Reference library

Developments in clinical genomics

Over the past 15 years there have been huge leaps in our understanding of the human genome, the information it encodes, and the biology that underpins disease.  Much of this scientific advance has been enabled by new sequencing technologies, which can ‘read’ a person’s entire genome in days, rather than years. These technologies also offer the potential to use personal genomic information to diagnose genetic disease, to categorise complex disease, and to guide medical treatment.

The purpose of this library is to provide an up-to-date resource of key advances and milestones in genomic medicine. The resources have been divided into two sections under the following topics:

I. Science, Technology and clinical practice of genomic medicine

  1. International reports and perspectives
  2. Australian reports and perspectives
  3. Clinical sequencing
  4. Practices and policies of clinical sequencing
  5. Australian reports and guidance
  6. Case studies
  7. Pharmacogenomics
  8. New technologies
  9. Coverage and variant detection sensitivity
  10. Other applications of clinical and population genomics
  11. Original human genome sequencing papers
  12. Useful links and data

II. Ethical, social and legal issues (ELSI) of genomic medicine

  1. Guidelines
  2. Disclosing results and incidental findings
  3. Communicating genomic information and DNA-based disease risk
  4. Privacy and data sharing
  5. Australian legislation and guidelines
  6. Genome economics

I. Science, Technology and clinical practice of genomic medicine

1. International reports and perspectives

The Academy of Medical Sciences (2013). Realising the potential of stratified medicineLondon: The Academy of Medical Sciences, July 2013.

American Society of Clinical Oncology (2011). Accelerating progress against cancer: ASCO's Blueprint for Transforming Clinical and Translational Cancer Research. ASCO: November 2011.

House of Lords Science and Technology Committee (2009). Genomic Medicine 2009 Report. 1:1-127.

Human Genomics Strategy Group (2012). Building on our inheritance: Genomic technology in healthcare. UK Department of Health; 2012.

Wright C et al (2011). Next steps in the sequence: the implications of whole genome sequencing for health in the UK. PHG Foundation: 2011.

Green EDGuyer MSNational Human Genome Research Institute (2011). Charting a course for genomic medicine from base pairs to bedsideNature Feb 10;470(7333):204-13. [SUBSCRIBERS ONLY]

2. Australian perspectives

Doble B et al (2016). The promise of personalised medicine. Lancet 387:433-4.

Winship I and Smith T (2015). Precision medicine offers the hope of cures made just for you. The Conversation.

Bauer DC et al. Genomics and personalised whole-of-life healthcare. Trends in Molecular Medicine 20:479-86. [SUBSCRIBERS ONLY]

Mattick JS et al (2014). The impact of genomics on the future of medicine and health. The Medical Journal of Australia 201:17-20.

3. Clinical sequencing

Green RC et al. (2016). Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic MedicineAm J Hum Genet Jun 2;98(6):1051-66.

Mallawaarachchi AC, Hort Y, Cowley MJ, McCabe MJ, Minoche A, Dinger M, Shine J, Furlong TJ (2016). Whole-genome sequencing overcomes pseudogene homology to diagnose autosomal dominant polycystic kidney diseaseEur J Hum Genet May [SUBSCRIBERS ONLY]

Beck TF et al (2016).  Systematic Evaluation of Sanger Validation of NextGen Sequencing VariantsClin Chem 62:647-654. [SUBSCRIBERS ONLY]

Delaney SK et al (2016). Toward clinical genomics in everyday medicine: perspectives and recommendationsExp Rev Mol Diagn 24:1-12.  [OPEN ACCESS]

Vassy JL, Korf BR, Green RC (2015). How to know when physicians are ready for genomic medicineSci Trans Med 7:287fs19.  [OPEN ACCESS]

Stark Z et al (2016). A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med March [SUBSCRIBERS ONLY]

Uzilov AV, Ding W, Fink MY, et al. (2016). Development and clinical application of an integrative genomic approach to personalized cancer therapy. Genome Med 8:62.

Turner TN, Hormozdiari F, Duyzend MH, McClymont SA, Hook PW, et al (2016). Genome Sequencing of Autism-Affected Families Reveals Disruption of Putative Noncoding Regulatory DNAAm J Hum Genet Jan 7;98(1):58-74. [SUBSCRIBERS ONLY]

Burke W and Korngiebel DM (2015). Closing the Gap Between Knowledge and Clinical Application: Challenges for Genomic TranslationPLoS Genetics 11:e1004978.  [OPEN ACCESS]

Taylor JC, Martin HC, Lise S, Broxholme J, Cazier JB, Rimmer A, et al (2015). Factors influencing success of clinical genome sequencing across a broad spectrum of disordersNat Genet 47:717-26. 

Topol EJ (2014). Individualized Medicine from Pre-womb to TombCell 157:241-53. [SUBSCRIBERS ONLY]

Soden SESaunders CJWillig LKFarrow EGSmith LDPetrikin JE (2014). Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disordersSci Transl Med 6:265ra168.

Gilissen C et al (2014). Genome sequencing identifies major causes of severe intellectual disability. Nature 511:344-7. [SUBSCRIBERS ONLY]

Priest JR, Ceresnak SR, Dewey FE, Malloy-Walton LE, Dunn K, Grove ME, Perez MV, Maeda K, Dubin AM, Ashley E (2014). Molecular diagnosis of long QT syndrome at 10 days of life by rapid whole genome sequencingHeart Rhythm 11:1707-13. 

Vassy JL, Lautenbach DM, McLaughlin HM, et al. (2014). The MedSeq Project: a randomized trial of integrating whole genome sequencing into clinical medicine. Trials Mar 20;15:85.

McLaughlin HM et al (2014). A systematic approach to the reporting of medically relevant findings from whole genome sequencing. BMC Med Genet 15:134.

A 'primer' for doctors about clinical genome and exome sequencing
Biesecker LG and Green RC (2014). Diagnostic Clinical Genome and Exome Sequencing. New England Journal of Medicine 370:2418-25. [SUBSCRIBERS ONLY]

Dewey FE et al (2014). Clinical interpretation and implications of whole-genome sequencing. JAMA 311:1035-45. [SUBSCRIBERS ONLY]

Luheshi L. and Raza S (2014). Clinical whole genome analysis: delivering the right diagnosis. PHG Foundation: 2014.

Shashi V et al (2014). The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. Genet Med. 16:176-82. [SUBSCRIBERS ONLY]

Tyner JW (2014). Functional genomics for personalized cancer therapy. Science Translational Medicine 6:243fs26. [SUBSCRIBERS ONLY]

Jiang YH et al (2013). Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencingAm J Hum Genet Aug 8;93(2):249-63. [OPEN ACCESS]

Yang Y et al (2013). Clinical Whole-Exome Sequencing for the Diagnosis of Mendelian DisordersNew England Journal of Medicine 369:1502-11.

Wagle N et al (2012). High-Throughput Detection of Actionable Genomic Alterations in Clinical Tumor Samples by Targeted, Massively Parallel Sequencing. Cancer Discovery 2:82-93.

Green ED, Guyer MS (2011). Charting a course for genomic medicine from base pairs to bedsideNature 470:204-213. [SUBSCRIBERS ONLY]

Lupski JR et al (2010). Whole-genome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med 362:1181-91. 

4. Practices and policies of clinical sequencing

Baudhuin LM, Funke BH, Bean LH, Deignan JL, Hofherr S, Miller DT, Nagan N, Santani A, Saunders C (2016). Classifying Germline Sequence Variants in the Era of Next-Generation SequencingClin Chem Jun;62(6):799-806. [OPEN ACCESS]

ACMG Board of Directors (2015). Clinical utility of genetic and genomic services: a position statement of the American College of Medical Genetics and Genomics. Genetics in Medicine 17:505-507 [SUBSCRIBERS ONLY]

Caulfield T et al (2015). Reflections on the cost of "low-cost" whole genome sequencing: framing the health policy debate. PLOS Biology 11:e1001699.

An evaluation of the practicies and policies of exome/whole genome sequencing providers in the US
Jamal SM et al (2013). Practices and policies of clinical exome sequencing providers: analysis and implications. American Journal of Medical Genetics Part A. 161a:935-50.

Schrijver I et al (2012). Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology. Journal of Molecular Diagnostics 14:525-40.

van El CG et al (2013). Whole-genome sequencing in health care: recommendations of the European Society of Human Genetics. Eur J Hum Genet 21:580-4.

5. Australian reports and guidance

Deloitte Economics (2008). Improving the Quality Use of Medicines in Australia: Realising the Potential of Pharmacogenomics: Australian Centre for Health Research.

National Health and Medical Research Council (2012). Direct-to-Consumer DNA Genetic Testing: An information resource for consumers. (PS0004). Australian Government.

National Health and Medical Research Council (2011). Clinical Utility of Personalised Medicine. (PS0001). Australian Government.

National Health and Medical Research Council (2010). Medical Genetic Testing: information for health professionals. (E99). Australian Government.

6. Case studies

Genome sequencing to determine cancer therapy 
Yatabe Y (2014). Era of Comprehensive Cancer Genome Analyses. JCO 32:4029-30 [SUSBCRIBERS ONLY]

Whole genome sequencing of twins’ DNA to diagnose a rare genetic disorder, which then led to a successful change in treatment
Bainbridge MN et al (2011). Whole-Genome Sequencing for Optimized Patient Management. Science Translational Medicine 3: 87re83
See also: Check Hayden E (2011). Genome study solves twins' mystery condition. Nature 15 June 2011.

Taft RJ et al (2013) Mutations in DARS Cause Hypomyelination with Brain Stem and Spinal Cord Involvement and Leg Spasticity. Am J Hum Genet 92:774-80.

See also: Cracking the Code.

Comprehensive genomic and medical analysis of an individual
Chen R et al (2012). Personal Omics Profiling Reveals Dynamic Molecular and Medical Phenotypes. Cell 148:1293-1307.
See also: Conger K (2012). Revolution in personalized medicine: First-ever integrative 'omics' profile lets scientist discover, track his diabetes onset. Inside Stanford Medicine March 15, 2012.

Successive targeted therapies for an individual's cancer
Jones SJ et al (2010). Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors. Genome Biology 11:R82.
See also: Lusky K. Cancer genomics: the exception now, but semi-routine soon? CAP Today: College of American Pathologists: June 2011.

Whole genome sequencing of a researcher to understand his genetic disorder
Lupski JR et al (2010). Whole-Genome Sequencing in a Patient with Charcot–Marie–Tooth Neuropathy. New England Journal of Medicine 362:1181-1191.

Multi-gene assay to predict patient prognosis
Onken MD et al (2012). Collaborative Ocular Oncology Group Report Number 1: Prospective Validation of a Multi-Gene Prognostic Assay in Uveal Melanoma. Ophthalmology 119:1596-1603. [SUBSCRIBERS ONLY]
See also
Kolata G (2012). A Life-Death Predictor Adds to a Cancer's Strain. New York Times 10 July 2012.

A proof-of-principle paper showing that rapid (50-hour) genome sequencing processes could provide useful information for monogenic disease diagnosis
Saunders CJ  et al (2012). Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Science Translational Medicine 4:154ra35. [FREE WITH REGISTRATION]

Genome sequencing that clarified diagnosis and guided therapy
Welch JS et al (2011). Use of whole-genome sequencing to diagnose a cryptic fusion oncogene. JAMA 305:1577-1584.
See also:
Maher B (2011). Human genetics: Genomes on prescription. Nature 478:22-24.

Genome sequencing for undiagnosed disease
Worthey EA 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 13:255-262.

See also: Johnson M, Gallagher K. One in a Billion: A Boy's Life, A Medical Mystery. JSOnline: Milkwaukee Wisconsin Journal Sentinel December 25, 2010.

7. Pharmacogenomics

A description of the practice and evidence supporting pharmacogenomic testing
Sheffield LJ, Phillimore HE (2009). Clinical use of pharmacogenomic tests in 2009. Clin Biochem Rev 30:55-65.

Harper AR, Topol EJ (2012). Pharmacogenomics in clinical practice and drug development. Nature Biotechnology 30:1117-1124.

Bielinski SJ et al (2014). Preemptive genotyping for personalized medicine: design of the right drug, right dose, right time-using genomic data to individualize treatment protocol. Mayo Clinic Proceedings 89:25-33.

8. New technologies

Lo YM and Chiu RW (2011). Plasma nucleic acid analysis by massively parallel sequencing: pathological insights and diagnostic implications. Journal of Pathology 225:318-23. [SUBSCRIBERS ONLY]

Kitzman et al (2012). Noninvasive whole-genome sequencing of a human fetus. Science Translational Medicine 4:137ra76.

9. Coverage and variant detection sensitivity

Lelieveld SHSpielmann MMundlos SVeltman JAGilissen C (2015)Comparison of Exome and Genome Sequencing Technologies for the Complete Capture of Protein-Coding Regions. Hum Mut Aug;36:815-22.

Meynert AM, Ansari M, FitzPatrick DR, Taylor MS (2014). Variant detection sensitivity and biases in whole genome and exome sequencingBMC Bioinformatics 15:247.

Herdewyn S et al (2012). Whole-genome se se of amyotrophic lateral sclerosisHum Mol Genet 21:2412-9.

10. Other applications of clinical and population genomics

Kohane IS (2011). Using electronic health records to drive discovery in disease genomics. Nature Reviews Genetics 12:417-28. [SUBSCRIBERS ONLY]

Genome of the Netherlands Consortium (2014). Whole-genome sequence variation, population structure and demographic history of the Dutch population. Nature Genetics 46:818-25. [SUBSCRIBERS ONLY]

11. Original human genome sequencing papers

Papers arising from the announcement of the completion of the draft Human Genome. The ‘public’ genome project published in Nature, the private company genome in Science.
International Human Genome Sequencing Consortium (2001). Initial sequencing and analysis of the human genome. Nature 409:860-921.
Venter JC et al (2001). The Sequence of the Human Genome. Science 291:1304-1351.

The sequence of entrepreneur researcher J Craig Venter
Levy S et al (2007). The Diploid Genome Sequence of an Individual Human. PLoS Biology 5:e254.

The sequence of Nobel laureate James D Watson
Wheeler DA et al (2008). The complete genome of an individual by massively parallel DNA sequencing. Nature 452:872-876.

Sequences of individuals representing key global populations and consortia mapping global genetic variation:

Wang J et al (2008). The diploid genome sequence of an Asian individual. Nature 456:60-65.

Schuster SC et al (2010). Complete Khoisan and Bantu genomes from southern Africa. Nature 463:943-947.

The 1000 Genomes Project Consortium (2012). An integrated map of genetic variation from 1,092 human genomes. Nature 491:56-65.

12. Useful links and data

A listing of genetic tests and laboratories in Australia
Royal College of Pathologists of Australia (2009). RCPA Catalogue of Genetic Tests and Laboratories. RCPA: 2009.

Sequencing costs, as tracked by the National Human Genome Research Institute, USA.
Wetterstrand KA. (2014)  DNA Sequencing Costs: Data from the NHGRI Genome Sequencing Program (GSP). Revised July 2014. 

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II. Ethical, social and legal issues (ELSI)

 1. Guidelines

Bowdin et al. Recommendations for the integration of genomics into clinical practice. Genetics in Medicine.

Ormond KE and Cho MK (2014). Translating personalized medicine using new genetic technologies in clinical practice: the ethical issues. Per Med 11:211-22.

Clarke AJ (2014). Managing the ethical challenges of next-generation sequencing in genomic medicine. British Medical Bulletin. [SUBSCRIBERS ONLY]

Dondorp WJ, de Wert GM (2013). The 'thousand-dollar genome': an ethical exploration. Eur J Hum Genet 21 Suppl 1:S6-26.

Sanderson SC (2013). Genome sequencing for healthy individuals. Trends in Genetics 29:556-8.

2. Disclosing results and incidental findings

Biesecker LG (2014). Incidental variants are critical for genomics. American Journal for Human Genetics 92:648-651.

Van Driest SL et al (2016). Association of Arrythmia-Related Genetic Variants With Phenotypes Documented in Electronic Medical Records. JAMA. 315:47-57. [SUBSCRIBERS ONLY]

Jarvik G et al (2014). Return of genomic results to research participants: The floor, the ceiling, and the choices in betweenAm J Hum Genet 94:818–826.

Hedge M et al (2015). Reporting Incidental Findings in Genomic Scale Clinical Sequencing - A Clinical Laboratory Perspective: A Report of the Association for Molecular Pathology. J Mol Diagn 17:107-117.

Jurgens J et al (2015). Assessment of incidental findings in 232 whole-exome sequences from the Baylor-Hopkins Centre for Mendelian Genomics. Genetics in Medicine 17:782-788

Dorschner M et al (2013). Actionable, Pathogenic, Incidental Findings in 1,000 Participants' Exomes. Am J Hum Genet 93:631-40. 

Brandt DS et al (2013). A closer look at the recommended criteria for disclosing genetic results: perspectives of medical genetic specialists, genomic researchers, and institutional review board chairs. J Genet Couns 22:544-53. [SUBSCRIBERS ONLY]

In 2013, the American College of Medical Genetics and Genomics released its recommendations for doctors about disclosure of ‘incidental findings’ – genetic results that are unrelated to the condition for which the testing took place. These guidelines have been hotly debated and have sparked international policy responses.

Green RC et al (2013). ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genetics in Medicine 15:565-74.

The authors have since clarified their stance in a Nature paper and updated their recommendations to enable individual patients to opt out of receiving ‘medically actionable’ results.

A response from UK researchers to the ACMG guidelines:
Wright CF et al (2013). Policy challenges of clinical genome sequencing BMJ 347:f6845.
See also: Genomes Unzipped blog post.

Presidential Commission for the Study of Bioethical Issues (2013). ANTICIPATE and COMMUNICATE: Ethical Management of Incidental and Secondary Findings in the Clinical, Research, and Direct-to-Consumer Contexts. Washington, D.C., December 2013.

3. Communicating genomic information and DNA-based disease risk

Wilkinson D et al (2015). Genomic intensive care: should we perform genome testing in critically ill newborns? Arch Dis Child Fetal Neonatal Ed.

Johns AL et al (2014). Returning individual research results for genome sequences of pancreatic cancer. Genome Medicine 6:42.

Marteau TM et al (2010). Effects of communicating DNA-based disease risk estimates on risk-reducing behaviours. Cochrane Database of Systematic Reviews 10:CD007275.

4. Privacy and data sharing

A Global Alliance for Genomics and Health (2013). Creating a Global Alliance to enable responsible sharing of genomic and clinical data. GA4GH June 2013.

Ball M et al (2014). Harvard Personal Genome Project: lessons from participatory public research. Genome Medicine 6:1-7.

Presidential Commission for the Study of Bioethical Issues (2012). PRIVACY and PROGRESS in Whole Genome Sequencing. Washington D.C October 2012.

5. Australian legislation and guidelines

Australian Law Reform Commission (2003). Essentially Yours: The Protection of Human Genetic Information in Australia (ALRC Report 96). Australian Government.

National Health and Medical Research Council (2014). Genetics and Human Health. Australian Government.

Human Genetics Society of Australasia (2013). Position Statement: Genetic Testing and Life Insurance in Australia. Human Genetics Society of Australasia.

Centre for Genetics Education (2016). Fact Sheet 20: Life Insurance Products and Genetic Testing in Australia. NSW Health.

Standard adopted by members of the life insurance business in Australia.
The Financial Services Council (FSC) (2005). Standard 11. Genetic testing policy. The Financial Services Council.

6. Genome economics

Battelle Technology Partnership (2013). The impact of genomics on the US economy. United for Medical Research (UMR) June 2013.