The Future of Genetic Medicine

Educational Objectives

The goal of this program is to improve prenatal and postnatal genetic screening. After hearing and assimilating this program, the clinician will be better able to:

1. Differentiate between whole genome sequencing and whole exome sequencing.

2. Explain single-molecule real-time sequencing.

3. Weigh the possible risks and benefits associated with direct-to-consumer genetic testing.

Summary

Clinical genetics: limited availability — ≈1500 geneticists certified by American Board of Medical Genetics and Genomics (<1000 in clinical practice); decreasing numbers of students entering field of genetics; genetic counselors playing increasingly important role; increased opportunity — new technologies with interesting clinical problems and varied consultations; genetic issues increasingly addressed by primary care providers because clinical geneticists not available; evolution of clinical genetics — <100 yr ago, number of human chromosomes undetermined; modern gene sequencing available for ≈40 yr; clinically based DNA sequencing available over past 15 to 20 yr

Human Genome Project (HGP): sequencing initially expensive (≈$1 per base pair); by 1999, cost had dropped to $13,000 per megabase; tools necessary to complete HGP not available at inception; development of shotgun sequencing allowed project to finish 2 yr ahead of deadline (April 2003); shotgun sequencing — short, random fragments (instead of long fragments) sequenced in parallel to create multiple, overlapping, short strands of DNA; information-handling technology performs multiple reads of overlapping segments to create continuous sequence; technique requires greater computer-processing power compared with old methods; Moore’s law — estimates computing power and computing cost; observed processing power doubled and cost halved every 12 to 24 mo until 2012; cost of sequencing mirrored Moore’s law until 2008, then decreased significantly per megabase (7 cents) and per genome

Next-generation sequencing: encompasses innovative methods used for DNA sequencing (ie, high-throughput, parallel sequencing); began in 1980s with automated sequencers; pyrosequencing available in 1996; used for research in mid-2000s, followed by integration into clinical practice; by 2008, multiple vendors and technologies available

Whole genome sequencing (WGS): cost — HGP ≈$2.7 billion over 13 yr; first human sequenced for $100 million; WGS currently available for ≈$1500 (raw data); expense previously related to sequencing process (now human interpretation of data)

Whole exome sequencing (WES): exome represents coding regions of genes; constitutes small percentage of entire genome; 85% of mutations occur within entire exome; costs dropped significantly, but less expensive WES may not represent whole exome (ie, “you get what you pay for”) and does not include interpretation of data; clinical WES — not routinely performed currently; consider in patient if genetic condition strongly suspected but undiagnosed or tests negative; test each parent along with patient (helps identify benign familial variations); limitations of WES — whole exome accounts for only 85% to 90% of entire coding region; mutations in noncoding regions can be important for disease; genetic information extremely variable and not well understood

Kabuki syndrome: characterized by short stature, intellectual impairment, craniofacial changes, and skeletal and cardiac abnormalities; etiology undetermined until ≈2006; etiology — data from WES of patients with similar abnormalities collected and analyzed; data compared with exome databases of healthy controls; candidate gene mutations decreased from >1000 to 25; Ng et al (2010) identified MLL2 (now KMT2D) mutation as cause of most cases of Kabuki syndrome

Proteus syndrome: characterized by overgrowth of tissue; easy to diagnose but difficult to identify etiology if not present in blood; etiology — activating changes of AKT1 identified in samples taken from overgrown skin

Emerging technology: next-next-generation sequencing — third-generation sequencing technology increases throughput and speed (and may reduce cost); single-molecule real-time sequencing — looks at sequencing of individual strands; detects epigenetic changes (eg, methylation) that alter gene expression; nanopore DNA sequencing — place sample in reservoir and plug device into computer via USB; sequence obtained for small amounts of DNA

Direct-to-consumer technology: defined as genetic testing that occurs without health care provider acting as intermediary; companies established large internet footprints and offered various products; by 2013, only 23andMe continued to offer health-based genetic testing; Food and Drug Administration (FDA) ordered 23andMe to stop offering services; 23andMe switched focus to using genetic data to examine ancestry (unregulated area); applied and granted approval by FDA to offer carrier reports, ancestry reports, and “wellness” reports

Ancestry reports: in 2002, researcher traced evolutionary path of modern humans out of Africa using polymorphisms on Y chromosomes; National Geographic launched Geographic Project in 2005; controversial for exploitation of small populations and for lack of diversity; ability to take adequate family history most important tool (not genetic testing)

Rationale for testing: gain information (carrier status); prevention (assess risk for disease, family planning); seek specific information (Alzheimer disease, cancers); altruism (donate genetic information to help others)

Possible benefits: reassurance nothing significant in DNA; carrier testing may help with family planning (eg, prenatal testing); less expensive than traditional genetic testing

Possible risks: lack of counseling — companies not required to have genetic counselor speak with clients; consumers often rely on other consumers to discuss distressing results; unclear whether informed consent occurs; confusion between Mendelian disease (one gene mutation confers disease) and risk of developing disease (most common diseases); flaws in scientific basis — risk profiling for common disorders not well defined and varies from company to company; privacy concerns — Genetic Information Nondiscrimination Act applicable but has not been tested; security lapses have occurred; uncertain whether website portals are compliant with Health Insurance Portability and Accountability Act

“Disruptive” technology: diagnostic testing traditionally under purview of health care system; traditional workflow — clinician sees patient and orders appropriate diagnostic tests; specimens sent to reference laboratory; results sent back to clinician, who makes medical decisions based partially on those results; problems with traditional workflow — tests expensive (possibly exacerbated by reference laboratories); pricing not transparent (patients and providers often unaware of costs); new concepts — price for diagnostic testing needs to be increasingly transparent and affordable to avoid excluding patients; detect disease prior to clinical onset

Cost and genetic testing: cost for genetic testing $7 billion in 2014; cost growing ≈10% per year; testing too expensive for patients to afford; insurances may cover some testing, but logistics difficult; as cost decreases, barriers to testing on per person and institutional basis decrease; maintain reasonable access to diagnostics but avoid removing all barriers to testing; experiences show unintended consequences associated with direct-to-consumer testing; direct-to-provider testing represents future of genetic testing (ie, order appropriate testing at point of care with adequate counseling and transparent pricing)

Readings

American College of Medical Genetics Board of Directors: Direct-to-consumer genetic testing: a revised position statement of the American College of Medical Genetics. Genet Med, 2016 Feb;18(2):207-8; Cronin M, Ross JS: Comprehensive next-generation cancer genome sequencing in the era of targeted therapy and personalized oncology. Biomark Med, 2011 Jun;5(3):293-305; Davey S: Next generation sequencing: considering the ethics. Int J Immunogenet, 2014 Dec;41(6):457-62; Ng SB et al: Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet, 2010 Sep;42(9):790-3; Tucker T et al: Massively parallel sequencing: the next big thing in genetic medicine. Am J Hum Genet, 2009 Aug;85(2):142-54; Turrini M, Prainsack B: Beyond clinical utility: the multiple values of DTC genetics. Appl Transl Genom, 2016 Feb;8:4-8.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Rush was recorded at the 19th Annual Practical Pediatrics: 2016 Update, held March 4, 2016, in Omaha, NE, and presented by the Creighton University School of Medicine, Creighton University Health Sciences Continuing Education, and Ambassador Health. For information about upcoming CME activities from Creighton University Health Sciences Continuing Education, please visit healthsciences.creighton.edu/continuing-education. The Audio Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 0 CE contact hours.

Lecture ID:

PD622602

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.