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This educational module is for physicians and providers to familiarize themselves with the various types of genetic tests available to order for their patients. Also, to establish a methodology for ...

This educational module is for physicians and providers to familiarize themselves with the various types of genetic tests available to order for their patients. Also, to establish a methodology for how providers may approach each test to feel comfortable ordering and resulting them to their patients.

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  • Primary Care Genomics Education Program_101 :: Introduction to Molecular Genetic TestingKey PointsThe purpose of the followingprogram is to educate primary care physicians overseeing a limited set of molecular genetic tests and ensure that they have the relevant competencies to evaluate and order genetic tests and be able to interpret the results of the molecular genetic test results for their patients.Given that genetics tests now have a range of clinical utilities from family planning and postnatal screening to utility in assessing dosing and specific pharmacogeneticresponses individuals might have, physicians who order genetic tests and review the results with patients need to be trained on the emerging technologies for genetic testing, how to evaluate the clinical validity of molecular genetic tests and how best to communicate the results from reports that are generated to the patients in a meaningful, and if necessary actionable, way.
  • Educational ObjectivesKey PointsThe content is aligned with identified competencies in molecular genetic testing and genomic medicine for public health professionals. The program was developed using the most current publicly available resources. After completion of the educational program physicians will increase their skill and ability to:Evaluate the ability of current molecular genetic tests to identify the spectrum of human genetic variation that contributes to diseaseOrder and use molecular genetic tests in clinical practiceDescribe the core laboratory methodologies for molecular genetic testing and analysis including the general limitations of molecular genetic testsReferences1. Center for Disease Control. Office Public Health Genomics, Genomics Translation, Genomic Workforce Competencies, 2001. Genomic competencies for public health professionals in clinical services evaluating individuals and families. Available at http://www.cdc.gov/genomics/translation/competencies/.2. American Board of Medical Genetics. Content outline for Clinical Molecular Genetics Certification Examination. Available at http://www.abmg.org/2011/cert_essentials.shtml
  • Chapter 1. Introduction to Genetics and the Role of Genetic Testing in Clinical Medicine(0.5 hrs) Key PointsThe following topics will be addressed in this section:Molecular genetic tests in clinical practiceGenetic variation may or may not be expressed clinically in the individualKey points to consider in the interpretation and limitations of molecular genetic testsFederal regulation of molecular genetic testsPersonal privacy, genetic information and legal protectionAdditional Information at the following links:Gene structure and functionDegeneracy of the DNA code, SNPs and gene/protein functionClinical relevance of genetic variation: pharmacogeneticsMethodology for molecular genetic analysis of SNPs
  • Molecular Genetic Tests in Clinical PracticeKey PointsGenetic testing in clinical practice is based on analysis of heritable material contained in the chromosomes of individuals;the study of heritable biological variation has proven to be a valuable tool to diagnose, prevent, treat, mitigate and predict health and disease. Genetic tests have been developed for >2200 diseases; ~2000 are currently available for use in clinical settings. >90% of human genetic variation are single nucleotide polymorphisms [SNPs] which can be assayed using genomic technologies such as polymerase chain reaction or microarray analysis that enable analysis of the entire genetic material of a person.According to the CDC genetic testing includes a broad range of laboratory tests performed to analyze DNA, RNA, chromosomes, proteins and certain metabolites using biochemical, cytochemical and molecular methods.Genomic medicine is the use of information from an individual's genome and their derivatives (RNA, proteins, and metabolites) to guide medical decision making.Genetic tests can be used in family planning; to disease diagnosis; in the diagnosis and management of oncologic conditions; to determine drug dosing, predict drug response, to reduce adverse events; to predict a phenotypic trait such as eye color; and to provide predictive probabilities and risk for complex medical conditions.References1. CDC Public Health Genomics. Genetic Testing. Available at: http://www.cdc.gov/genomics/gtesting/.2.Chen B, Gagnon M, Shahangian S, Anderson NL, Howerton DA, Boone JD; CDC. Good laboratory practices for molecular genetic testing for heritable diseases and conditions.MMWR Recomm Rep. 2009 3. Hindorff LA, Junkins HA, Hall PN, Mehta JP, and Manolio TA. A Catalog of Published Genome-Wide Association Studies. Available at: www.genome.gov/gwastudies. 4. FDA. Table of Pharmacogenomic Biomarkers in Drug Label. Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm. 5. NCBI. Genetests Resource Center. Available at: http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests.
  • Federal regulation of Genetic TestsKey PointsAs mandated by the Federal Food, Drug and Cosmetic Act, the FDA regulates the scope of requirements for oversight of genetic tests by overseeing the categorization of the complexity of the tests and reagents [ASRs] used for the test. In contrast the CMS is tasked through CLIA'88 to establish quality standards and accreditation to ensure laboratories are staffed appropriately to be able to perform each test according to the complexity of that test. Genetic tests are considered of moderate to high complexity requiring special personnel for the molecular biology techniques used.In vitro diagnostics [IVDs] are reagents, instruments, and systems intended for use:in diagnosis of disease or other conditions, including determination of the state of health, in order to cure, mitigate, treat, or prevent diseaseand are intended for use in the collections, preparation and examination of specimens taken from the human body [21 CFR 809, IVD for Human Use]Laboratory-developed tests [LDTs] use analyte-specific reagents [ASRs] to develop proprietary/in-house tests; LDTs are not sold commercially.LDTs and IVDs can be identical in function however, LDTs cannot be commercially sold by a lab.IVDMIAs are a subset of LDT/IVD genetic tests considered Class II/III medical devices by the FDA, however, no final ruling has been issued by the FDA on the classification of IVDMIAs.References1. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/IVDRegulatoryAssistance/OverviewofIVDRegulation/2. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/IVDRegulatoryAssistance/CLIAComplexityProcess/
  • Personal Privacy, Genetic Information and Legal ProtectionKey PointsInformed consentRequired prior to any genetic testing or molecular genetic analysis.HIPAA Rules of HIPPA applies to molecular genetic analysis of an individual's DNA as with any clinical laboratory test.The Genetic Information Nondiscrimination Act (GINA) Signed into law in 2008 with all aspects of the law in effect as of November 2009.GINA does not change, and should not impede medical practice. GINA regulates health insurers and employers, not health care professionals.Under GINA group and individual health insurers cannotuse a person's genetic information to set eligibility requirements or establish premium or contribution amountsrequest or require that a person undergo a genetic testUnder GINA employers cannot use a person's genetic information in decisions about hiring, firing, job assignments, or promotions.request, require, or purchase genetic information about an employee or family memberReferences1. The Genetic Information Nondiscrimination Act (GINA)
  • Kay Points to Consider in the Interpretation and Limitations of Molecular Genetic TestsKey PointsNeed to know reference rangeWhat is the normal prevalence of a genotype for a given population?Does the reference population match the individual receiving the test? Is information available for additional populations?LimitationsUnrecognized sequence variations or polymorphisms can affect the ability of molecular genetic tests to detect or distinguish the genotypes being analyzed, leading to false-positive or false-negative test results Laboratory methodologies are generally robust with >99% accuracy according to available data in package inserts.Clinical validity of each testAbility of test to diagnose or predict risk for a particular health conditionMeasured by sensitivity and specificity, predictive value for given disease/conditionInfluenced by prevalence of disease or health condition, penetrance [% of persons with genetic variation that exhibit phenotype]modifiers [genetic or environment factors that might affect the variability of signs or symptoms that occur with a phenotype of a genetic variation]References1. Chen B, Gagnon M, Shahangian S, Anderson NL, Howerton DA, Boone JD; Centers for Disease Control and Prevention (CDC). Good laboratory practices for molecular genetic testing for heritable diseases and conditionsMMWRRecomm Rep. 2009 Jun 12;58(RR-6):1-37; quiz CE-1-4.PMID: 19521335.2. Autogenomics Package Insert. INFINITI CYP2C19 Assay. Available at: www.autogenomics.com. Accessed 12.31.2010.
  • Clinical Relevance of Genetic VariabilityKey PointsAnalysis of single nucleotide polymorphisms and genome-wide association studies are used to establish genetic variation associated with a disease risk, pharmacogenetic response or phenotypic trait.Both single gene and complex disorders are characterized by multiple genetic, developmental and environmental factors. In single-gene disorders one gene has a dominant effect in producing a specific phenotype. Some single-gene disorders require a stimulus such as phenylalanine in PKU or various pharmacologic therapies which demonstrate allelic diversity with regard to metabolism. Complex diseases have multiple gene products interacting with environmental factors resulting in a given individual phenotype.The explanation of causation is generally more difficult with common, complex disorders than with single-gene disorders. The risk for disease imparted by the same gene product can differ from individual to individual even among member of the same family as a result of heterogeneity of genes, development and experiences within each individual and the epigenetic [environmental/life experiences] factors influencing phenotypic traits.Therefore the majority of genetic variants have low RR/OR, however, if you combine genetic risk across multiple low-effect size loci to look at genomic risk, the overall risk of disease is increased.In instances where genetic testing makes possible susceptibility testing for complex diseases physicians must communicate complex causation of many diseases, meaning of susceptibility, limited predictive value of positive or negative results.ReferencesFeero WG, Guttmacher AE, Collins FS. Genomic Medicine-An Updated Primer. N Engl J Med. 2010;362:2001-2011.Hindorff LA, Junkins HA, Hall PN, Mehta JP, and Manolio TA. A Catalog of Published Genome-Wide Association Studies. Available at: www.genome.gov/gwastudies. Accessed [12.3.2010].
  • Chapter 2. Categories of Genetic Testing Currently in Broad Use including Common Questions for Each Test** (0.5 hrs) Diagnostic: Thrombophilias [Factor V, XIII]Drug Response: warfarin metabolism Predictive for disease risk or phenotypic trait:polygenic dyslipidemia, cardiovascular diseaseFamily Planning: Newborn screening [Cystic Fibrosis, DFNB1-related hearing loss, Sickle cell trait]; Prenatal [Down's syndrome]; Carrier [Tay-Sachs, Sickle cell trait] Oncology-specific diagnostic and predictive applications: K-RAS mutationsReferences1. Chen B, Gagnon M, Shahangian S, Anderson NL, Howerton DA, Boone JD; Centers for Disease Control and Prevention (CDC). Good laboratory practices for molecular genetic testing for heritable diseases and conditions. MMWR Recomm Rep. 2009 Jun 12;58(RR-6).2. Center for Disease Control. Office Public Health Genomics, Genomics Translation, Genomic Workforce Competencies, 2001. Genomic competencies for public health professionals in clinical services evaluating individuals and families. Available at http://www.cdc.gov/genomics/translation/competencies/ 3. National Center for Biotechnology Information [NCBI]. GENETests. Educational materials. Available at http://www.ncbi.nlm.nih.gov/projects/GeneTests/static/concepts/teachtool/teachintro.shtml4. National Coalition for Health Professional Education in Genetics [NCHPEG Nutr]. Genetics and Nutrition-A Resource for Dietetic Faculty and Practitioners. 2010. Available at http://www.nchpeg.org/nutrition/5. CETT. Guidelines for developing CETT materials. Available at http://www.cettprogram.org/
  • Categories of Genetic Testing in Broad UseKey PointsFive categories of genetic tests are in broad use including diagnostic, predictive for a disease risk or phenotypic trait, predictive of drug response, family planning and oncology. Genetic and genomic tests should be evaluated and understood for use based:the type of sample is accepted for analysis [blood, saliva, tumor, other]the analyte to be evaluated-gene name(s), variants, mutations, chromosome(s); the instrument used in the analysis of the analyte; the category of test [IVD or LDT]the numerical values and references supporting the analytical and clinical validity of the test the data and citations demonstrating the clinical utility or value to the public of the testCommon questions to be able to answer when using genetic and genomic tests include:What is the test analyzing?What is it not analyzing? What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk, predictive vs probabilistic risk. Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?Is the test looking for a single mutation or all known mutations for a gene?How does the information from the genetic test fit within an individual's family health history?References1. Javitt G, Katsanis S, Scott J, Hudson K. Developing the Blueprint for a Genetic Testing Registry. Public Health Genomics. 2010;13:95-105.2. CETT. Guidelines for developing CETT materials. Accessed 11.15.2010. Available at http:/www.cettprogram.org/3. Lesko LJ, Zineh I, Huang S-M. What is Clinical Utility and Why Should we Care? ClinPharm Therapeutics. 2010;88(6):729-733.
  • Diagnostic Test to Confirm DiseaseKey PointsReview the key elements of genetic testing for suspected thrombophilia using tests for Factor II, Factor V and 5, 10-Methylenetetrahydrofolate reductase (MTHFR.) [Factor II (G20210A) and Factor V Leiden (G1691A) mutations are present in 2% and 5% of the general population, respectively.The term "factor V Leiden" refers to the specific G-to-A substitution at nucleotide 1691 in the gene for factor V that predicts a single amino-acid replacement (R506Q) at one of three APC cleavage sites in the factor Va molecule; the SNP in Factor II is a single point mutation G to A at position 20210 of the human Factor II prothrombin gene; the SNP in the human 5, 10-methylenetetrahydrofolate reductase gene (MTHFR) is a single point mutation C to T at position 677.References1. Kujovich J. Factor V Leiden Thrombophilia. GeneReviews March 9, 2010. Accessed 12.7.2010. Available at http://www.ncbi.nlm.nih.gov/sites/GeneTests/review/disease/factor%20V?db=genetests&search_param=contains2. Grody WW, Griffin JH, Taylor AK, Korf BR, Heit JA. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001;3:139–48.3. http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Databases/default.htm
  • Diagnostic Test to Confirm DiseaseKey PointsWhat is the test analyzing? Specific known mutations for thrombophilia.What is it not analyzing? All known mutations for thrombophilia.What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative riskIf the genetic test is positive for a mutation for thrombophilia the test can be diagnostic of suspected thrombophilia.If the genetic test is negative for a known mutation for thrombophiliaWill the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?Yes, the test can help diagnose patients whoHow does the information from the genetic test fit within an individual's family health history? Thrombophilias have Mendelian inheritance – a family health history can help identify other potential family members with suspected thrombophilias.
  • Drug ResponseKey PointsPharmacogenetic analysis is used to identify genetic variations that are the basis of drug resistance or toxicity which can provide additional information when selecting the appropriate medication and dosage for each patientReview the key elements of genetic testing and the application of pharmacogenomics to patient carePGx used to predict dosage requirement, select drug regiment, optimize patient's response to their medication, prevent ADE'sCase study: Genotype-guided dosing for initiation of warfarinFDA-approved tests: Nanosphere, Autogenomics, ParagonDx, Osmetech, TrimGenWarfarin Genotyping kit is an in vitro diagnostic test for the detection and genotyping of two single nucleotide polymorphisms (SNP) in the cytochrome P450 enzyme gene CYP2C9 known as CYP2C9*2 (C430T) and CYP2C9*3 (A1075C), and a SNP in the vitamin K epoxidereductase complex 1 gene VKORC1, known as VKORC1 (–1639G>A).Used as an aid in the identification of patients at risk for increased warfarin sensitivity. It is a qualitative assay for use in clinical laboratories upon prescription by the attending physician.ReferencesTable of Valid Genomic Biomarkers for Approved Drug Labels. Accessed 12.7.2010. Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htmhttp://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Databases/default.htmGrossniklaus D. Testing of VKORC1 and CYP2C9 alleles to guide warfarin dosing: Test Category: Pharmacogenomic (Treatment) PLoSCurr. 2010 September 14; 2: RRN1155. doi:10.1371/currents.RRN1155.
  • Diagnostic Test to Confirm DiseaseKey PointsWhat is the test analyzing?The genetic markers that determine warfarin metabolism.What is it not analyzing? All the possible genes responsible for warfarin metabolism. Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change? Genotypic characterization can be used to guide warfarin dose selection for individuals at risk of a thromboembolic event to shorten the time to a stable, effective dose, and minimize the risk of adverse events such as that can lead to a reduction in bleeding, a common adverse event in 10-16% of patients using warfarin.How does the information from the genetic test fit within an individual's family health history? These genetic markers exhibit Mendelian inheritance so if a patient has a mutation, family members should be notified if clinically indicated.References1. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007 Jul 9;167(13):1414-9.2. Grossniklaus D. Testing of VKORC1 and CYP2C9 alleles to guide warfarin dosing: Test Category: Pharmacogenomic (Treatment) PLoSCurr. 2010 September 14; 2: RRN1155. doi:10.1371/currents.RRN1155.
  • Predictive for disease risk or phenotypic traitKey PointsCase study: GWAS study of blood lipoprotein and lipid phenotypes which demonstrates common genetic variants at 30 loci which contribute to polygenic dyslipidemia and lipoprotein concentrations in humans.LDL, HDL and TG levels were correlated in over >40K patients with specific genetic loci. Using genome-wide association analyses 30 loci were identified as varying in a dose dependent manner with LDL, HDL and TG levels.Although randomized clinical trials need to confirm these variants can be used to help identify individuals at risk of cardiovascular disease, these studies suggest an allelic dosage score may allow for early identification and treatment of at-risk individuals.References1. Kathiresan et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009;41(1)56-65.
  • Diagnostic Test to Confirm DiseaseKey PointsWhat is the test analyzing? Multiple common genetic variants that can contribute to a risk for dyslipidemia.Use of the term mutation means that changes in the DNA [genotype] are phenotypically pathologic, eg Huntington's disease, cystic fibrosis, thus it is more acceptable to use the term allelic variation or single nucleotide polymorphisms for genetic variation to include the full range of genetic variation expression from disease-causing to benign.The most common variant at a genetic marker in a given population is considered the 'wild type' with minor allelic frequencies >1% considered polymorphisms.What is it not analyzing? The genetic test is not diagnostic test for dyslipidemia.What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative riskThe genetic analysis provides insights into an individual's relative risk for developing dyslipidemia.Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change? Yes, the results can be used to motivate patients to improve their health.How does the information from the genetic test fit within an individual's family health history?Dyslipidemia is the result of an individual's genetic background and environmental influences, such as diet/exercise/lifestyle choices. The family health history is important to inform those environmental influences that can be modified.
  • Family PlanningKey PointsUse of genetic tests in family planning fall into 3 broad categoriesCarrier [Tay-Sachs, Sickle cell trait]; Prenatal [Down's syndrome]; Newborn screening [cystic fibrosis, DFNB1-related hearing loss, Sickle cell trait]Newborn screening programs in many states require newborn screening [NBS] for cystic fibrosis.In this context the diagnosis of CF may be made in the absence of phenotypic features of CF in a newborn screening program (based on the presence of two disease-causing mutations in the CFTR gene or abnormal sweat chloride value). In 2002, 12.8% of newly diagnosed individuals were identified through newborn screening [Cystic Fibrosis Foundation 2003].Cystic fibrosis is the most common autosomal recessive disorder in the Caucasian population with an incidence of approximately 1 in 3,200 live births. The incidence of CF in other ethnic groups varies: approximately 1 in 9500 in Hispanics, 1 in 15,300 in African Americans, and 1 in 32,100 in Asian Americans. The CFTR gene is 230 kb long, contains 27 coding exons, and produces a 6.5-kb mRNA product.More than 1000 mutations are known; almost all are point mutations or small (1-84 bp) deletions. The most common mutation is ΔF508 (Phe508del), accounting for an estimated 30%-80% (depending on the ethnic group) of mutant alleles.ReferencesNCBI. Genetests Resource Center. Available at: http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests.http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Databases/default.htmWatson MS, Cutting GR, Desnick RJ, Driscoll DA, Klinger K, Mennuti M, Palomaki GE, Popovich BW, Pratt VM, Rohlfs EM, Strom CM, Richards CS, Witt DR, Grody WW. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med. 2004;6:387–91.
  • Diagnostic Test to Confirm DiseaseKey PointsWhat is the test analyzing? A panel of known mutations in the CFTR gene.What is it not analyzing? All known mutations in the CFTR gene.What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative riskThe information learned will establish if an individual has mutations in the CFTR gene that require further confirmation with a sweat test to diagnose CF.Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?A qualitative genotyping test which provides information intended to be used as an aid in newborn screening and in confirmatory diagnostic testing in newborns and children.How does the information from the genetic test fit within an individual's family health history? Yes, CF is inherited in an autosomal recessive gene and family members can be tested to determine if they also carry mutations in the CFTR gene.In newborn screening the CF gene test provides confirmation for the trypsinogen test or sweat test about the specific mutations an individual in the CFTR gene.Both genetic and environmental factors likely influence the severity of the CF which might help explain why some people with cystic fibrosis are more severely affected than others.
  • Oncology-specific diagnostic and predictive applicationsKey PointsMutant K-ras is present in approximately 35 to 45 percent of colorectal cancers, in 15 to 50 percent of lung cancers and in 72 to 90 percent of pancreatic cancers. The most common mutations have been localized in codons 12, 13 (exon 2) and 59, 61, 117 and 146 (exon 3). Studies have shown KRAS mutation status in colorectal cancer can be a predictor of a poor response for treatment with anti-EGFR therapies such as Erbitux and Vectibix.Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR-inhibiting drugs is to test for certain “activating” mutations in the gene that encodes KRAS, which occur in 40% of colorectal cancers. Although presence of the wild-type (or normal) KRAS gene does not guarantee that these drugs will work, a number of large studieshave shown that cetuximab has significant efficacy in mCRC patients with KRAS wild-type tumors. In the Phase III CRYSTAL study (2009) patients with the wild-type KRAS gene treated with Erbitux plus chemotherapy showed a response rate of up to 59% compared to those treated with chemotherapy alone. Patients with the KRAS wild-type gene showed a 32% decreased risk of disease progression compared to patients receiving chemotherapy alone.ReferencesLièvre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66 (8): 3992–5. L. van Epps, PhD, Heather (Winter, 2008). "Bittersweet Gene: A gene called KRAS can predict which colorectal cancers will respond to a certain type of treatment—and which will not.". CURE (Cancer Updates, Research and Education).Bokemeyer C, et al. (February 2009). Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J ClinOncol. 2009;27 (5): 663–71.Van Cutsem E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360 (14): 1408–17.
  • Diagnostic Test to Confirm DiseaseKey PointsWhat is the test analyzing? Known mutations in the K-RAS gene that decrease response to anti-EGFR therapies.What is it not analyzing? All mutations that might contribute to the decrease in therapeutic response.What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR-inhibiting drugs is to test for certain “activating” mutations in the gene that encodes KRAS, which occur in 40% of colorectal cancers. Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change? Yes – will help determine if a patient will respond to an EGFR therapy.How does the information from the genetic test fit within an individual's family health history?Cancer is a complex disease and has both environmental and inherited contributors.
  • Learn to look at the type of test being ordered. Whether it is for diagnosing a specific disease, looking for guidance in medication management, predicting complex diseases, or for family planning, you can approach these tests in a systematic way. Understanding what exactly the test is used for, what it tests, and the limitations will help you determine whether or not it should be ordered, how to counsel your patient prior to the test, and what to tell them once the result is back.Using these tools in practice will help to provide a significant level of comfort in evaluating the need for, ordering, and resulting genetic tests.
  • Genetic Structure and FunctionKey PointsFoundations of current molecular genetic testing and analysis rest upon fundamentals of gene structure and function.DNA and RNA are made of nucleic acids that form base-pairs according to specific rules.DNA: A-T, C-G RNA: A-U, C-GThe identification of the gene as the unit of heredity in concert with the Central Dogma of molecular biology, DNA->RNA-> protein, established a foundation for understanding how genetic variations [genotype] are manifest in phenotypic traits.Genes have a specific functional structures coded by the nucleic acid sequence including:Promoter regions for initiation of transcriptionExons and introns which are protein coding and non-coding sequences respectively with the exon/intron boundary representing splice sites for mRNA processingUntranslated regions [UTRs] which regulate transcription rates and volumeNucleic acids within a gene are numbered in a specific manner which is relevant for understanding molecular genetic analysis resultsIn the example shown the negative DNA sequence locations are upstream of the 1stexon start site of ATG codon 1 DNA sequences without a +/- reflect the exon coding sequenceDNA sequences with a + are downstream of the stop codonImportantly the function of a gene is not only for protein production, but also for storage of DNA information. An evolutionary aspect of the DNA->RNA->protein system is the redundancy in the genetic code for proteins. The design of the redundancy or degeneracy of the code means that many genes have sequences with different single nucleotide polymorphisms that code for the same protein.ReferencesFeero WG, Guttmacher AE, Collins FS. Genomic Medicine-An Updated Primer. N Engl J Med. 2010;362:2001-2011.Guttmacher AE, Collins FS. Genomic Medicine – a primer. N Engl J Med. 2002;347:1512-1520.
  • Degeneracy of the DNA Code, SNPs, and Gene/Protein FunctionKey PointsAs a result of the degeneracy of the genetic code genes can have sequence variations that do not change the amino acid sequence or protein function Synonymous SNPs, or silent mutations, lead to the same polypeptide sequenceNonsynonymous SNPs, either missense [different amino acid] or nonsense [premature stop codon]A single nucleotide polymorphism is defined as a genetic polymorphisms between 2 genomes that is based on the deletion, insertion, or exchange of a single nucleotide.Genetic polymorphism is defined as the occurrence together in the same population of 2 or more genetically determined phenotypes in such proportions that the rarest of them cannot be maintained merely by recurrent mutation.SNPs, which make up about 90% of all human genetic variation, occur every 100 to 300 bases along the 3-billion-base human genome. Two of every three SNPs involve the replacement of cytosine (C) with thymine (T). SNPs can occur in coding (gene) and noncoding/intergenic regions of the genome. For a variation to be considered a SNP, it must occur in at least 1% of the population. Although most SNPs associated with common diseases explain less than 5-10% of the observed contribution of heredity to risk of disease, the relative risk identified with specific genetic variations is often equivalent to environmental factors such as lifestyle, personal and family history, making genetic variation an important tool to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change.References1. U.S. Department of Energy Genome Programs. SNP Fact Sheet. Available at: http://www.ornl.gov/sci/techresources/Human_Genome/faq/snps.shtml
  • Clinical Relevance of Genetic Variation: PharmacogeneticsKey PointsUse of the term mutation means that changes in the DNA [genotype] are phenotypically pathologic, eg Huntington's disease, cystic fibrosis, thus it is more acceptable to use the term allelic variation or single nucleotide polymorphisms for genetic variation to include the full range of genetic variation expression from disease-causing to benign.The most common variant at a genetic marker in a given population is considered the 'wild type' with minor allelic frequencies >1% considered polymorphisms.A common genetic variation that is well characterized is that seen in the P450 CYP2C19 gene. It was observed that Impaired metabolism of commonly used drugs results from a defect in a cytochrome P450 enzyme, CYP2C19. Moreover, there is an observable phenotype with ethnic differences: The Poor Metabolizer phenotype occurs in 2-5% of Caucasian populations but at higher frequencies (18-23%) in Asian populations.Studies have shown CYP2C19 catalytic efficiency is mainly influenced by the 681G->A polymorphism in exon 5 (CYP2C19*2), which creates an aberrant splice site and results in a truncated and nonfunctional enzyme. The principal defect in patients who are identified as poor metabolizers is a single base pair (G + A) mutation in exon 5 of CYP2C19, which creates an aberrant splice site. This change alters the reading frame of the mRNA starting with amino acid 215 and produces a premature stop codon 20 amino acids downstream, which results in a truncated, non functional protein. Thus, clopidogrel responsiveness is reduced in subjects carrying a single *2 allele is in keeping with previous reports of a “gene-dose effect” CYP2C19*2 681G>A (rs4244285) 681A: cryptic splicing site No enzyme activity; Allele frequency:G (85.7%); A (14.%3) References1. de Morais SM, Wilkinson GR, Blaisdell J, et al. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem. 1994;269:15419-22.2. Hulot JS, Bura A, Villard E, et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244-7.3. FDA. Table of Pharmacogenomic Biomarkers in Drug Label. Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm.
  • Methodology for Molecular Genetic Analysis of SNPsKey PointsClinical laboratory technologies for molecular genetic testing and analysis are based on two fundamental methods: polymerase chain reaction(PCR) and micro-array based screening systems.Molecular genetic analysis of an individual's DNA can be accomplished using a variety of sample types including whole blood, buccal swab or saliva sample with cheek cells.The DNA is purified, then amplified to increase the amount of DNA for analysis.The analysis of the DNA for SNPs can be performed using quantitative PCR or micro-array based methods.SNP Genotyping TechnologiesReal-time quantitative PCR [TaqMan 1996]First rapid technology in broad useIn vitro method for the amplification of short (up to ~5000bp) pieces of DNARelies on a thermostable form of DNA polymeraseThermusaquaticusHigh-density photolithographic microarrays [Affymetrix 1995]25-bp oligonucleotide sequences matching major or minor alleles of known SNPsUses spatial encoding of sequences on chips to give address for each SNP to be queried thus allowing for high throughputHigh-density bead microarrays [Illumina 2005]Uses sequence encoding rather than spatial, beads rather than flat matrixOnce the analysis is complete the results are the compared to reference data.In the example given the sample analyzed for GeneX at nucleotide 1917 has a single nucleotide polymorphism of C -> A which is the GeneX*2 allele.References1. Chen B, Gagnon M, Shahangian S, Anderson NL, Howerton DA, Boone JD; Centers for Disease Control and Prevention (CDC). Good laboratory practices for molecular genetic testing for heritable diseases and conditions. MMWR Recomm Rep. 2009 Jun 12;58(RR-6).2. Feero WG, Guttmacher AE, Collins FS. Genomic Medicine-An Updated Primer. N Engl J Med. 2010;362:2001-2011.

Medivo Genomics 101 Medivo Genomics 101 Presentation Transcript

  • Primary Care Genomics Education Program_101
    Introduction to
    Molecular Genetic Testing
  • Educational Objectives
    Improve primary care clinicians comfort in ordering and using genetic tests in clinical practice.
    • Provide a methodology to enable physicians to evaluate the benefits and limitations of current molecular genetic tests.
    • Prior to completing this program, please take the following Pre-Program evaluation :
    • http://www.surveymonkey.com/s/M8LMJVH
    The content is aligned with published competencies in molecular genetic testing and genomic medicine for public health professionals. The program was developed using the most current publicly available resources.
  • Chapter 1. Introduction to Genetics and the Role of Molecular Genetic Testing in Clinical Medicine
  • Molecular Genetic Tests in Clinical Practice
    Genetic tests developed for >2200 diseases of which ~2000 are currently available for use in clinical settings
    >90% of human genetic variation are single nucleotide polymorphisms, SNPs, which can be assayed using molecular genetic tests.
    Family Planning
    &Perinatal Health
    Disease Diagnosis
    Predictive Trait
    or Disease
    Oncology
    Drug Response
    • Diagnosis
    • Disease
    • Prognosis
    • Drug Response
    • Hereditary
    colon cancer
    • Breast & ovarian
    cancer
    • BRCA 1,2
    • Herceptin
    response
    - Irinotecan toxicity
    • Cetuximab/
    panitumumab
    response
    • Preimplantation
    genetic diagnosis
    • Carrier status
    • Newborn screening
    - Tay Sachs
    - Canavan
    - Cystic fibrosis
    - Sickle-cell anemia
    - Phenylketonuria
    • Factor V Leiden
    thromobophilia
    - Hereditary
    hemochromatosis
    • Muscular dystrophy
    • Fragile X
    syndrome
    • Huntington's
    - Thalassemias
    • Health
    Assessment
    • Disease Risk
    - Heart disease
    • Alzheimer's disease
    - Stroke
    - Diabetes
    - Lung cancer risk
    • Metabolism
    • Response
    • Resistance
    • Toxicity
    - Warfarin response
    - Plavix resistance
    • Abacavir
    hypersensitivity
    - Tamoxifen
    resistance
    - Azathioprine metabolism
    - Allomap heart
    transplant
  • Optional Basic Science Review
    Click on the topics below to dive into more detail.
    Gene structure and function (slide 26)
    DNA, RNA, structure, and function
    Why Genetic Variation Doesn't Always Cause Disease (slide 27)
    Mutation and variation
    The science and application of genomics to medicine (slide 28)
    SNP’s and their role in variation
    Methodology of genetic testing (slide 29)
    Sample collection and analysis
  • Molecular Genetic Tests are Regulated at the Federal Level by both CLIA and the FDA
    CMS and CLIA
    CMS regulates laboratories that conduct tests using Laboratory Developed Tests [LDTs]
    Establish quality standards for laboratory testing and accreditation program for clinical labs
    CLIA-certification requirements depend upon complexity of tests performed to ensure labs/analysts/operators are competent to perform tests of different complexity
    3 categories: moderate/high/waived
    FDA [CDER]
    Regulates to ensure tests are safe and effective
    Tasked through FFDCA with oversight of IVDs, ASRs, categorizing complexity of LDTs
    Categorizes tests into 3 classes according to level of control needed to assure safety and effectiveness
    Genetic tests are considered Class I (most complex)
    IVDMIA [In vitro diagnostic multivariate index assay]
    Test that assays multiple variables such as gender/age/weight + results of genetic testcomputer algorithm=health risk assessment
    These are the most controversial types of tests
  • Personal Privacy, Genetic Information and Legal Protection
    Informed Consent
    Required prior to ANY genetic testing or molecular genetic analysis
    Consent laws created and enforced at the state government level
    Required even for population level analysis, employers, etc.
    HIPAA
    Covers individual's right to privacy for their medical and health information includes information related to genetic testing
    GINA
    Genetic Information Nondiscrimination Act signed into law 2008
    Protects individuals from misuse of genetic information in health insurance by insurers and in employment by employers
    Designed to removed barriers to the appropriate use of genetic services by the public
  • There are Some Key Points to Consider in the Interpretation and Limitations of Molecular Genetic Tests
    Reference range
    What is the normal prevalence of a genotype for a given population?
    Does the reference population match the individual receiving the test? Is information available for additional populations?
    Limitations
    Unrecognized sequence variations or polymorphisms can affect ability of tests to detect or distinguish the genotypes being analyzed, leading to false-positive or false-negative test results
    Clinical validity of each test
    Ability of test to diagnose or predict risk for a particular health condition or drug response
    Measured by sensitivity and specificity, predictive value for given disease
    Influenced by prevalence of disease or health condition, penetrance, and genetic and environmental modifiers
    Sample Package Insert for CYP2C19 for Expected Values/Reference Range
  • Genetic Variation May or May Not Be Expressed Clinically in the Individual
    Disease Outcome
    Probabilistic
    Predictable
    Mendelian
    Single Gene
    Mixed
    non-Mendelian
    Complex
    Mode of Inheritance
    Penetrance
    High
    Low
    # Genes Analyzed
    One
    Many
    Low
    Trait Prevalence
    High
  • Chapter 2. Categories of Genetic Testing Currently in Broad Use including Common Questions for Each Test
  • Common questions to be able to answer when using genetic and genomic tests:
    • What is the test analyzing?
    • What is it not analyzing?
    • What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk, predictive vs probabilistic risk.
    • Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?
    • Is the test looking for a single mutation or all known mutations for a gene?
    • How does the information from the genetic test fit within an individual's family health history?
    Categories of Genetic Testing in Use Issues and Common Questions
  • Diagnostic Test to Confirm Disease:Suspected Thrombophilia
  • Common questions to be able to answer when using this genetic test:
    What is the test analyzing?
    Specific known mutations for thrombophilia.
    What is it not analyzing?
    All known mutations for thrombophilia.
    What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk
    If the test is positive for a mutation for thrombophilia it can be diagnostic of suspected thrombophilia.
    Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?
    Yes, the test can help diagnose patients who carry a mutation that increases their risk of a clotting disorder and can be counseled and managed appropriately.
    How does the information from the genetic test fit within an individual's family health history?
    Thrombophilias have Mendelian inheritance – a family health history can help identify other potential family members with suspected thrombophilias.
  • Drug Response: Warfarin
  • Common questions to be able to answer when using this genetic test:
    What is the test analyzing?
    The known genetic markers that determine warfarin metabolism.
    What is it not analyzing?
    All the possible genes responsible for warfarin metabolism.
    Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?
    The test results can be used, in conjunction with other clinical information, to guide warfarin dose selection for individuals in need of anticoagulation, potentially shortening the time needed to reach a stable, effective dose. Studies have also shown that using genetic test information to calculate dosage can minimize the risk of adverse bleeding events, which occurs in 10-16% of patients using warfarin.
    How does the information from the genetic test fit within an individual's family health history?
    These genetic markers exhibit Mendelian inheritance so if a patient has a mutation, family members should be notified if clinically indicated.
  • Predictive for Disease Risk/Phenotypic Trait-Polygenic Dyslipidemia-
    Use of the term mutation means that changes in the DNA [genotype] are phenotypically pathologic, eg Huntington's disease, cystic fibrosis, thus it is more acceptable to use the term allelic variation or single nucleotide polymorphisms for genetic variation to include the full range of genetic variation expression from disease-causing to benign. The most common variant at a genetic marker in a given population is considered the 'wild type' with minor allelic frequencies >1% considered polymorphisms.
  • Common questions to be able to answer when using this genetic test:
    What is the test analyzing? Multiple common genetic variants that can contribute to a risk for dyslipidemia.
    What is it not analyzing? The genetic test is not diagnostic test for dyslipidemia.
    What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk The genetic analysis provides insights into an individual's relative risk for developing dyslipidemia.
    Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change? Yes, the results can be used to motivate patients to improve their health and potentially decrease their chances of developing the condition.
    How does the information from the genetic test fit within an individual's family health history? Dyslipidemia is the result of an individual's genetic background and environmental influences, such as diet/exercise/lifestyle choices. The family health history is important to inform those environmental influences that can be modified
  • Family Planning and Perinatal Health:Newborn Screening for Cystic Fibrosis
  • Common questions to be able to answer when using this genetic test:
    What is the test analyzing? A panel of known mutations in the CFTR gene.
    What is it not analyzing? All known mutations in the CFTR gene.
    What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk, predictive vs probabilistic risk.The information learned will establish if an individual has mutations in the CFTR gene that require further confirmation with a sweat test to diagnose CF.
    Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?A qualitative genotyping test which provides information intended to be used as an aid in newborn screening and in confirmatory diagnostic testing in newborns and children.
    Is the test looking for a single mutation or all known mutations for a gene? All currently known mutations, but not all possible mutations.
    How does the information from the genetic test fit within an individual's family health history?
    Yes, CF is inherited in an autosomal recessive gene and family members can be tested to determine if they also carry mutations in the CFTR gene.
    In newborn screening the CF gene test provides confirmation for the trypsinogen test or sweat test about the specific mutations in the CFTR gene.
    Both genetic and environmental factors likely influence the severity of the CF which might help explain why some people with cystic fibrosis are more severely affected than others.
  • Diagnostic or Predictive for Oncology-K-RAS Mutations-
  • Common questions to be able to answer when using this genetic test:
    What is the test analyzing?
    Known mutations in the K-RAS gene that decrease response to anti-EGFR therapies.
    What is it not analyzing?
    All mutations that might contribute to the decrease in therapeutic response.
    What will the information learned from the test be able to tell you? - and how is this information conveyed?, i.e. absolute vs relative risk
    Currently, the most reliable way to predict whether a colorectal cancer patient will respond to one of the EGFR-inhibiting drugs is to test for certain “activating” mutations in the gene that encodes KRAS, which occur in 40% of colorectal cancers.
    Will the test be able to provide information that can be used to guide patient treatment or help inform clinical care decisions such as motivating a specific behavioral change?
    Yes – will help determine if a patient will respond to an EGFR therapy.
    How does the information from the genetic test fit within an individual's family health history?
    Cancer is a complex disease and has both environmental and inherited contributors.
  • Looking at Genomic testing with a trained eye
    Recognize the category of test being performed
    Understand the utility and limitations of the test category
    Explain the relevance of the test and it’s utility and limitations to the patient
    Thank you for your participation. Please complete the following post-program evaluation.
    http://www.surveymonkey.com/s/TCJL9JZ
  • Citations1
    American Board of Medical Genetics [ABMGMolGen]. Content outline for Clinical Molecular Genetics Certification Examination. Accessed 11.10.2010. Available at http://www.abmg.org/2011/cert_essentials.shtml
    Altshuler D, Daly MJ, Lander ES. Genetic mapping in human disease. Science. 2008;322(5903):881-8.
    Autogenomics Package Insert. INFINITI CYP2C19 Assay. Available at: www.autogenomics.com.
    Bokemeyer C, et al. (February 2009). Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J ClinOncol. 2009;27 (5): 663–71.
    Centers for Disease Control and Prevention [MMWR]. Good Laboratory Practices for Molecular Genetic Testing for Heritable Diseases and Conditions. MMWR 2009;58(No. RR-6):[1-35].
    Center for Disease Control [CDC OPHG]. Office Public Health Genomics, Genomics Translation, Genomic Workforce Competencies, 2001. Genomic competencies for public health professionals in clinical services evaluating individuals and families. Accessed 11.10.2010. Available at http://www.cdc.gov/genomics/translation/competencies/
    CDC Public Health Genomics. Genetic Testing. Accessed 11.15.2010. Available at: http://www.cdc.gov/genomics/gtesting/.
    CETT. Guidelines for developing CETT materials. Accessed 11.15.2010. Available at http://www.cettprogram.org/
    Chen B, Gagnon M, Shahangian S, Anderson NL, Howerton DA, Boone JD; Centers for Disease Control and Prevention (CDC). Good laboratory practices for molecular genetic testing for heritable diseases and conditions. MMWR Recomm Rep. 2009 Jun 12;58(RR-6):1-37; quiz CE-1-4.PMID: 19521335.
    de Morais SM, Wilkinson GR, Blaisdell J, Nakamura K, Meyer UA, Goldstein JA. The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans. J Biol Chem. 1994;269(22):15419-22.
    FDA. Device Regulation and Guidance. Available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Databases/default.htm Accessed 12.10.2010.
    FDA. IVD Regulation. Available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/IVDRegulatoryAssistanceOverviewofIVDRegulation/ Accessed 12.10.2010.
    FDA CLIA Process. Available at: http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/IVDRegulatoryAssistance/CLIAComplexityProcess/ Accessed 12.10.2010.
    FDA. Table of Pharmacogenomic Biomarkers in Drug Label. Accessed 12.10.2010.
    Available at: http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm. Feero WG, Guttmacher AE, Collins FS. Genomic Medicine-An Updated Primer. N Engl J Med. 2010;362:2001-2011.
    Grody WW, Griffin JH, Taylor AK, Korf BR, Heit JA. American College of Medical Genetics consensus statement on factor V Leiden mutation testing. Genet Med. 2001;3:139–48.
    Grossniklaus D. Testing of VKORC1 and CYP2C9 alleles to guide warfarin dosing: Test Category: Pharmacogenomic (Treatment) PLoSCurr. 2010 September 14; 2: RRN1155. doi:10.1371/currents.RRN1155.
    Guttmacher AE, Collins FS. Genomic Medicine – a primer. N Engl J Med. 2002;347:1512-1520.
  • Citations2
    Handoff LA, Junkins HA, Hall PN, Mehta JP, and Manolio TA. A Catalog of Published Genome-Wide Association Studies. Accessed 12.3.2010. Available at: www.genome.gov/gwastudies. Hulot JS, Bura A, Villard E, Azizi M, Remones V, Goyenvalle C, Aiach M, Lechat P, Gaussem P. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006;108(7):2244-7.
    Javitt G, Katsanis S, Scott J, Hudson K. Developing the Blueprint for a Genetic Testing Registry. Public Health Genomics. 2010;13:95-105.
    Kathiresan et al. Common variants at 30 loci contribute to polygenic dyslipidemia. Nat Genet 2009;41(1)56-65.
    Lesko LJ, Zineh I, Huang S-M. What is Clinical Utiliity and Why Should we Care? ClinPharm Therapeutics. 2010;88(6):729-733.
    Lièvre A, Bachet JB, Le Corre D, et al. KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 2006;66 (8): 3992–5.
    L. van Epps, PhD, Heather (Winter, 2008). "Bittersweet Gene: A gene called KRAS can predict which colorectal cancers will respond to a certain type of treatment—and which will not.". CURE (Cancer Updates, Research and Education).
    Kujovich J. Factor V Leiden Thrombophilia. GeneReviews March 9, 2010. Accessed 12.7.2010. Available at http://www.ncbi.nlm.nih.gov/sites/GeneTests/review/disease/factor%20V?db=genetests&search_param=contains
    National Center for Biotechnology Information. GENETests. Educational materials. Accessed 11.16.2010. Available at http://www.ncbi.nlm.nih.gov/projects/GeneTests/static/concepts/teachtool/teachintro.shtml
    National Coalition for Health Professional Education in Genetics [NCHPEG Core]. Core competencies in Genetics for Health Professionals. Third Edition. September 2007. Accessed 11.10.2010. Available at http://www.nchpeg.org/index.php?option=com_content&view=article&id=94&Itemid=84
    National Coalition for Health Professional Education in Genetics [NCHPEG Nutr]. Genetics and Nutrition-A Resource for Dietetic Faculty and Practitioners. 2010. Accessed 11.10.2010. Available at http://www.nchpeg.org/nutrition/ NCBI. Genetests Resource Center. Available at: http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests.
    The Genetic Information Nondiscrimation Act (GINA). Information for Researchers and Health Care Professionals. Accessed 12.10.2010. Available at: http://www.genome.gov/Pages/PolicyEthics/GeneticDiscrimination/GINAInfoDoc.pdf
    Van Cutsem E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 2009; 360 (14): 1408–17.
    U.S. Department of Energy Genome Programs. SNP Fact Sheet. Accessed 12.10.2010. Available at: http://www.ornl.gov/sci/techresources/Human_Genome/faq/snps.shtml
    Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007 Jul 9;167(13):1414-9.
  • Appendix
    Optional Deep Dive
  • Gene Structure and Function
    DNA [deoxyribonucleic acid]
    Double helix of complementary nucleotides [base+sugar+phosphate]
    adenine (A), cytosine (C), guanine (G), thymine (T)
    RNA [ribonucleic acid]
    A, C, G, uracil (U)
    Specific base pairing rules
    DNA: A-T, C-G
    RNA: A-U, C-G
    Gene Structure
    transcription occurs 5'  3'
    promoter contains sequences for polymerases to initiate transcription DNA transcribed into mRNA = exons + introns
    UTR or untranslated regions of the DNA regulate transcription rates
    exons code for protein when translated
    introns or intragenic sequences regulate mRNA splicing
    Gene Function
    Storage of DNA code
    DNA -> mRNA -> protein
    For a basic overview, click on the following links:
    http://en.wikipedia.org/wiki/Gene
    http://www.ornl.gov/sci/techresources/HumanGenome/project/info.shtml
    Return to slide 5 »
  • Why Genetic Variation Doesn't Always Cause Disease
    Redundancy in genetic code for DNA -> RNA -> protein means that single nucleotide polymorphisms may or may not change the expression and/or function of a protein
    Types of Genetic Variation
    Silent – does not alter amino acid GCC -> GCG
    Missense – substitution of an amino acid AAA -> AAC
    Nonsense – creates a stop codon for premature termination of translation TAT -> TAG
    Impact of Genetic Variation
    Synonymous
    variation does not alter gene expression or protein function
    Nonsynonymous
    variation alters protein function
    information, click on the following link:
    http://www.ornl.gov/sci/techresources/HumanGenome/faq/snps.shtml
    Return to slide 5 »
  • Clinical Relevance of Genetic Variation: Pharmacogenetics
    Single nucleotide polymorphisms, SNPs, can be used to understand an individual's response to drugs.
    Example: P450 CYP2C19 gene polymorphism in exon 5 associated with variable drug response
    • Variant allele SNP 19154 G>A *2
    SNP creates aberrant splice site which ultimately results in a premature stop codon
    Allelic Function
    Wild type allele *1
    Variant allele reduced metabolism *2
    Variant allele no metabolism *3
    Allelic variation associated with different drug metabolizer states:
    Extensive metabolizer [normal] *1/*1
    Intermediate metabolizer *1/*2
    Poor metabolizer *2/*3
    For more information, click on the following links:
    http://www.ornl.gov/sci/techresources/Human_Genome/medicine/pharma.shtml
    http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm
    Return to slide 5 »
  • Methodology For Molecular Genetic Analysis of SNPs
    PCR principles
    Sample Path: Collection to Result
    Molecular Genetic Analysis Results
    Whole Blood or Buccal Swab or Saliva Sample/Cheek Cells
    DNA Purification
    DNA Amplification via Polymerase Chain Reaction (PCR)
    Microarray-based or PCR-based genotyping
    Genetic Analysis Results for SNPs Variants
    WT
    a-t-c-g-t-t-c-a-a-t-t
    Sample
    a-t-c-g-t-t-a-t-t-a-a
    Microarray
    Variant allele for GeneX nucleotide position: 1917
    SNP polymorphism: C>A
    Allelic designation: *2
    Return to slide 5 »