Genetic and Ethics Navigating the Maze of Genetic and Genomic Ethical and Social Issues Howard M. Saal, M.D. Division of Human Genetics Genomics and Ethics in Research and Medical Decision Making March 12, 2015
Genetic and Ethics Why do genetic/genomic testing? • Diagnosis of a genetic condition • Identify genetic predisposition • Test for carrier status for a specific disorder • Prenatal testing • Testing for identity • Testing for status of a specific illness (usually related to malignancy)
Genetic and Ethics Genetic testing • Assays designed to provide a “definitive diagnosis” • Criteria for testing include – Positive screening results – Family history – Ethnicity/race – Physical stigmata
Genetic and Ethics Genetic screening • Assays undertaken on a population-wide basis to identify at-risk individuals • Screening criteria 1 – Important health problem – Accepted treatment for a recognized condition – Suitable test or examination – Natural history should be adequately understood – Agreed policy on whom to treat – Cost of case finding should be balanced – Should be a continuing process 1 Wilson JMG, Jungner G. http://whqlibdoc.who.int/phpWHO_PHP34.pdf
Genetic and Ethics Types of genetic tests • Analyte – Presence – Quantity • Enzyme activity • Chromosome analysis • Chromosomal microarray • DNA – Sequencing – Mutation analysis
Genetic and Ethics History of genetic testing • Archibald Garrod described alkaptanuria in 1902 – Analyte – Autosomal recessive – In 1908 Garrod reported pentosuria, cystinuria and albinism as autosomal recessive biochemical disorders • ABO blood groups described by Karl Landsteiner in 1900 – 1920s familial nature described
Genetic and Ethics History of genetic testing • Tjio and Levan discovered a reproducible method for evaluation of chromosomes in 1956 • They established that there were 46 human chromosomes
Genetic and Ethics Diagnoses of genetic disorders • Down syndrome - 1959 • Turner syndrome -1959 • Trisomy 13 - 1960 • Trisomy 18 - 1960 • Klinefelter syndrome - 1961 • Cri du chat syndrome - 1963
Genetic and Ethics Chromosomal Microarray • Microarray uses special technologies for comprehensive coverage of the entire genome to detect submicroscopic chromosomal imbalances • Single nucleotide polymorphism (SNP) microarray is most commonly used technology today • High coverage with over 4,000,000 SNP markers across the entire genome • Ideal for small deletions and duplications
Genetic and Ethics -IUGR -Cleft palate -Multiple VSDs -Dysmorphic
Genetic and Ethics Human Genome Project Completed 2003 • Identify all the approximately 20,000 genes • Determine the sequences of the 3 billion base pairs that make up human DNA • Store this information in databases • Improve tools for data analysis • Transfer related technologies to the private sector • Address the ethical, legal, and social issues (ELSI) that may arise from the project.
Genetic and Ethics Single gene disorders and gene sequencing • 20,000 human genes • 99.99% of human genes have been identified and sequenced • Clinical genetic testing is available for over 2500 different single gene disorders
Genetic and Ethics Testing for single gene disorders • Helpful for suspected specific genetic condition • Not useful for multiple anomaly disorders with no suspected diagnosis • Gene sequencing is not available for all genetic disorders • Sensitivity of testing rarely 100% • Genetic heterogeneity
Genetic and Ethics Whole Exome sequence: Technology moves on • Human genome is comprised of 3 billion base pairs • Human exome encompasses primarily protein coding genes – Refers to only the coding portion of the genes – Comprise only 1-2% of the genome – Accounts for 85% of disease causing gene mutations 1 • Current technology is whole exome sequencing (WES) 1 Choi et al, PNAS, 106:10196, 2009
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Genetic and Ethics Creative Commons, 2012
Genetics and Ethics Genetic and genomic testing and screening • Genetic/genomic testing is usually a one time event • Genetic testing has implications for other family members – Recurrence risks – Potentially affected biologic family members • Diagnosis of a genetic disorder may not change outcome or prognosis • Genetic testing should always be accompanied by counseling
Genetics and Ethics General recommendations • Decisions about genetic/genomic testing should be driven by the best interest of the patient • Respect autonomy • Genetic and genomic testing should be offered in the context of genetic counseling – Need better education of healthcare professionals in genetic counseling
Genetics and Ethics Diagnostic testing • Use same criteria for testing as other medical diagnostic evaluations • Inform patients of benefits and risks of testing • Get permission for testing • Consider cost of testing as well – Genetic tests are expensive – Third party payer coverage is an issue
Genetics and Ethics Predictive genetic testing • Usually associated with risk for onset of clinical manifestations later in life • May be offered for asymptomatic children at risk for childhood onset of conditions • Predictive or predisposition testing for adult onset disorders should be deferred in children – Intervention in childhood would reduce morbidity or mortality – Diagnostic uncertainty poses a psychological burden
Genetics and Ethics Disclosure • Results disclosure to family – Ideally should address disclosure issues prior to genetic testing • Who owns the results – Genetic information belongs to the patient being tested – Encourage parents or guardians to inform their child of the test results at an appropriate age
Genetic Testing American College of Medical Genetics and Genomics ACMG Recommendations for Reporting of Incidental Findings in Clinical Exome and Genome Sequencing Robert C. Green, MD, MPH, Jonathan S. Berg, MD, PhD, Wayne W. Grody, MD, PhD, Sarah S. Kalia, ScM, CGC, Bruce R. Korf, MD, PhD, Christa L. Martin, PhD, FACMG, Amy McGuire, JD, PhD, Robert L. Nussbaum, MD, Julianne M. O’Daniel, MS, CGC, Kelly E. Ormond, MS, CGC, Heidi L. Rehm, PhD, FACMG, Michael S. Watson, MS, PhD, FACMG, Marc S. Williams, MD, FACMG, Leslie G. Biesecker, MD
Genetics and Ethics Genome sequencing recommendations • Defined a list of 57 genes corresponding with 24 disorders that should be analyzed and returned to the ordering physician • Estimate that 1% of tests will return an incidental actionable finding • Excluded returning results of conditions for which there is no definitive medical surveillance or intervention
Genetics and Ethics Incidental findings • Hereditary breast and ovarian cancer • Lynch syndrome • Familial adenomatous polyposis • Hypertrophic cardiomyopathy • Neurofibromatosis type 2 • Li-Fraumeni syndrome • MEN type 1 • MEN type 2
Genetics and Ethics Rationale for reporting • These are serious disorders • These are actionable disorders • Do not recommend reporting for disorders for which no intervention is currently available – Huntington disease – Alzheimer disease
Genetics and Ethics Responses to ACMG recommendations • Patients decisions and right not to know – No informed consent to search for a deliberate search for the incidental findings – Ethically and legally, the clinician has the core fiduciary duty to respect the patient’s right to decide what testing to undergo and what information to receive • The child’s right to limits on testing – Reverses the standard of predictive testing for adult onset disorders in children Wolf SM et al, Science 340:1049-1050, 2013
Genetics and Ethics Next Generation Whole exome sequencing (WES) • Diagnosis of extremely rare and possibly unique genetic disorders – Diagnostic yield increased by 30% • Costly • Tedious – Technical aspects are straightforward – Bioinformatic resources are limited – Analysis of data is time consuming
Genetics and Ethics Patients should be informed about • Potential benefits • Potential risks • Possibility of no diagnosis being made • Possibility of a diagnosis being made for a condition for which there is no known treatment • Identification of possible variants of unknown significance • Possible identification of misattributed parentage
Genetics and Ethics Knowledge is Ignorance is Power Bliss
Genetics and Ethics Challenges to guideline development • Next Generation WES is hampered by insufficient data from normal individuals to assist with clinical patient data interpretation • Even if a diagnosis is made, what is the likelihood that there will be an available intervention?
Genetics and Ethics Whole Exome and Genome Sequencing Variants of Unknown Significance • When is a variant of unknown significance significant? – Results can lead to unnecessary testing and surveillance – Psychological trauma – Misappropriated reassurance • Your are not just testing the patient (child), you may be testing other family members as well
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