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Genetics, Genomics, and Precision Medicine Cnn Anne m4 Daniel Judith @ a James [Maternal [Maternal [Paternal [Paternal Grandmother] Grandfather] | Grandmother] Grandfather] Catherine Robert Elizabeth John Margaret [Maternal Aunt] [Maternal Uncle] [Mother] [Father] [Paternal Aunt] Mary's Mary Michael's Michael Isabelle’s Isabelle Spouse [Self] Spouse [Brother] Spouse [Sister] Erin William Kelly [Daughter] [Nephew] [Niece] Related by Has Specific ou Male Female Alive Deceased Adopted Marriage Disease H®@ Z2@ HO LO BO FIGURE 30. Example of a family history generated using the CDC My Family Health Portrait tool (https://phgkb.cdc.gov/FHH/html/index.html). Agreement on the essential components of a family his- Genetic Tests and Testing tory is lacking. Obtaining a complete three-generation fam- ily history is a reasonable initial approach to screening for Strategies genetically inherited disease; an increasing number of clini- Genetic testing indications can be broadly categorized as pri-

Agreement on the essential components of a family his- Genetic Tests and Testing tory is lacking. Obtaining a complete three-generation fam- ily history is a reasonable initial approach to screening for Strategies genetically inherited disease; an increasing number of clini- Genetic testing indications can be broadly categorized as pri- cal practice guidelines (e.g., colon cancer screening guide- marily diagnostic or predictive. Diagnostic testing is per- lines) incorporate information on first- and second-degree formed in patients with clinical features suggestive of a genetic relatives. Documenting the history in the form of a family disease or disorders with a suspected genetic basis, such as pedigree provides a helpful pictorial representation of the hereditary hemochromatosis or cystic fibrosis. Predictive test- relationship between family members and the presence of ing is typically performed in asymptomatic patients, such as medical conditions. Obtaining an appropriately complete those with a strong family history of a disease for which early family history is time consuming, however, and often intervention would alter the clinical course, or as part of pre- requires investigation on the part of the patient. Self- natal counseling. As newer types of genetic testing measure administered online tools, such as the My Family Health large portions of the genome, diagnostic testing for one indica- Portrait tool from the CDC (https://phgkb.cdc.gov/FHH/ tion can also yield potentially predictive findings for other html/index.html), can greatly streamline the acquisition of conditions. family disease patterns (Figure 30). Diagnostic and predictive tests may be performed as single-gene, panel, or whole exome or genome sequencing. Most clinical genetic tests are administered as panels that target ¢ Obtaining a family history is an important risk assess- specific disorders, such as hereditary cancer, or pharmacologi- ment strategy that can increase severalfold the propor- cally important genes (“pharmacogenes”). The specific testing tion of patients identified as needing screening, genetic indication and abnormality being assessed guide the method of testing, or preventive treatment for some conditions. testing (Table 64). The Genetic Testing Registry of the National

cal practice guidelines (e.g., colon cancer screening guide- marily diagnostic or predictive. Diagnostic testing is per- lines) incorporate information on first- and second-degree formed in patients with clinical features suggestive of a genetic relatives. Documenting the history in the form of a family disease or disorders with a suspected genetic basis, such as pedigree provides a helpful pictorial representation of the hereditary hemochromatosis or cystic fibrosis. Predictive test- relationship between family members and the presence of ing is typically performed in asymptomatic patients, such as medical conditions. Obtaining an appropriately complete those with a strong family history of a disease for which early family history is time consuming, however, and often intervention would alter the clinical course, or as part of pre- requires investigation on the part of the patient. Self- natal counseling. As newer types of genetic testing measure administered online tools, such as the My Family Health large portions of the genome, diagnostic testing for one indica- Portrait tool from the CDC (https://phgkb.cdc.gov/FHH/ tion can also yield potentially predictive findings for other html/index.html), can greatly streamline the acquisition of conditions. family disease patterns (Figure 30). Diagnostic and predictive tests may be performed as single-gene, panel, or whole exome or genome sequencing. Most clinical genetic tests are administered as panels that target ¢ Obtaining a family history is an important risk assess- specific disorders, such as hereditary cancer, or pharmacologi- ment strategy that can increase severalfold the propor- cally important genes (“pharmacogenes”). The specific testing tion of patients identified as needing screening, genetic indication and abnormality being assessed guide the method of testing, or preventive treatment for some conditions. testing (Table 64). The Genetic Testing Registry of the National 102

Genetics, Genomics, and Precision Medicine TABLE 64. Commonly Used Genetic Tests Physicians Ethics Manual recommends that physicians con- sider the following: ype of Testing Description T e Analytical validity: ability of the test to accurately detect | Cytogenetic testing or Analyzes chromosomal karyotyping (Giemsa staining, structure (e.g., for Down the presence or absence of a mutation in situ hybridization, syndrome) ¢ Clinical validity: ability of the test to accurately relate the microarray analysis) Giemsa staining produces mutation to the disease banding pattern, allowing for gross structural analysis * Clinical utility: ability of the test results to inform the diag-

e Analytical validity: ability of the test to accurately detect | Cytogenetic testing or Analyzes chromosomal karyotyping (Giemsa staining, structure (e.g., for Down the presence or absence of a mutation in situ hybridization, syndrome) ¢ Clinical validity: ability of the test to accurately relate the microarray analysis) Giemsa staining produces mutation to the disease banding pattern, allowing for gross structural analysis * Clinical utility: ability of the test results to inform the diag- In situ hybridization and nosis, treatment, or prevention of a disease microarray analysis detect ¢ Personal utility: ability of the test results to provide pa- more subtle abnormalities tients with important personal or familial information to | Direct DNA testing (Sanger Analyzes a desired set of inform decision making | sequencing, genome genes and detects specific | sequencing, Southern blot genetic mutations (e.g., Patients for whom genetic testing is being considered, espe- | analysis) single-nucleotide cially those undergoing predictive testing, should receive genetic polymorphisms for detection of factor V Leiden) counseling. Clinicians and patients can use a searchable data-

In situ hybridization and nosis, treatment, or prevention of a disease microarray analysis detect ¢ Personal utility: ability of the test results to provide pa- more subtle abnormalities tients with important personal or familial information to | Direct DNA testing (Sanger Analyzes a desired set of inform decision making | sequencing, genome genes and detects specific | sequencing, Southern blot genetic mutations (e.g., Patients for whom genetic testing is being considered, espe- | analysis) single-nucleotide cially those undergoing predictive testing, should receive genetic polymorphisms for detection of factor V Leiden) counseling. Clinicians and patients can use a searchable data- Indirect DNA testing Useful when the genetic base provided by the American College of Medical Genetics and location for a condition is Genomics (www.acmg.net/GIS) to locate available genetic coun- known, but the genetic seling services. The basic components of genetic counseling are mutation is unknown education on the condition being tested, including the natural Biochemical testing Measures metabolite levels history, possible treatments, and preventive measures; the risks to assess enzymatic activity controlled by genes (e.g., and benefits of testing; alternatives to testing, including the 4-antitrypsin measurement option to forgo testing; the implications for the patient and fam- to assess MM, MT, or TT ily members; and the costs, including the possibility of denial of genotypes) coverage for disability, long-term care, and life insurance. Whole exome sequencing? Sequences protein-coding Patients should be informed that the Genetic Information region of the entire genome Nondiscrimination Act of 2008 protects against discrimination Useful when there is a clear family history of a genetic from obtaining employment (for companies with 15 or more disorder based on pedigree, employees) and health insurance; however, this protection does but the affected gene is not extend to discrimination involving other types of insurance. } unknown Patients who undergo genetic testing must understand Genome-wide association Identifies genetic variations the possibility of uncovering information that is incidental to study and attempts to associate the variants with disease conditions | the reason for testing and that such information may be of uncertain significance, which may produce stress and anxiety Used as a research tool for hypothesis generation in that is not easily relieved. populations rather than in individual patients Pharmacogenetics and Pharmacogenomics RNA expression analysis Evaluates the expression of (Northern blot, serial analysis genes by measuring Pharmacogenomics is the study of how genetic variation affects of gene expression) messenger RNA or microRNA the effects and metabolism of medications. Variation in response

Indirect DNA testing Useful when the genetic base provided by the American College of Medical Genetics and location for a condition is Genomics (www.acmg.net/GIS) to locate available genetic coun- known, but the genetic seling services. The basic components of genetic counseling are mutation is unknown education on the condition being tested, including the natural Biochemical testing Measures metabolite levels history, possible treatments, and preventive measures; the risks to assess enzymatic activity controlled by genes (e.g., and benefits of testing; alternatives to testing, including the 4-antitrypsin measurement option to forgo testing; the implications for the patient and fam- to assess MM, MT, or TT ily members; and the costs, including the possibility of denial of genotypes) coverage for disability, long-term care, and life insurance. Whole exome sequencing? Sequences protein-coding Patients should be informed that the Genetic Information region of the entire genome Nondiscrimination Act of 2008 protects against discrimination Useful when there is a clear family history of a genetic from obtaining employment (for companies with 15 or more disorder based on pedigree, employees) and health insurance; however, this protection does but the affected gene is not extend to discrimination involving other types of insurance. } unknown Patients who undergo genetic testing must understand Genome-wide association Identifies genetic variations the possibility of uncovering information that is incidental to study and attempts to associate the variants with disease conditions | the reason for testing and that such information may be of uncertain significance, which may produce stress and anxiety Used as a research tool for hypothesis generation in that is not easily relieved. populations rather than in individual patients Pharmacogenetics and Pharmacogenomics RNA expression analysis Evaluates the expression of (Northern blot, serial analysis genes by measuring Pharmacogenomics is the study of how genetic variation affects of gene expression) messenger RNA or microRNA the effects and metabolism of medications. Variation in response *The exome contains the parts of genes that encode proteins. Because over 85% to medications can originate from genetic effects on the body’s of known disease-causing proteins are limited to exons, exome sequencing is response to drugs (pharmacokinetics), how the drug affects the more cost-effective than whole genome sequencing. body (pharmacodynamics), or drug hypersensitivity (Table 65). More than 95% of individuals carry functional variants in

*The exome contains the parts of genes that encode proteins. Because over 85% to medications can originate from genetic effects on the body’s of known disease-causing proteins are limited to exons, exome sequencing is response to drugs (pharmacokinetics), how the drug affects the more cost-effective than whole genome sequencing. body (pharmacodynamics), or drug hypersensitivity (Table 65). More than 95% of individuals carry functional variants in Center for Biotechnology Information (www.ncbi.nlm.nih.gov/ a handful of the most important pharmacogenes. Significant gtr/) provides a user-friendly index of clinical genetic tests and pharmacokinetic alterations are most commonly caused by conditions. alleles in genes affecting the cytochrome P450 system, such as Clinical context must always be considered when order- CYP2C19 or CYP2D6. Clinical phenotypes are assigned on the

gtr/) provides a user-friendly index of clinical genetic tests and pharmacokinetic alterations are most commonly caused by conditions. alleles in genes affecting the cytochrome P450 system, such as Clinical context must always be considered when order- CYP2C19 or CYP2D6. Clinical phenotypes are assigned on the ing genetic testing because certain types of genetic variation basis of enzyme activity: (e.g., copy number variation, in which a segment of the ¢ Poor metabolizer: little to no enzyme activity genome may be duplicated or deleted) can be missed ¢ Intermediate metabolizer: reduced enzyme activity by certain tests. Specialist involvement is appropriate e Extensive/normal metabolizer: normal enzyme activity when genetic test results are negative but clinical suspicion remains high. e Rapid metabolizer: increased enzyme activity Test performance characteristics should also be accounted ¢ Ultrarapid metabolizer: significantly increased enzyme for when ordering genetic testing. The American College of activity 103

Genetics, Genomics, and Precision Medicine TABLE 65. Mechanisms of Pharmacogenomic Variants Mechanism Drug Associated Gene Comments Pharmacokinetic | Altered metabolism of Pantoprazole; other CYP2C19 Ultrarapid metabolizers of CYP2C19 deactivate active compound proton pump pantoprazole quickly, leading to reduced efficacy at inhibitors to a lesser standard doses extent Altered metabolism of | Codeine CYP2D6 Ultrarapid metabolizers of CYP2D6 convert codeine into prodrug morphine more quickly, potentially leading to toxicity Poor and intermediate metabolizers of CYP2Dé6 convert codeine into morphine slowly, resulting in attenuated effect | Clopidogrel CYP2C19 Poor and intermediate metabolizers of CYP2C19 slowly convert clopidogrel to its active form; the FDA warns of an increased risk for treatment failure in this population Altered drug uptake Simvastatin; other SLCO1B1 SLCO1B1 alters hepatic uptake by the OATP1B1 transporter; statins to a lesser reduced uptake may increase myopathy risk extent Pharmacodynamic

Altered drug uptake Simvastatin; other SLCO1B1 SLCO1B1 alters hepatic uptake by the OATP1B1 transporter; statins to a lesser reduced uptake may increase myopathy risk extent Pharmacodynamic Altered receptor Warfarin VKORC1 Increased warfarin affinity in certain VKORC7 polymorphisms binding affinity may indicate that a lower dose of warfarin is needed to achieve a therapeutic INR Off-target effects Sulfa drugs, NSAIDs, G6PD Reduced GéPD activity increases susceptibility to oxidative quinine, fluoroquino- stress, leading to hemolysis lones Hypersensitivity Non-anaphylactic Abacavir HLA-B*57:01 Increased risk for hypersensitivity reaction; the FDA systemic recommends testing before prescribing hypersensitivity | Non-anaphylactic Carbamazepine HLA-B*15:02 Increased risk for STS or TEN; the FDA recommends testing cutaneous patients of Asian descent before prescribing

Non-anaphylactic Abacavir HLA-B*57:01 Increased risk for hypersensitivity reaction; the FDA systemic recommends testing before prescribing hypersensitivity | Non-anaphylactic Carbamazepine HLA-B*15:02 Increased risk for STS or TEN; the FDA recommends testing cutaneous patients of Asian descent before prescribing hyPSsEnetisity Allopurinol HLA-B*58:01 Increased risk for severe cutaneous adverse reactions (i.e., STS or TEN); the American College of Rheumatology conditionally recommends testing patients of Southeast Asian (e.g., Han Chinese, Korean, Thai) descent and African American patients before prescribing CYP2C19 = cytochrome P450 2C19; CYP2D6 = cytochrome P450 2D6; G6PD = glucose-6-phosphate dehydrogenase; OATP1B1 = organic anion transporting protein B1; SLCO1B1 = solute carrier organic anion transporter family member 1B1; STS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; VKORC1 = vitamin K 2,3-epoxide reductase complex subunit 1.

CYP2C19 = cytochrome P450 2C19; CYP2D6 = cytochrome P450 2D6; G6PD = glucose-6-phosphate dehydrogenase; OATP1B1 = organic anion transporting protein B1; SLCO1B1 = solute carrier organic anion transporter family member 1B1; STS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; VKORC1 = vitamin K 2,3-epoxide reductase complex subunit 1. The effect of the phenotype on a particular medication are prescribed in routine practice, focusing on situations in depends on whether the medication is an active drug or a which serious adverse effects or treatment failures can occur. prodrug. Levels of medications that are taken in their active Examples include testing for the HLA-B*5701 allele before form, such as omeprazole, will be reduced in patients who are prescribing abacavir and testing for mutations in the thiopu- ultrarapid metabolizers and increased in patients who are rine methyltransferase (TPMT) gene before initiating azathio- poor metabolizers. Conversely, prodrugs, such as clopidogrel, prine therapy. More broadly, however, the FDA issued a require conversion to their active form; ultrarapid metaboliz- warning in November 2018 that pharmacogenomic testing ers will have increased drug levels, whereas poor metabolizers companies have promulgated drug dosing recommendations will have reduced levels. Correlating pharmacogenetic pheno- using information that has not been evaluated by the FDA. The types with clinical drug effect is not always straightforward regulatory landscape in this area continues to evolve. because other factors can influence drug levels and the clinical response may be nonlinear. Direct-to-Consumer Genomic Testing Guidance on the use of pharmacogenetic information in Direct-to-consumer (DTC) genomic testing is a commercial clinical practice is available from the Clinical Pharmacogenetics service that allows patients to obtain genetic information Implementation Consortium (https://cpicpgx.org/genes-drugs/). without a physician order or prescription. Consumer-directed Although predictive pharmacogenomic testing is mostly genomic testing is a similar process in which patients request investigational, the FDA and other organizations have that their physician authorize specific testing to be performed described a role for genetic testing when certain medications by a third-party laboratory or company. The FDA has approved

The effect of the phenotype on a particular medication are prescribed in routine practice, focusing on situations in depends on whether the medication is an active drug or a which serious adverse effects or treatment failures can occur. prodrug. Levels of medications that are taken in their active Examples include testing for the HLA-B*5701 allele before form, such as omeprazole, will be reduced in patients who are prescribing abacavir and testing for mutations in the thiopu- ultrarapid metabolizers and increased in patients who are rine methyltransferase (TPMT) gene before initiating azathio- poor metabolizers. Conversely, prodrugs, such as clopidogrel, prine therapy. More broadly, however, the FDA issued a require conversion to their active form; ultrarapid metaboliz- warning in November 2018 that pharmacogenomic testing ers will have increased drug levels, whereas poor metabolizers companies have promulgated drug dosing recommendations will have reduced levels. Correlating pharmacogenetic pheno- using information that has not been evaluated by the FDA. The types with clinical drug effect is not always straightforward regulatory landscape in this area continues to evolve. because other factors can influence drug levels and the clinical response may be nonlinear. Direct-to-Consumer Genomic Testing Guidance on the use of pharmacogenetic information in Direct-to-consumer (DTC) genomic testing is a commercial clinical practice is available from the Clinical Pharmacogenetics service that allows patients to obtain genetic information Implementation Consortium (https://cpicpgx.org/genes-drugs/). without a physician order or prescription. Consumer-directed Although predictive pharmacogenomic testing is mostly genomic testing is a similar process in which patients request investigational, the FDA and other organizations have that their physician authorize specific testing to be performed described a role for genetic testing when certain medications by a third-party laboratory or company. The FDA has approved 104