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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Mol+Genet+Genomic+Med
2016 ; 4
(5
): 504-12
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Concordance between whole-exome sequencing and clinical Sanger sequencing:
implications for patient care
#MMPMID27652278
Hamilton A
; Tétreault M
; Dyment DA
; Zou R
; Kernohan K
; Geraghty MT
; Hartley T
; Boycott KM
Mol Genet Genomic Med
2016[Sep]; 4
(5
): 504-12
PMID27652278
show ga
The clinical translation of next-generation sequencing has created a paradigm
shift in the diagnostic assessment of individuals with suspected rare genetic
diseases. Whole-exome sequencing (WES) simultaneously examines the majority of
the coding portion of the genome and is rapidly becoming accepted as an efficient
alternative to clinical Sanger sequencing for diagnosing genetically
heterogeneous disorders. Among reports of the clinical and diagnostic utility of
WES, few studies to date have directly compared its concordance to Sanger
sequencing, which is considered the clinical "gold standard". We performed a
direct comparison of 391 coding and noncoding polymorphisms and variants of
unknown significance identified by clinical Sanger sequencing to the WES results
of 26 patients. Of the 150 well-covered coding variants identified by Sanger
sequencing, 146 (97.3%) were also reported by WES. Nine genes were excluded from
the comparison due to consistently low coverage in WES, which might be attributed
to the use of older exome capture kits. We performed confirmatory Sanger
sequencing of discordant variants; including five variants with discordant bases
and four with discordant zygosity. Confirmatory Sanger sequencing supported the
original Sanger report for three of the five discordant bases, one was shown to
be a false positive supporting the WES data, and one result differed from both
the Sanger and WES data. Two of the discordant zygosity results supported Sanger
and the other two supported WES data. We report high concordance for well-covered
coding variants, supporting the use of WES as a screening tool for heterogeneous
disorders, and recommend the use of supplementary Sanger sequencing for
poorly-covered genes when the clinical suspicion is high. Importantly, despite
remaining difficulties with achieving complete coverage of the whole exome, 10
(38.5%) of the 26 compared patients were diagnosed through WES.
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