Use of Personalized Genomic Information

Abstract

Advances in deoxyribonucleic acid (DNA) sequencing technologies have driven down the cost of obtaining individualised genomic information, however, interested parties must consider the potential benefits and risks to the individual in applying this data to healthcare. Previously, the cost of genetic testing was such that it was used sparingly to query a small number of genes and only in cases in which there was a high pretest probability of a diagnostic result. It is now possible to receive whole‐genome data for similar costs. While technically feasible, our collective ability to interpret variation observed in the entire genome has not progressed as quickly as the technology. Currently, only a small fraction of observed variation in the human genome is interpretable with certainty. There exists a risk of over‐interpretation of variants of uncertain significance; therefore, individuals with interest in the personalised use of this information should seek consultation with clinical experts.

Key Concepts:

  • Personalised use of genomic information as a tool in clinical medicine is not a new concept; genomic information has long been used to guide patient care. Traditional clinical genetic and genomic testing has been used in selected patients for decades.

  • Advances in DNA sequencing technology, namely the advent of next generation sequencing techniques, have improved accuracy, decreased costs, and led to whole genome, whole exome, and multi‐gene panel sequencing as new offerings in clinical molecular testing; these new methods add to traditional approaches of Sanger sequencing, multiplex ligation‐dependent probe amplification (MLPA), array‐based chromosomal analysis and karyotype, among others.

  • While whole genome sequencing allows for rapid reading of an individual's entire genetic code, the analytic interpretation of this data has not yet met the speed and precision of the sequence acquisition.

  • Given the current state of technology, whole exome and whole genome sequencing will be best employed in a select subset of patients as a diagnostic test at this point in time.

  • Widespread application of whole genome sequencing in all patients will eventually be feasible, but at the current time application of these technologies could raise significant uncertainty, in the form of incidental findings, variants of uncertain significance and uninterpretable data. Targeted sequencing or targeted analysis of data can be used with currently available tools to provide useful diagnostic information in some individuals.

  • High definition clinical genomics (HDCG), where the detailed effects of any DNA sequence variant is understood at the individual nucleotide level, will be achieved sometime in this century and will lead to significantly greater utility in the use of genomic technologies to personalise health management.

Keywords: whole‐genome sequencing; whole exome sequencing; next‐generation sequencing; personalised medicine

References

Adzhubei I, Jordan DM and Sunyaev SR (2013) Predicting functional effect of human missense mutations using PolyPhen‐2. Current Protocols in Human Genetics 7. Chapter 7: Unit7.20. doi:10.1002/0471142905.hg0720s76.

Adzhubei IA, Schmidt S, Peshkin L et al. (2010) A method and server for predicting damaging missense mutations. Nature Methods 7(4): 248–249.

Ashley EA, Butte AJ, Wheeler MT et al. (2010) Clinical assessment incorporating a personal genome. Lancet 375(9725): 1525–1535.

Bainbridge MN, Wiszniewski W, Murdock DR et al. (2011) Whole‐genome sequencing for optimized patient management. Science Translational Medicine 3(87): 87re3. doi:10.1126/scitranslmed.3002243.

Bamshad MJ, Ng SB, Bigham AW et al. (2011) Exome sequencing as a tool for Mendelian disease gene discovery. Nature Reviews Genetics 12(11): 745–755.

Bilgüvar K, Oztürk AK, Louvi A et al. (2010) Whole‐exome sequencing identifies recessive WDR62 mutations in severe brain malformations. Nature 467(7312): 207–210.

Brownstein CA, Beggs AH, Homer N et al. (2014) An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. Genome Biology 15(3): R53. doi:10.1186/gb-2014-15-3-r53.

Coste B, Houge G, Murray MF et al. (2013) Gain‐of‐function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis. Proceedings of the National Academy of Sciences of the United States of America 110(12): 4667–4672.

Dave BJ and Sanger WG (2007) Role of cytogenetics and molecular cytogenetics in the diagnosis of genetic imbalances. Seminars in Pediatric Neurology 14(1): 2–6.

Green RC, Berg JS, Grody WW et al. (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in Medicine 15(7): 565–574.

Haack TB, Danhauser K, Haberberger B et al. (2010) Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nature Genetics 42(12): 1131–1134.

Hicks S, Wheeler DA, Plon SE, and Kimmel M (2011) Prediction of missense mutation functionality depends on both the algorithm and sequence alignment employed. Human Mutation 32: 661–668.

Kumar P, Henikoff S and Ng PC (2009) Predicting the effects of coding non‐synonymous variants on protein function using the SIFT algorithm. Nature Protocols 4(7): 1073–1081.

Lee C, Iafrate AJ and Brothman AR (2007) Copy number variations and clinical cytogenetic diagnosis of constitutional disorders. Nature Genetics 39(suppl. 7): S48–S54.

Lupski JR, Reid JG, Gonzaga‐Jauregui C et al. (2010) Whole‐genome sequencing in a patient with Charcot–Marie–Tooth neuropathy. New England Journal of Medicine 362(13): 1181–1191.

McKusick VA (2007) Mendelian inheritance in man and its online version OMIM. American Journal of Human Genetics 80: 588–607.

Musunuru K, Pirruccello JP, Do R et al. (2010) Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. New England Journal of Medicine 363(23): 2220–2227.

Ng PC and Henikoff S (2001) Predicting deleterious amino acid substitutions. Genome Research 12: 436–446.

Ng SB, Bigham AW, Buckingham KJ et al. (2010) Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nature Genetics 42(9): 790–793.

Ng SB, Buckingham KJ, Lee C et al. (2010a) Exome sequencing identifies the cause of a Mendelian disorder. Nature Genetics 42(1): 30–35.

Ng SB, Nickerson DA, Bamshad MJ, Shendure J (2010b) Massively parallel sequencing and rare disease. Human Molecular Genetics 19(R2): R119–R124.

Otto EA, Hurd TW, Airik R et al. (2010) Candidate exome capture identifies mutation of SDCCAG8 as the cause of a retinal‐renal ciliopathy. Nature Genetics 42(10): 840–850.

Ramensky V, Bork P and Sunyaev S (2002) Human non‐synonymous SNPs: server and survey. Nucleic Acids Research 30: 3894–3900.

Shendure J and Ji H (2008) Next‐generation DNA sequencing. Nature Biotechnology 26(10): 1135–1145.

St Hilaire C, Ziegler SG, Markello TC et al. (2011) NT5E mutations and arterial calcifications. New England Journal of Medicine 364(5): 432–442.

Vassy JL, Lautenbach DM, McLaughlin HM et al. (2014) The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine. Trials 15: 85. doi:10.1186/1745-6215-15-85.

Worthey EA, Mayer AN, Syverson GD et al. (2011) Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genetics in Medicine 13(3): 255–262.

Züchner S, Dallman J, Wen R et al. (2011) Whole‐exome sequencing links a variant in DHDDS to retinitis pigmentosa. American Journal of Human Genetics 88(2): 201–206.

Further Reading

Almasy L (2012) The role of phenotype in gene discovery in the whole genome sequencing era. Human Genetics 131(10): 1533–1540.

Cordero P and Ashley EA (2012) Whole‐genome sequencing in personalized therapeutics. Clinical Pharmacology and Therapeutics 91(6): 1001–1009.

Kingsmore SF and Saunders CJ (2011) Deep sequencing of patient genomes for disease diagnosis: when will it become routine? Science Translational Medicine 3(87): 87ps23. doi:10.1126/scitranslmed.3002695.

Ku CS, Naidoo N and Pawitan Y (2011) Revisiting Mendelian disorders through exome sequencing. Human Genetics 129(4): 351–370.

Murray MF (2014) Vascular Ehlers‐Danlos syndrome, pixels, and high‐definition clinical genomics. Genetics in Medicine. doi:10.1038/gim.2014.88 [Epub ahead of print].

Ng SB, Turner EH, Robertson PD et al. (2009) Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461(7261): 272–276. PMID: 19684571

Ormond KE, Wheeler MT, Hudgins L et al. (2010) Challenges in the clinical application of whole‐genome sequencing. Lancet 375(9727): 1749–1751.

Tabor HK, Berkman BE, Hull SC and Bamshad MJ (2011) Genomics really gets personal: how exome and whole genome sequencing challenge the ethical framework of human genetics research. American Journal of Medical Genetics Part A 155A(12): 2916–2924.

Tennessen, JA, Bigham, AW, O'Connor, TD et al. (2012) Evolution and functional impact of rare coding variation from deep sequencing of human exomes. Science 337: 64–69.

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Giovanni, Monica A, and Murray, Michael F(Nov 2014) Use of Personalized Genomic Information. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024126]