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

TitleExome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot-Marie-Tooth neuropathy.
Publication TypeJournal Article
Year of Publication2013
AuthorsLupski, JR, Gonzaga-Jauregui, C, Yang, Y, Bainbridge, MN, Jhangiani, S, Buhay, CJ, Kovar, CL, Wang, M, Hawes, AC, Reid, JG, Eng, CM, Muzny, DM, Gibbs, RA
JournalGenome Med
Volume5
Issue6
Pagination57
Date Published2013
Abstract

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.

DOI10.1186/gm461
Alternate JournalGenome Med
PubMed ID23806086
PubMed Central IDPMC3706849
Grant ListU54 HG003273 / HG / NHGRI NIH HHS / United States
U54 HG006542 / HG / NHGRI NIH HHS / United States