UNDERSTANDING GENETICS A NEW YORK – MID-ATLANTIC GUIDE FOR PATIENTS AND HEALTH PROFESSIONALS The New York – Mid-Atlantic Consortium for Genetic and Newborn Screening Services The New York – Mid-Atlantic Guide for Patients and Health Professionals was produced thanks to a partnership between Genetic Alliance and NYMAC, the New York – Mid-Atlantic Consortium for Genetic and Newborn Screening Services. Genetic Alliance Project Staff ProjectDirector GeneticAllianceReviewers AmeliaChappelle,MA,MS JudithBenkendorf,MS,CGC AssociateDirectorofGeneticsResourcesandServices, ProjectManager,AmericanCollegeofMedicalGenetics GeneticAlliance JoannBoughman,PhD ExecutiveEditor ExecutiveVicePresident, SharonF.Terry,MA AmericanSocietyofHumanGenetics PresidentandCEO,GeneticAlliance SiobhanM.Dolan,MD,MPH AssociateStaff Professor,DepartmentofObstetricsandGynecologyand BeverlyC.Burke,MSW Women’sHealth,AlbertEinsteinCollegeofMedicine Co-Chair,LeadPlanner/Genomics,Connecticut LubaDjurdjinovic,MS DepartmentofPublicHealth Director,GeneticsProgram,FerreInstitute W.AndrewFaucett,MS,CGC KurtChristensen,MPH Instructor/DepartmentofHumanGenetics,Emory Fellow,GeneticAlliance UniversitySchoolofMedicine&IPA-CDC/NCHM& AmyGarrison,Intern,GeneticAlliance CETTProgramCoordinator,NIH/ORD AliceHawkins,MS,MPH NancyGreen,MD Consultant,CenterforAppliedEthics, AssociateDean,ColumbiaMedicalCenter, UniversityofBritishColumbia ClinicalResearchOperations HanaaRifaey,MA MaggieHoffman InternationalOutreachLiaison,GeneticAlliance Co-Director,ProjectDOCC(DeliveryofChronicCare) ElizabethTerry DaleHalseyLea,MPH,RN,CGC,FAAN ProgramAssistant,GeneticAlliance HealthEducator,NationalHumanGenome MichelleWaite,MS ResearchInstitute,EducationandCommunity ProgramAssistant,GeneticAlliance InvolvementBranch LisaWise,MA MicheleA.Lloyd-Puryear,MD,PhD VicePresident,GeneticAlliance Chief,GeneticServicesBranch,DivisionofServicesfor ChildrenwithSpecialHealthNeeds,MaternalandChild SeniorWriterandEditor HealthBureau SusanneB.Haga,PhD AssistantResearchProfessor,InstituteforGenome JoanO.Weiss,MSW,ACSW SciencesandPolicy,DukeUniversity NationalAssociationofSocialWorkers,Founding Director,GeneticAlliance(formerlyAllianceofGenetic SupportGroups) NYMAC Personnel KennethA.Pass,PhD BonnieL.Fredrick,MS NYMACPrincipalInvestigator,WadsworthCenter, NYMACProjectCoordinator,WadsworthCenter, NewYorkStateDepartmentofHealth NewYorkStateDepartmentofHealth LouisE.Bartoshesky,MD,MPH,MALS KateTullis,PhD NYMACCo-PrincipalInvestigator, NYMACPatientandFamilyCoordinator A.I.duPontHospitalforChildren A.I.duPontHospitalforChildren KatharineB.Harris,MBA NYMACProjectDirector,WadsworthCenter, NewYorkStateDepartmentofHealth TABLE OF CONTENTS Preface 3 Chapter 1 Genetics 101 5 1.1 Cells,Genomes,DNA,andGenes 6 1.2 TypesofGeneticDisease 6 1.3 LawsofInheritance 7 1.4 GeneticVariation 9 Chapter 2 Diagnosis of a Genetic Disease 11 2.1 HistoryandPhysicalExamination 12 2.2 RedFlagsforGeneticDisease 12 2.3 UsesofGeneticTesting 13 2.4 TypesofGeneticTesting 13 2.4.1 CytogeneticTesting 13 2.4.2 BiochemicalTesting 14 2.4.3 MolecularTesting 14 Chapter 3 Pedigree and Family History-taking 15 3.1 ImportanceofFamilyHistory 16 3.2 HowtoTakeaFamilyMedicalHistory 17 3.3 Pedigrees 17 Chapter 4 Newborn Screening 19 4.1 OverviewofNewbornScreening 20 4.1.1 ScreeningProcedureandFollow-up 20 4.1.2 Retesting 20 4.1.3 ClinicalEvaluationand DiagnosticTesting 20 4.1.4 Treatment 20 4.1.5 TestsPerformed 21 4.2 NewbornScreeningPrograms 21 4.3 NewbornHearingScreening 22 4.3.1 ScreeningProcedure 22 4.3.2 Retesting 22 4.3.3 Treatment 22 4.4 NewbornHearingScreeningPrograms 23 Chapter 5 Genetic counseling 25 5.1 RoleofGeneticCounseling 26 5.2 ProcessofGeneticCounseling 26 5.3 PatientEducation 27 Chapter 6 Indications for a Genetic Referral 29 6.1 WhentoRefertoaGeneticSpecialist 30 6.1.1 FamilyHistory 30 6.1.2 DelayedGrowthandDevelopment 30 6.1.3 ReproductiveIssues 30 Chapter 7 Psychological and Social Implications 33 7.1 GeneticInformationandOther MedicalInformation 34 7.2 ALifetimeofAffectedRelationships 34 2 7.3 ImpactofaGeneticDiagnosis 35 7.3.1 Patients 35 7.3.2 Parents 35 7.3.3 Family 35 7.3.4 Communities 36 7.4 CopingMechanisms 36 Chapter 8 Ethical, Legal, and Social Issues 39 8.1 DescriptionofEthical,Legal,andSocialIssues 40 8.1.1 CommunicatingTestResults 40 8.1.2 Direct-to-consumerTests 40 8.1.3 DutytoDisclose 40 8.1.4 GeneticDiscrimination 40 8.1.5 InformedConsent 41 8.1.6 Privacy 41 8.1.7 PsychosocialImpact 41 8.1.8 ReproductiveIssues 41 8.1.9 SocietalValues 42 8.1.10 TestUtility 42 8.1.11 TestValidity 42 Chapter 9 Patient stories and consumer profiles 43 9.1 InheritedBreast&OvarianCancer 44 9.2 TheValueofNewbornScreening 44 9.3 HereditaryHemachromatosis 45 9.4 TypeIIDiabetes 46 Chapter 10 Genetics Resources and Services 47 Appendices 61 A. Basic Genetics Information 62 B. FamilyHistoryisImportantforYourHealth 64 C. Family Health History Questionnaire 66 D. Healthcare Provider Card 68 E. Inheritance Patterns 70 F. Chromosomal Abnormalities 72 G. GeneticTesting 73 H. Prenatal Screening andTesting 75 I. GeneticTesting Methodologies 78 J. Newborn Screening 80 K. Birth Defects 81 L. Genetics and the Environment 82 M. Pharmacogenomics and Pharmacogenetics 84 N. Integrated Health Data Systems 86 O. Making Sense ofYour Genes: A Guide to Genetic Counseling 87 P. Cultural Competency in Genetics 90 Q. National Coalition for Health Professional EducationinGenetics(NCHPEG)—Principles of Genetics for Health Professionals 91 R. Centers for Disease Control and Prevention (CDC)—Genomic Competencies for All Public Health Professionals and Clinicians 98 Preface 3 PREFACE Over the past few decades, advances in genetics and genomics have revolutionized the way we think about health. Although genetics has traditionally been associated with pregnancy, birth defects, and newborn screening, almost every disease is influenced in part by an individual’s genetic makeup.Therefore, it is important to consider the impact of genetics in health and disease throughout an individual’s lifetime. The purpose of this manual is to provide an educational genetics resource for individuals, families, and health professionals in the NewYork – Mid-Atlantic region and increase awareness of specialty care in genetics.The manual begins with a basic introduction to genetics concepts, followed by a description of the different types and applications of genetic tests. It also provides information about diagnosis of genetic disease, family history, newborn screening, and genetic counseling. Resources are included to assist in patient care, patient and professional education, and identification of specialty genetics services within the NewYork – Mid-Atlantic region. At the end of each section, a list of references is provided for additional information. Appendices can be copied for reference and offered to patients.These take-home resources are critical to helping both providers and patients understand some of the basic concepts and applications of genetics and genomics. The original manual was created by Genetic Alliance with funding from the District of Columbia Department of Health, through U.S. Department of Health and Human Services (HHS) Health Resource and Services Administration (HRSA) Grant #5 H91 MC 00228-03. Genetic Alliance transforms health through genetics.We promote an environment of openness centered on the health of individuals, families, and communities. We bring together diverse stakeholders to create novel partnerships in advocacy. Genetic Alliance’s network includes hundreds of disease-specific advocacy organizations, as well as universities, companies, government agencies, and policy organizations.The network is an open space for thousands of shared resources, creative tools, and dozens of focused programs. Werevolutionizeaccesstoinformationtoenabletranslationofresearchintoservicesand individualizeddecision-making.GeneticAllianceofferstechnicalassistancetoorganizations,builds andsustainsrobustinformationsystems,andactivelyworksforpublicpoliciesthatpromotethe translationofbasicresearchintotherapiesandtreatments.Inparticular,GeneticAllianceidentifies solutionstoemergingproblemsandworkstoreduceobstaclestorapidandeffectivetranslationof researchintoaccessibletechnologiesandservicesthatimprovehumanhealth.Inallwedo,we integrateindividual,family,andcommunityperspectivestoimprovehealthsystems. Genetic Alliance is supported by a HRSA Collaborative Agreement. NYMAC, the NewYork – Mid-Atlantic Consortium for Genetic and Newborn Screening Services, is one of seven federally-funded regions in the U.S., created to ensure that individuals with heritable disorders and their families have access to quality care and appropriate genetic expertise and information. It is funded by HRSA Collaborative Agreement #U22 MC 03956. ThismanualisavailableontheGeneticAlliancewebsite,www.geneticalliance.org/publications,and ontheNYMACwebsite,www.wadsworth.org/newborn/nymac/resources.html. 44 Genetic Alliance Mandate for Quality Genetic Services Access to quality genetics services is critical to healthcare. 1. Individuals and families partner with their healthcare providers to identify needs, develop and monitor treatment plans, and manage their genetic condition. 2. Healthcare providers refer individuals to appropriate specialists, as needed, including those outside of their health insurance plans. 3. Providers and payers consider the psychosocial, as well as the medical, effects of a genetic condition—on both the individual and the individual’s family—at each stage of life. 4. Healthcare insurance plans reimburse genetic testing, diagnosis, and treatment for genetic conditions. 5. Quality resources are available to assist individuals and their families in understanding family health history, signs/symptoms, screening/testing options and their implications, diagnosis, treatment, and long-term follow-up, as needed. 6. A healthcare provider with experience in genetic services is available to all individuals. 7. Providers, payers, and employers create and use policies, guidelines, and procedures to ensure the appropriate use of genetic information. s l a 8. Information about genetic conditions is provided to individuals and families in a culturally- n o i appropriate manner, which may include primary language, appropriate educational level, and s s e f various media. o r P h 9. Information about genetic research and clinical trials is available to the affected individuals t l a and integrated into clinical practice when appropriate. e H d n 10. Referrals to support groups and resources are offered at regular office visits. a s t n 11. Outpatient, home, and hospital care for individuals with genetic conditions is available e i at and integrated. P r o f e d i u G c i t n a l t A - d i M – k r o Y w e N A Chapter 1 : Genetics 101 Almost every human trait and disease has a genetic component, whether inherited or influenced by behavioral factors such as exercise. Genetic components can also modify the body’s response to environmental factors such as toxins. Understanding the underlying concepts of human genetics and the role of genes, behavior, and the environment is important for appropriately collecting and applying genetic and genomic information and technologies during clinical care. It is important in improving disease diagnosis and treatment as well. This chapter provides fundamental information about basic genetics concepts, including cell structure, the molecular and biochemical basis of disease, major types of genetic disease, laws of inheritance, and the impact of genetic variation. 6 1.1 Cells, Genomes, DNA, and Genes Cells are the fundamental structural and functional units of every known living organism. Instructions needed to direct activities are contained within a DNA (deoxyribonucleic acid) sequence. DNA from all organisms is made up of the same chemical units (bases) called adenine, thymine, guanine, and cytosine, abbreviated as A,T, G, and C. In complementary DNA strands, A matches withT, and C with G, to form base pairs.The human genome (total composition of genetic material within a cell) is packaged into larger units known as chromosomes—physically separate molecules that range in length from about 50 to 250 million base pairs. Human cells contain two sets of chromosomes, one set inherited from each parent. Each cell normally contains 23 pairs of chromosomes, which consist of 22 autosomes (numbered 1 through 22) and one pair of sex chromosomes (XX or XY). However, sperm and ova normally contain half as much genetic material: only one copy of each chromosome. Each chromosome contains many genes, the basic physical and functional units of heredity. Genes are specific sequences of bases that encode instructions for how to make proteins.The DNA sequence is the particular side-by-side arrangement of bases along the DNA strand (e.g., ATTCCGGA). Each gene has a unique DNA sequence. Genes comprise only about 29 percent of the human genome; the remainder consists of non-coding regions, whose functions may include providing chromosomal structural integrity and regulating where, when, and in what quantity proteins are made.The human genome is estimated to contain 20,000 to 25,000 genes. AlthougheachcellcontainsafullcomplementofDNA,cellsusegenesselectively.Forexample,the genesactiveinalivercelldifferfromthegenesactiveinabraincellbecauseeachcellperformsdifferent functionsand,therefore,requiresdifferentproteins.Differentgenescanalsobeactivatedduring developmentorinresponsetoenvironmentalstimulisuchasaninfectionorstress. s l a n o si 1.2 Types of Genetic Disease s e f ro Many, if not most, diseases are caused or influenced by genetics. Genes, through the proteins P h they encode, determine how efficiently foods and chemicals are metabolized, how effectively t l a toxins are detoxified, and how vigorously infections are targeted. Genetic diseases can be e H categorized into three major groups: single-gene, chromosomal, and multifactorial. d n a s Changes in the DNA sequence of single genes, also known as mutations, cause thousands t n ie of diseases. A gene can mutate in many ways, resulting in an altered protein product that t a P is unable to perform its normal function.The most common gene mutation involves a change r o or “misspelling” in a single base in the DNA. Other mutations include the loss (deletion) f e d or gain (duplication or insertion) of a single or multiple base(s).The altered protein product i u G may still retain some normal function, but at a reduced capacity. In other cases, the protein may c ti be totally disabled by the mutation or gain an entirely new, but damaging, function.The n la outcome of a particular mutation depends not only on how it alters a protein’s function, but t A - also on how vital that particular protein is to survival. Other mutations, called polymorphisms, d i M are natural variations in DNA sequence that have no adverse effects and are simply differences – among individuals. k r o Y w In addition to mutations in single genes, genetic diseases can be caused by larger mutations in e N chromosomes. Chromosomal abnormalities may result from either the total number of A chromosomes differing from the usual amount or the physical structure of a chromosome differing from the usual structure.The most common type of chromosomal abnormality is Chapter 1 : Genetics 101 7 ImageCredit:U.S.DepartmentofEnergyHumanGenomeProgram,http://www.ornl.gov/hgmis. known as aneuploidy, an abnormal number of chromosomes due to an extra or missing chromosome. A usual karyotype (complete chromosome set) contains 46 chromosomes including an XX (female) or an XY (male) sex chromosome pair. Structural chromosomal abnormalities include deletions, duplications, insertions, inversions, or translocations of a chromosome segment. (SeeAppendixFformoreinformationaboutchromosomalabnormalities.) Multifactorial diseases are caused by a complex combination of genetic, behavioral, and environmental factors. Examples of these conditions include spina bifida, diabetes, and heart disease. Although multifactorial diseases can recur in families, some mutations such as cancer can be acquired throughout an individual’s lifetime. All genes work in the context of environment and behavior. Alterations in behavior or the environment such as diet, exercise, exposure to toxic agents, or medications can all influence genetic traits. 1.3 Laws of Inheritance The basic laws of inheritance are useful in understanding patterns of disease transmission. Single-gene diseases are usually inherited in one of several patterns, depending on the location of the gene (e.g., chromosomes 1-22 or X andY) and whether one or two normal copies of the gene are needed for normal protein activity. Five basic modes of inheritance for single-gene diseases exist: autosomal dominant, autosomal recessive, X-linked dominant, X-linked recessive, and mitochondria. (See diagram on following page.) 8 Affected Unaffected Autosomal Dominant Autosomal Recessive Mitochondrial •Individualscarryingonemutated •Affectedindividualsmustcarrytwo •Onlyfemalescanpasson copyofageneineachcellwillbe mutatedcopiesofagene mitochondrialconditionstotheir affectedbythedisease •Parentsofaffectedindividualare children(maternalinheritance) •Eachaffectedpersonusuallyhasone usuallyunaffected,andeachcarrya •Bothmalesandfemalescanbeaffected affectedparent singlecopyofthemutatedgene •Canappearineverygenerationofafamily •Tendstooccurineverygenerationof (knownascarriers) anaffectedfamily •Nottypicallyseenineverygeneration s l a n o i s s e f o r P h t l a e H d n a s t n e i t a P r o f e d i u G X-linked Dominant X-linked Recessive c i t n •Femalesaremorefrequentlyaffected •Malesaremorefrequentlyaffectedthanfemales a tl thanmales •FamilieswithanX-linkedrecessivedisorderoften A d- •FatherscannotpassX-linked haveaffectedmales,butrarelyaffectedfemales, i M traitstotheirsons ineachgeneration – (nomale-to-maletransmission) •Bothparentsofanaffecteddaughtermust k or becarriers Y w •Onlymothermustbecarrierofaffectedson e N (fatherscannotpassX-linkedtraitstotheirsons) A