ;

Zhang, Zheng ;

Ranade, Swati S. ;

Dimalanta, Eileen T. ;

Hyland, Fiona C. ;

Sokolsky, Tanya D. ;

Zhang, Lei ;

Sheridan, Andrew ;

Fu, Haoning ;

Hendrickson, Cynthia L. ;

Li, Bin ;

Kotler, Lev ;

Stuart, Jeremy R. ;

Malek, Joel A. ;

Manning, Jonathan M. ;

Antipova, Alena A. ;

Perez, Damon S. ;

Moore, Michael P. ;

Hayashibara, Kathleen C. ;

Lyons, Michael R. ;

Beaudoin, Robert E. ;

Coleman, Brittany E. ;

Laptewicz, Michael W. ;

Sannicandro, Adam E. ;

Rhodes, Michael D. ;

Gottimukkala, Rajesh K. ;

Yang, Shan ;

Bafna, Vineet ;

Bashir, Ali ;

MacBride, Andrew ;

Alkan, Can ;

Kidd, Jeffrey M. ;

Eichler, Evan E. ;

Reese, Martin G. ;

De la Vega, Francisco M. ;

Blanchard, Alan P. .

GENOME RESEARCH, 2009, 19 (09) :1527-1541

[19] An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People [J].

Nelson, Matthew R. ;

Wegmann, Daniel ;

Ehm, Margaret G. ;

Kessner, Darren ;

Jean, Pamela St. ;

Verzilli, Claudio ;

Shen, Judong ;

Tang, Zhengzheng ;

Bacanu, Silviu-Alin ;

Fraser, Dana ;

Warren, Liling ;

Aponte, Jennifer ;

Zawistowski, Matthew ;

Liu, Xiao ;

Zhang, Hao ;

Zhang, Yong ;

Li, Jun ;

Li, Yun ;

Li, Li ;

Woollard, Peter ;

Topp, Simon ;

Hall, Matthew D. ;

Nangle, Keith ;

Wang, Jun ;

Abecasis, Goncalo ;

Cardon, Lon R. ;

Zoellner, Sebastian ;

Whittaker, John C. ;

Chissoe, Stephanie L. ;

Novembre, John ;

Mooser, Vincent .

SCIENCE, 2012, 337 (6090) :100-104

[20]

Shroyer NF, 2001, INVEST OPHTH VIS SCI, V42, P2757

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