Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas

McInerney-Leo, Aideen M., Marshall, Mhairi S., Gardiner, Brooke, Benn, Diana E., McFarlane, Janelle, Robinson, Bruce G., Brown, Matthew A., Leo, Paul J., Clifton-Bligh, Roderick J. and Duncan, Emma L. (2014) Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas. Clinical Endocrinology, 80 1: 25-33. doi:10.1111/cen.12331


 
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Author McInerney-Leo, Aideen M.
Marshall, Mhairi S.
Gardiner, Brooke
Benn, Diana E.
McFarlane, Janelle
Robinson, Bruce G.
Brown, Matthew A.
Leo, Paul J.
Clifton-Bligh, Roderick J.
Duncan, Emma L.
Title Whole exome sequencing is an efficient and sensitive method for detection of germline mutations in patients with phaeochromcytomas and paragangliomas
Journal name Clinical Endocrinology   Check publisher's open access policy
ISSN 0300-0664
1365-2265
Publication date 2014-01-01
Year available 2013
Sub-type Article (original research)
DOI 10.1111/cen.12331
Volume 80
Issue 1
Start page 25
End page 33
Total pages 9
Place of publication Chichester, West Sussex, United Kingdom
Publisher Wiley-Blackwell Publishing Ltd.
Language eng
Subject 2712 Endocrinology, Diabetes and Metabolism
Abstract Background Genetic testing is recommended when the probability of a disease-associated germline mutation exceeds 10%. Germline mutations are found in approximately 25% of individuals with phaeochromcytoma (PCC) or paraganglioma (PGL); however, genetic heterogeneity for PCC/PGL means many genes may require sequencing. A phenotype-directed iterative approach may limit costs but may also delay diagnosis, and will not detect mutations in genes not previously associated with PCC/PGL. Objective To assess whether whole exome sequencing (WES) was efficient and sensitive for mutation detection in PCC/PGL. Methods Whole exome sequencing was performed on blinded samples from eleven individuals with PCC/PGL and known mutations. Illumina TruSeq™ (Illumina Inc, San Diego, CA, USA) was used for exome capture of seven samples, and NimbleGen SeqCap EZ v3.0 (Roche NimbleGen Inc, Basel, Switzerland) for five samples (one sample was repeated). Massive parallel sequencing was performed on multiplexed samples. Sequencing data were called using Genome Analysis Toolkit and annotated using annovar. Data were assessed for coding variants in RET, NF1, VHL, SDHD, SDHB, SDHC, SDHA, SDHAF2, KIF1B, TMEM127, EGLN1 and MAX. Target capture of five exome capture platforms was compared. Results Six of seven mutations were detected using Illumina TruSeq™ exome capture. All five mutations were detected using NimbleGen SeqCap EZ v3.0 platform, including the mutation missed using Illumina TruSeq™ capture. Target capture for exons in known PCC/PGL genes differs substantially between platforms. Exome sequencing was inexpensive (<$A800 per sample for reagents) and rapid (results <5 weeks from sample reception). Conclusion Whole exome sequencing is sensitive, rapid and efficient for detection of PCC/PGL germline mutations. However, capture platform selection is critical to maximize sensitivity.
Q-Index Code C1
Q-Index Status Confirmed Code
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Document type: Journal Article
Sub-type: Article (original research)
Collections: UQ Centre for Clinical Research Publications
Official 2014 Collection
UQ Diamantina Institute Publications
 
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