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. 2017:2:8.
doi: 10.1038/s41525-017-0011-x. Epub 2017 Mar 28.

Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer

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Pitfalls of exome sequencing: a case study of the attribution of HABP2 rs7080536 in familial non-medullary thyroid cancer

Glenn S Gerhard et al. NPJ Genom Med. 2017.

Abstract

Next-generation sequencing using exome capture is a common approach used for analysis of familial cancer syndromes. Despite the development of robust computational algorithms, the accrued experience of analyzing exome data sets and published guidelines, the analytical process remains an ad hoc series of important decisions and interpretations that require significant oversight. Processes and tools used for sequence data generation have matured and are standardized to a significant degree. For the remainder of the analytical pipeline, however, the results can be highly dependent on the choices made and careful review of results. We used primary exome sequence data, generously provided by the corresponding author, from a family with highly penetrant familial non-medullary thyroid cancer reported to be caused by HABP2 rs7080536 to review the importance of several key steps in the application of exome sequencing for discovery of new familial cancer genes. Differences in allele frequencies across populations, probabilities of familial segregation, functional impact predictions, corroborating biological support, and inconsistent replication studies can play major roles in influencing interpretation of results. In the case of HABP2 rs7080536 and familial non-medullary thyroid cancer, these factors led to the conclusion of an association that most data and our re-analysis fail to support, although larger studies from diverse populations will be needed to definitively determine its role.

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Conflict of interest statement

COMPETING INTERESTS The authors declare no competing interests.

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References

    1. Boycott KM, Vanstone MR, Bulman DE, MacKenzie AE. Rare-disease genetics in the era of next-generation sequencing: discovery to translation. Nat. Rev. Genet. 2013;14:681–691. doi: 10.1038/nrg3555. - DOI - PubMed
    1. Ku CS, et al. Exome sequencing: dual role as a discovery and diagnostic tool. Ann. Neurol. 2012;71:5–14. doi: 10.1002/ana.22647. - DOI - PubMed
    1. Esteban-Jurado C, et al. New genes emerging for colorectal cancer predisposition. World J. Gastroenterol. 2014;20:1961–1971. doi: 10.3748/wjg.v20.i8.1961. - DOI - PMC - PubMed
    1. Yang Y, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N. Eng. J. Med. 2013;369:1502–1511. doi: 10.1056/NEJMoa1306555. - DOI - PMC - PubMed
    1. Gahl WA, et al. The National Institutes of Health undiagnosed diseases program: insights into rare diseases. Genet. Med. 2012;14:51–59. doi: 10.1038/gim.0b013e318232a005. - DOI - PMC - PubMed

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