Understanding Genetics PDF

UNDERSTANDING GENETICS A NEW YORK – MID-ATLANTIC GUIDE FOR PATIENTS AND HEALTH PROFESSIONALS T h e N e w Yo r k – M i d - A t l a n t i c C o n s o r t i u m f o r G e n e t i c a n d N e w b o r n S c r e e n i n g S e r v i c e s Th...

UNDERSTANDING GENETICS A NEW YORK – MID-ATLANTIC GUIDE FOR PATIENTS AND HEALTH PROFESSIONALS T h e N e w Yo r k – M i d - A t l a n t i c C o n s o r t i u m f o r G e n e t i c a n d N e w b o r n S c r e e n i n g S e r v i c e s 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. G e n e t i c A l l i a n c e Pr o j e c t St a ff Project Director Genetic Alliance Reviewers Amelia Chappelle, MA, MS Judith Benkendorf, MS, CGC Associate Director of Genetics Resources and Services, Project Manager, American College of Medical Genetics Genetic Alliance Joann Boughman, PhD Executive Editor Executive Vice President, Sharon F. Terry, MA American Society of Human Genetics President and CEO, Genetic Alliance Siobhan M. Dolan, MD, MPH Associate Staff Professor, Department of Obstetrics and Gynecology and Beverly C. Burke, MSW Women’s Health, Albert Einstein College of Medicine Co-Chair, Lead Planner/Genomics, Connecticut Luba Djurdjinovic, MS Department of Public Health Director, Genetics Program, Ferre Institute Kurt Christensen, MPH W. Andrew Faucett, MS, CGC Fellow, Genetic Alliance Instructor/Department of Human Genetics, Emory University School of Medicine & IPA-CDC/NCHM & Amy Garrison, Intern, Genetic Alliance CETT Program Coordinator, NIH/ORD Alice Hawkins, MS, MPH Nancy Green, MD Consultant, Center for Applied Ethics, Associate Dean, Columbia Medical Center, University of British Columbia Clinical Research Operations Hanaa Rifaey, MA Maggie Hoffman International Outreach Liaison, Genetic Alliance Co-Director, Project DOCC (Delivery of Chronic Care) Elizabeth Terry Dale Halsey Lea, MPH, RN, CGC, FAAN Program Assistant, Genetic Alliance Health Educator, National Human Genome Michelle Waite, MS Research Institute, Education and Community Program Assistant, Genetic Alliance Involvement Branch Lisa Wise, MA Michele A. Lloyd-Puryear, MD, PhD Vice President, Genetic Alliance Chief, Genetic Services Branch, Division of Services for Children with Special Health Needs, Maternal and Child Senior Writer and Editor Health Bureau Susanne B. Haga, PhD Assistant Research Professor, Institute for Genome Joan O. Weiss, MSW, ACSW Sciences and Policy, Duke University National Association of Social Workers, Founding Director, Genetic Alliance (formerly Alliance of Genetic Support Groups) N Y M AC Pe r s o n n e l Kenneth A. Pass, PhD Bonnie L. Fredrick, MS NYMAC Principal Investigator, Wadsworth Center, NYMAC Project Coordinator, Wadsworth Center, New York State Department of Health New York State Department of Health Louis E. Bartoshesky, MD, MPH, MALS Kate Tullis, PhD NYMAC Co-Principal Investigator, NYMAC Patient and Family Coordinator A.I. duPont Hospital for Children A.I. duPont Hospital for Children Katharine B. Harris, MBA NYMAC Project Director, Wadsworth Center, New York State Department of Health  TA B L E O F C O N T E N TS Preface 3 Chapter 1 Genetics 101 5 1.1 Cells, Genomes, DNA, and Genes 6 1.2 Types of Genetic Disease 6 1.3 Laws of Inheritance 7 1.4 Genetic Variation 9 Chapter 2 Diagnosis of a Genetic Disease 11 2.1 History and Physical Examination 12 2.2 Red Flags for Genetic Disease 12 2.3 Uses of Genetic Testing 13 2.4 Types of Genetic Testing 13 2.4.1 Cytogenetic Testing 13 2.4.2 Biochemical Testing 14 2.4.3 Molecular Testing 14 Chapter 3 Pedigree and Family History-taking 15 3.1 Importance of Family History 16 3.2 How to Take a Family Medical History 17 3.3 Pedigrees 17 Chapter 4 Newborn Screening 19 4.1 Overview of Newborn Screening 20 4.1.1 Screening Procedure and Follow-up 20 4.1.2 Retesting 20 4.1.3 Clinical Evaluation and Diagnostic Testing 20 4.1.4 Treatment 20 4.1.5 Tests Performed 21 4.2 Newborn Screening Programs 21 4.3 Newborn Hearing Screening 22 4.3.1 Screening Procedure 22 4.3.2 Retesting 22 4.3.3 Treatment 22 4.4 Newborn Hearing Screening Programs 23 Chapter 5 Genetic counseling 25 5.1 Role of Genetic Counseling 26 5.2 Process of Genetic Counseling 26 5.3 Patient Education 27 Chapter 6 Indications for a Genetic Referral 29 6.1 When to Refer to a Genetic Specialist 30 6.1.1 Family History 30 6.1.2 Delayed Growth and Development 30 6.1.3 Reproductive Issues 30 Chapter 7 Psychological and Social Implications 33 7.1 Genetic Information and Other Medical Information 34 7.2 A Lifetime of Affected Relationships 34 2 7.3 Impact of a Genetic Diagnosis 35 7.3.1 Patients 35 7.3.2 Parents 35 7.3.3 Family 35 7.3.4 Communities 36 7.4 Coping Mechanisms 36 Chapter 8 Ethical, Legal, and Social Issues 39 8.1 Description of Ethical, Legal, and Social Issues 40 8.1.1 Communicating Test Results 40 8.1.2 Direct-to-consumer Tests 40 8.1.3 Duty to Disclose 40 8.1.4 Genetic Discrimination 40 8.1.5 Informed Consent 41 8.1.6 Privacy 41 8.1.7 Psychosocial Impact 41 8.1.8 Reproductive Issues 41 8.1.9 Societal Values 42 8.1.10 Test Utility 42 8.1.11 Test Validity 42 Chapter 9 Patient stories and consumer profiles 43 9.1 Inherited Breast & Ovarian Cancer 44 9.2 The Value of Newborn Screening 44 9.3 Hereditary Hemachromatosis 45 9.4 Type II Diabetes 46 Chapter 10 Genetics Resources and Services 47 Appendices 61 A. Basic Genetics Information 62 B. Family History is Important for Your Health 64 C. Family Health History Questionnaire 66 D. Healthcare Provider Card 68 E. Inheritance Patterns 70 F. Chromosomal Abnormalities 72 G. Genetic Testing 73 H. Prenatal Screening and Testing 75 I. Genetic Testing 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 of Your Genes: A Guide to Genetic Counseling 87 P. Cultural Competency in Genetics 90 Q. National Coalition for Health Professional Education in Genetics (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  P re fac e 3 P R E FAC E 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 New York – 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 New York – 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. We revolutionize access to information to enable translation of research into services and individualized decision-making. Genetic Alliance offers technical assistance to organizations, builds and sustains robust information systems, and actively works for public policies that promote the translation of basic research into therapies and treatments. In particular, Genetic Alliance identifies solutions to emerging problems and works to reduce obstacles to rapid and effective translation of research into accessible technologies and services that improve human health. In all we do, we integrate individual, family, and community perspectives to improve health systems. Genetic Alliance is supported by a HRSA Collaborative Agreement. NYMAC, the New York – 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. This manual is available on the Genetic Alliance website, www.geneticalliance.org/publications, and on the NYMAC website, www.wadsworth.org/newborn/nymac/resources.html. 4 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. A N e w Yo r k – M i d - A t l a n t i c G u i d e f o r P at i e n t s a n d H e a lt h P r o f e s s i o n a l s 8. Information about genetic conditions is provided to individuals and families in a culturally- appropriate manner, which may include primary language, appropriate educational level, and various media. 9. Information about genetic research and clinical trials is available to the affected individuals and integrated into clinical practice when appropriate. 10. Referrals to support groups and resources are offered at regular office visits. 11. Outpatient, home, and hospital care for individuals with genetic conditions is available and integrated.  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 with T, 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. Although each cell contains a full complement of DNA, cells use genes selectively. For example, the genes active in a liver cell differ from the genes active in a brain cell because each cell performs different functions and, therefore, requires different proteins. Different genes can also be activated during development or in response to environmental stimuli such as an infection or stress. A N e w Yo r k – M i d - A t l a n t i c G u i d e f o r P at i e n t s a n d H e a lt h P r o f e s s i o n a l s 1.2 Types of Genetic Disease Many, if not most, diseases are caused or influenced by genetics. Genes, through the proteins they encode, determine how efficiently foods and chemicals are metabolized, how effectively toxins are detoxified, and how vigorously infections are targeted. Genetic diseases can be categorized into three major groups: single-gene, chromosomal, and multifactorial. Changes in the DNA sequence of single genes, also known as mutations, cause thousands of diseases. A gene can mutate in many ways, resulting in an altered protein product that is unable to perform its normal function. The most common gene mutation involves a change or “misspelling” in a single base in the DNA. Other mutations include the loss (deletion) or gain (duplication or insertion) of a single or multiple base(s). The altered protein product may still retain some normal function, but at a reduced capacity. In other cases, the protein may be totally disabled by the mutation or gain an entirely new, but damaging, function. The outcome of a particular mutation depends not only on how it alters a protein’s function, but also on how vital that particular protein is to survival. Other mutations, called polymorphisms, are natural variations in DNA sequence that have no adverse effects and are simply differences among individuals. In addition to mutations in single genes, genetic diseases can be caused by larger mutations in chromosomes. Chromosomal abnormalities may result from either the total number of 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 Image Credit: U.S. Department of Energy Human Genome Program, 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. (See Appendix F for more information about chromosomal abnormalities.) 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 and Y) 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 Individuals carrying one mutated Affected individuals must carry two Only females can pass on copy of a gene in each cell will be mutated copies of a gene mitochondrial conditions to their affected by the disease Parents of affected individual are children (maternal inheritance) Each affected person usually has one usually unaffected, and each carry a Both males and females can be affected affected parent single copy of the mutated gene Can appear in every generation of a family Tends to occur in every generation of (known as carriers) an affected family Not typically seen in every generation A N e w Yo r k – M i d - A t l a n t i c G u i d e f o r P at i e n t s a n d H e a lt h P r o f e s s i o n a l s X-linked Dominant X-linked Recessive Females are more frequently affected Males are more frequently affected than females than males Families with an X-linked recessive disorder often Fathers cannot pass X-linked have affected males, but rarely affected females, traits to their sons in each generation (no male-to-male transmission) Both parents of an affected daughter must be carriers Only mother must be carrier of affected son (fathers cannot pass X-linked traits to their sons)  Chapter 1 : Genetics 101 9 1.4 Genetic Variation All individuals are 99.9 percent the same genetically. The differences in the sequence of DNA among individuals, or genetic variation, explain some of the differences among people such as physical traits and higher or lower risk for certain diseases. Mutations and polymorphisms are forms of genetic variation. While mutations are generally associated with disease and are relatively rare, polymorphisms are more frequent and their clinical significance is not as straightforward. Single nucleotide polymorphisms (SNPs, pronounced “snips”) are DNA sequence variations that occur when a single nucleotide is altered. SNPs occur every 100 to 300 bases along the 3 billion-base human genome. A single individual may carry millions of SNPs. Although some genetic variations may cause or modify disease risk, other changes may result in no increased risk or a neutral presentation. For example, genetic variants in a single gene account for the different blood types: A, B, AB, and O. Understanding the clinical significance of genetic variation is a complicated process because of our limited knowledge of which genes are involved in a disease or condition and the multiple gene-gene and gene-behavior-environment interactions likely to be involved in complex, chronic diseases. New technologies are enabling faster and more accurate detection of genetic variants in hundreds or thousands of genes in a single process. Selected References Department of Energy, Human Genome Project Education Resources www.ornl.gov/sci/techresources/Human_Genome/education/education.shtml Genetics Home Reference www.ghr.nlm.nih.gov National Human Genome Research Institute www.genome.gov/health Online Mendelian Inheritance in Man www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=omim  Chapter 2 : Diagnosis of a Genetic Disease Advances in understanding the genetic mechanisms behind disease enable the development of early diagnostic tests, new treatments, or interventions to prevent disease onset or minimize disease severity. This chapter provides information about the importance of clinical signs that may be suggestive of a genetic disease, family history, the different uses of genetic testing, and the different types of genetic diseases. Mutations may be inherited or developed in response to environmental stresses such as viruses or toxins. The ultimate goal of this manual is to use this information to treat, cure, or, if possible, prevent the development of disease. 12 2.1 History and Physical Examination Diagnosing genetic disease requires a comprehensive clinical examination composed of three major elements: 1. Physical examination 2. Detailed medical family history 3. Clinical and laboratory testing, if appropriate and available Although primary care providers may not always be able to make a definitive diagnosis of a genetic disease, their role is critical in collecting a detailed family history, considering the possibility of a genetic disease in the differential diagnosis, ordering testing as indicated, and when available, appropriately referring patients to genetic specialists. 2.2 Red Flags for Genetic Disease Several factors indicate the possibility of a genetic disease in a Image Credit: U.S. Department of Energy Human Genome Program, differential diagnosis. One major factor is the occurrence of a www.ornl.gov/hgmis. condition among family members that is disclosed when the family history is obtained (see Chapter 3, Pedigree and Family History-taking). The occurrence of the same condition such as multiple miscarriages, stillbirths, or childhood deaths in more than one family member (particularly first-degree relatives) is suggestive of a genetic disease. Additionally, family history of common adult conditions (e.g., heart disease, cancer, and A N e w Yo r k – M i d - A t l a n t i c G u i d e f o r P at i e n t s a n d H e a lt h P r o f e s s i o n a l s dementia) that occur in two or more family members at relatively young ages may also suggest a genetic predisposition. Other clinical symptoms suggestive of a genetic disease include developmental delay, mental retardation, and congenital abnormalities. Dysmorphologies (unusual physical features), as well as growth problems, can be suggestive of a genetic disorder. Although these clinical features may be caused by a number of factors, genetic conditions should be considered as part of the differential diagnosis, particularly if the patient expresses several clinical features together that might be indicative of a syndrome (e.g., mental retardation, distinct facial features, and a heart defect or heart defects). Some physical features such as wide-set or droopy eyes, flat face, short fingers, and tall stature may appear unique or slightly different than the average. Even though these rare and seemingly mild features may not immediately be suggestive of a genetic disease to a primary care provider, an evaluation by a genetics specialist may be helpful in identifying the presence of a genetic disease. Genetic conditions should not be ruled out in adolescents or adults, though many genetic conditions appear during childhood. Genetic diseases can remain undetected for several years until an event such as puberty or pregnancy triggers the onset of symptoms or the accumulation of toxic metabolites results in disease later in life.  Chapter 2 : Diagnosis of a Genetic Disease 13 2.3 Uses of Genetic Testing Genetic tests can be used for many different purposes, some of which are listed in Table 2.1. Newborn screening is the most widespread use of genetic testing. (See Chapter 4 for more information about newborn screening.) Almost every newborn in the United States is screened for a number of genetic diseases. Early detection of these diseases can lead to interventions to prevent the onset of symptoms or minimize disease severity. Carrier testing can be used to help couples learn if they carry—and Table 2.1 thus risk passing to their children—an allele (variant form of the Uses of Genetic Tests same gene) for a recessive condition such as cystic fibrosis, sickle cell anemia, or Tay-Sachs disease. This type of testing is typically offered Newborn Screening to individuals who have a family history of a genetic disorder or Carrier Testing people in ethnic groups with an increased risk of specific genetic Prenatal Diagnosis conditions. If both parents are tested, the test can provide Diagnostic/Prognostic information about a couple’s chance of having a child with a specific Predictive/Predispositional genetic condition. Prenatal diagnostic testing is used to detect changes in a fetus’ genes or chromosomes. This type of testing is offered to couples with an increased risk of having a baby with a genetic or chromosomal disorder. A tissue sample for testing can be obtained through amniocentesis or chorionic villus sampling (see Appendix H). Genetic tests may be used to confirm a diagnosis in a symptomatic individual or used to monitor prognosis of a disease or response to treatment (see Appendix G). Predictive or predispositional testing can identify individuals at risk of getting a disease prior to the onset of symptoms. These tests are particularly useful if an individual has a family history of a specific disease and an intervention is available to prevent the onset of disease or minimize disease severity. Predictive testing can identify mutations that increase a person’s risk of developing conditions with a genetic basis such as certain types of cancer. 2.4 Types of Genetic Testing Several different methods are currently used in genetic testing laboratories. The type of test will depend on the type of abnormality being measured. In general, three major types of genetic testing are available: cytogenetic, biochemical, and molecular. 2.4.1 Cytogenetic Testing. Cytogenetics involves the examination of whole chromosomes for abnormalities. Chromosomes of a dividing human cell can be analyzed clearly under a microscope. White blood cells, specifically T lymphocytes, are the most readily accessible cells for cytogenetic analysis because they are easily collected from blood and are capable of rapid division in cell culture. Cells from tissues such as bone marrow (for leukemia), amniotic fluid (for prenatal diagnosis), and other tissue biopsies can also be cultured for cytogenetic analysis. Following several days of cell culture, chromosomes are fixed, spread on microscope slides, and then stained. The staining methods for routine analysis allow each of the chromosomes to be individually identified. The distinct bands of each chromosome revealed by staining allow for analysis of chromosome structure. 14 2.4.2 Biochemical Testing. The enormous numbers of biochemical reactions that routinely occur in cells require different types of proteins. Several classes of proteins such as enzymes, transporters, structural proteins, regulatory proteins, receptors, and hormones exist to fulfill multiple functions. A mutation in any type of protein can result in disease if the mutation results in failure of the protein to function correctly. (See Table 2.2 for types of protein alterations that may result in disease.) Clinical testing for a biochemical disease uses Table 2.2 Types of Protein Changes techniques that examine the protein instead of the gene. Resulting in Altered Function Tests can be developed to measure directly protein activity (enzymes), level of metabolites (indirect No protein made measurement of protein activity), and the size or Too much or too little protein made quantity of protein (structural proteins). These tests Misfolded protein made require a tissue sample in which the protein is present, Altered active site or other critical region typically blood, urine, amniotic fluid, or cerebrospinal Incorrectly modified protein fluid. Since proteins are less stable than DNA and can Incorrectly localized protein degrade quickly, the sample must be collected, stored (buildup of protein) properly, and shipped promptly according to the Incorrectly assembled protein laboratory’s specifications. 2.4.3 Molecular Testing. For small DNA mutations, direct DNA testing may be the most effective method, particularly if the function of the protein is unknown and a biochemical test cannot be developed. A DNA test can be performed on any tissue sample and requires very small amounts of sample. Some genetic diseases can be caused by many different mutations, making molecular testing challenging. For example, more than 1,000 mutations in the cystic A N e w Yo r k – M i d - A t l a n t i c G u i d e f o r P at i e n t s a n d H e a lt h P r o f e s s i o n a l s fibrosis transmembrane conductance regulator (CFTR) gene can cause cystic fibrosis (CF). It would be impractical to examine the entire sequence of the CFTR gene routinely to identify the causative mutation because the gene is quite large. However, since the majority of CF cases are caused by approximately 30 mutations, this smaller group of mutations is tested before more comprehensive testing is performed. (See Appendix I for more information on genetic testing methodologies.) Selected References American College of Medical Genetics www.acmg.net Gelehrter TD, Collins FS, Ginsburg D. Principles of Medical Genetics. 2nd Edition. Baltimore: Williams & Wilkins; 1998. GeneTests www.genetests.org Mahowald MB, McKusick VA, Scheuerle AS, Aspinwall TJ (eds). Genetics in the Clinic: Clinical, Ethical, and Social Implications for Primary Care. St. Louis: Mosby, Inc.; 2001. Scriver CR, Beaudet AL, Sly WS, Valle D (eds). The Molecular and Metabolic Basis of Inherited Disease. New York: McGraw-Hill; 2001. Thompson MW, McInnes RR, Willard HF. Thompson & Thompson: Genetics in Medicine, 5th Edition. Philadelphia: W.B. Saunders Company; 1991.  Chapter 3 : Pedigree and Family History-taking Healthcare professionals have long known that common diseases (e.g., heart disease, cancer, and diabetes) and rare diseases (e.g., hemophilia, cystic fibrosis, and sickle cell anemia) can run in families. For example, if one generation of a family has high blood pressure, it is not unusual for the next generation to have similarly high blood pressure. Family history can be a powerful screening tool and has often been referred to as the best “genetic test.” Family history should be updated on each visit, and patients should be made aware of its significance to their health. (See Appendix D for the Healthcare Provider Card.) 16 3.1 Importance of Family History Family history holds important information about an individual’s past and future life. Family history can be used as a diagnostic tool and help guide decisions about genetic testing for the patient and at-risk family members. If a family is affected by a disease, an accurate family history will be important to establish a pattern of transmission. A family history can also identify potential health problems such as heart disease, diabetes, or cancer that an individual may be at increased risk for in the future. Early identification of increased risk may allow the individual and health professional to take steps to reduce risk by implementing lifestyle changes, introducing medical interventions, and/or increasing disease surveillance. Although providers may be familiar with childhood-onset genetic conditions, many complex, adult-onset conditions can also run in families. For example, about 5 to 10 percent of all breast cancers are hereditary. These cancers may be caused by mutations in particular genes such as BRCA1 or BRCA2. The U.S. Preventive Services Task Force (USPSTF) recommends that doctors and patients be aware of family history patterns associated with an increased risk for BRCA mutations. A N e w Yo r k – M i d - A t l a n t i c G u i d e f o r P at i e n t s a n d H e a lt h P r o f e s s i o n a l s Another example of an adult-onset disease that can be inherited is Alzheimer’s disease. Although most Alzheimer’s disease cases are not seen in many consecutive generations, a small number of cases are hereditary. Hereditary Alzheimer’s disease is an extremely aggressive form of the disease and typically manifests before the age of 65. Three genes that cause early-onset Alzheimer’s disease have been identified to-date. Despite the importance of family history in helping define occurrence of a genetic disorder within a family, it should be noted that some genetic diseases—such as single-gene disorders like Duchenne muscular dystrophy and hemophilia A, as well as most cases of Down syndrome, chromosomal deletion syndromes, and other chromosomal disorders—are caused by spontaneous mutations. Therefore, a genetic disorder cannot be ruled out in the absence of a family history.  C h a p t e r 3 : Pe d i g r e e a n d F a m i l y H i s t o r y - t a k i n g 17 3.2 How to Take a Family Medical History A basic family history should include three generations. To begin taking a family history, healthcare professionals start by asking the patient about his/her health history and then ask about siblings and parents. Questions should include: 1. General information such as names and birthdates 2. Family’s origin or racial/ethnic background 3. Health status, including medical conditions and ages at diagnoses 4. Age at death and cause of death of each deceased family member 5. Pregnancy outcomes of the patient and genetically-related relatives It may be easier to list all the members of the nuclear family first, then go back and ask about the health status of each one. After you have taken the family history of the patient’s closest relatives, go back one generation at a time and ask about aunts, uncles, grandparents, and first cousins. 3.3 Pedigrees One can record a family history in several ways, including charts, checklists, forms, and drawings of a family tree or “pedigree.” Pedigrees are sometimes the preferred method of collecting family history information because a pedigree can be drawn more quickly than the information can be written and allows patterns of disease to emerge as it is drawn. A pedigree represents family members and relationships using standardized symbols (see Pedigree Symbols below). Because the family history continually changes, the pedigree can be updated easily on future visits. Patients should be encouraged to record information and update their family histories regularly. PEDIGREE SYMBOLS 18 The sample pedigree below contains information such as age or date of birth (and age at death and cause of death for all deceased family members), major medical problems (with age of onset), birth defects, learning problems and mental retardation, and vision or hearing loss at a young age. For family members with known medical problems, ask if they smoke, what their diet and exercise habits are, and if they are overweight. SAMPLE PEDIGREE A N e w Yo r k – M i d - A t l a n t i c G u i d e f o r P at i e n t s a n d H e a lt h P r o f e s s i o n a l s Selected References Bennett RL. The Practical Guide to the Genetic Family History. New York: Wiley-Liss, Inc.; 1999. Centers for Disease Control and Prevention. Office of Genomics and Disease Prevention. Using Family History to Promote Health. www.cdc.gov/genomics/public/famhist.htm Genetic Alliance. Taking a Family History; 2004. www.geneticalliance.org/ws_display.asp?filter=fhh March of Dimes–Genetics and Your Practice. www.marchofdimes.com/gyponline/index.bm2 My Family Health Portrait familyhistory.hhs.gov U.S. Department of Health and Human Services. U.S. Surgeon General's Family Health Initiative; 2004. www.hhs.gov/familyhistory/  Chapter 4 : Newborn Screening Almost every child born in the United States undergoes state-mandated newborn screening. In each state, a small blood sample (“heel stick”) is collected within 48 hours of birth. The sample is sent to a laboratory and tested for a panel of medical conditions. State newborn screening panels include testing for an ever-increasing number of conditions. Every year, over 100,000 newborns have an abnormal screen for one of these conditions. In the event that a newborn is affected by one of the diseases screened for, early medical intervention can reduce the severity of the condition and possibly even prevent symptoms from occurring. This chapter provides an overview of newborn screening programs in the New York – Mid- Atlantic region. In the U.S., newborn screening programs are state-mandated, and each state’s list of screened conditions varies. Efforts are underway to develop a consistent panel to be used throughout the U.S. New technologies have enabled substantial expansion of newborn screening programs. 20 4.1 Overview of Newborn Screening By state law, all newborns are screened for various serious medical conditions. Babies with any of these conditions may look healthy at birth; but, if left untreated, these conditions can cause health problems such as mental retardation, slow growth, and even death. These outcomes may be prevented with treatment and long-term follow-up. Newborn screening programs began in the U.S. in the 1960s with the work of Dr. Robert Guthrie, who developed a screening test for phenylketonuria (PKU). PKU is an inherited metabolic disease caused by a mutation of the gene for an enzyme responsible for metabolism of the amino acid phenylalanine. Children who are identified early can avoid foods with phenylalanine, thereby avoiding buildup of the amino acid, which would otherwise lead to brain damage and mental retardation. When Dr. Guthrie introduced a system for collecting and transporting blood samples on filter paper, cost-effective, wide-scale genetic screening became possible. 4.1.1 Screening Procedure and Follow-up. A nurse or other medical professional takes a few drops of blood from the baby’s heel. The blood should be drawn after the baby is 24 hours old, but before the baby leaves the hospital. This blood sample is sent to a newborn screening laboratory. The baby’s doctor contacts the parent(s) if the results are not in normal range for any of the A N e w Yo r k – M i d - A t l a n t i c G u i d e f o r P at i e n t s a n d H e a lt h P r o f e s s i o n a l s screened conditions. If this scenario occurs, follow-up testing may be required. 4.1.2 Retesting. Sometimes a baby must be screened again. This does not necessarily mean that a medical condition is present. Retesting may need to be done if: The blood sample was taken before the baby was 24 hours old A problem occurred with the way the blood sample was taken The first test showed risk of a possible medical condition The baby’s doctor or the state’s newborn screening program will contact the parent(s) if retesting is necessary. It is important to get this testing done right away. 4.1.3 Clinical Evaluation and Diagnostic Testing. Occasionally, the results of the newborn screen strongly suggest that the infant has one of the conditions. The newborn screening program notifies one of four specialty-care centers, depending on which test was abnormal. The specialties are metabolic, cystic fibrosis, endocrine, and hematology. The parents will be notified by the newborn screening program, the primary physician, the hospital of birth, or the specialty- care center, depending on the newborn screening program’s protocol. If this happens, it is extremely important that the parents bring their child to the specialist as soon as possible, sometimes that very day, for further evaluation and laboratory testing. 4.1.4 Treatment. The treatment for each condition is different and may include a special diet, hormones, and/or medications. It is very important to start the treatment of affected infants as soon as possible.  Chapter 4 : Ne wborn Screening 21 4.1.5 Tests Performed. Completed tests vary from state to state. Typically, each state has an advisory committee that reviews and selects which conditions are screened for based on current scientific and clinical data. Social and ethical issues are also included in the decision-making process. Increasingly, tandem mass spectrometry is being used for newborn screening. This technology is capable of screening for over 50 metabolic conditions from dried blood-spot specimens. In 1999, the American College of Medical Genetics released a report commissioned by the U.S. Health Resources and Services Administration recommending a uniform screening panel of 29 genetic conditions. Efforts are under way to examine the feasibility of instituting a uniform newborn screening policy so that every infant is screened for the same conditions, regardless of the state in which he or she is born. In general, the conditions on newborn screening panels fall into one of the following groups: metabolic conditions, endocrine conditions, hemoglobin conditions, and pulmonary conditions. For information on the diseases tested for in a particular state, contact that state’s newborn screening program or the National Newborn Screening and Genetics Resource Center (genes-r-us.uthscsa.edu). Screening for more conditions may be available at other laboratories for a fee. 4.2 Newborn Screening Programs Delaware New Jersey Delaware Health and Social Services, New Jersey Department of Health and Division of Public Health Senior Services Delaware Public Health Laboratory Public Health and Environmental Laboratories 30 Sunnyside Road Newborn Genetic and Biochemical P.O. Box 1047 Screening Program Smyrna, DE 19977 Health and Agriculture Building Ph: 302.223.1520 Market & Warren Streets, P.O. Box 371 www.dhss.delaware.gov/dhss/dph/chca/dphnsp1. Trenton, NJ 08625 html Ph: 609.292.4811 www.state.nj.us/health/fhs/nbs/index.shtml District of Columbia District of Columbia Department of Health New York Newborn Screening Program New York State Department of Health 825 North Capital Street, NE Wadsworth Center Washington, DC 20002 Newborn Screening Program Ph: 202.650.5000 Empire State Plaza, P.O. Box 509 www.dchealth.dc.gov/doh/site/default.asp Albany, NY 12201 Ph: 518.473.7552 Maryland www.wadsworth.org/newborn Maryland Department of Health and Mental Hygiene Pennsylvania Division of Newborn and Pennsylvania Department of Health Childhood Screening Bureau of Family Health 201 West Preston Street, Room 1A6 Division of Newborn Screening Baltimore, MD 21201 Health and Welfare Building Ph: 410.767.6099 7th and Forster Streets www.fha.state.md.us/genetics/newprog.cfm 7th Floor, East Wing Harrisburg, PA 17120 Ph: 717.783.8143 www.dsf.health.state.pa.us/health/cwp/view.asp?a =179&q=232592 22 Virginia West Virginia Virginia Department of Health West Virginia Department of Health and Division of Child and Adolescent Health Human Resources Pediatric Screening and Genetic Services Office of Maternal, Child, and Family Health 109 Governor Street, 8th Floor Newborn Metabolic Screening Program Richmond, VA 23219 350 Capitol Street, Room 427 Ph: 804.864.7712 Charleston, WV 25301 www.vahealth.org/genetics Ph: 304.558.5388 www.wvdhhr.org/nbms 4.3 Newborn Hearing Screening Hearing loss is a common condition present in as many as one in every 300 babies. When hearing loss goes undetected, even for just a year or two, serious delays in speech and language can result. When hearing loss is discovered in infancy, treatment can be started early enough to prevent or lessen these delays. 4.3.1 Screening Procedure. Babies are usually screened in the first few days of life, before they are discharged from the hospital. The screen, which is quick and A N e w Yo r k – M i d - A t l a n t i c G u i d e f o r P at i e n t s a n d H e a lt h P r o f e s s i o n a l s painless, is done by one of two methods: otoacoustic emissions (OAE) or automatic brainstem response (ABR). Both of these methods involve placing tiny earplugs in the ear canals or earphones on the ears and using a computer to measure the baby’s reactions to sound. The OAE test measures how the baby’s inner ear responds to sound, and the ABR test measures how the brain responds to sound. Typically, testing is done when the baby is asleep and unaware of the testing. Passing the hearing screening indicates that the baby’s hearing is within the normal range at the time of the test. However, some babies with a family history of hearing loss, repeated ear infections, or serious illness may develop hearing loss later. The child’s hearing and speech should be monitored as he or she grows. 4.3.2 Retesting. Babies who do not pass the first screening are retested and may be referred to an audiologist (hearing specialist). The second screening should occur while the baby is still in the hospital or within two weeks after leaving the hospital. If the baby does not pass the initial hearing screening, it does not mean that the baby has permanent hearing loss since most babies who do not pass the first hearing screening pass the second screening. Often, babies can have fluid, blockage, or debris in the ear that clears naturally. If further testing shows that a baby has hearing loss, an audiologist along with an ear, nose, and throat specialist can best determine the next steps. 4.3.3 Treatment. Treatment will depend on the type and degree of hearing loss. If hearing loss is permanent, treatment options include hearing aids, cochlear implants, or early intervention services.  Chapter 4 : Ne wborn Screening 23 4.4 Newborn Hearing Screening Programs Delaware New York Delaware Health and Social Services, New York State Department of Health Division of Public Health Division of Family Health Delaware Newborn Hearing Early Intervention Program Screening Program Empire State Plaza 655 Bay Road, Suite 216 Corning Tower, Room 287 Dover, DE 19903 Albany, NY 12237 Ph: 302.741.2975 Ph: 518.473.7016 www.dhss.delaware.gov/dhss/dph/chca/ www.health.state.ny.us/community/infants_child dphnhsp1.html ren/early_intervention/newborn_hearing_screening District of Columbia Pennsylvania District of Columbia Department of Health Pennsylvania Department of Health Newborn Hearing Screening Program Pennsylvania Newborn Hearing Screening and 825 North Capital Street NE, 3rd Floor Intervention Program Washington, DC 20002 Health and Welfare Building Ph: 202.671.5000 7th and Forster Streets 7th Floor, East Wing Maryland Harrisburg, PA 17108 Maryland Department of Health and Ph: 717.783.8143 Mental Hygiene www.dsf.health.state.pa.us/health/CWP/view.asp? Office of Genetics and Children with A=179&QUESTION_ID=232585 Special Health Care Needs Infant Hearing Virginia 201 West Preston Street, Room 423A Virginia Department of Health Baltimore, MD 21201 Virginia Early Hearing, Detection, and Ph: 410.767.6432 Intervention Program www.fha.state.md.us/genetics/inf_hrg.cfm 109 Governor Street, 8th Floor Richmond, VA 23219 New Jersey Ph: 804.864.7713 New Jersey Department of Health and www.vahealth.org/hearing Senior Services Early Hearing Detection and West Virginia Intervention Program West Virginia Department of Health and 50 East State Street, P.O. Box 364 Human Resources Trenton, NJ 08625 Office of Maternal, Child, and Family Health Ph: 609.292.5676 Right From The Start Project www.nj.gov/health/fhs/ehdi/index.shtml Department of Health 350 Capitol Street, Room 427 Charleston, WV 25301 Ph: 304.558.5388 www.wvdhhr.org/rfts/newbornhearing.asp 24 Selected References Advisory Committee on Heritable Disorders and Genetic Diseases in Newborns and Children www.hrsa.gov/heritabledisorderscommittee/ American Academy of Pediatrics, Newborn Screening Overview www.medicalhomeinfo.org/screening/newborn.html Centers for Disease Control and Prevention, Early Hearing Detection and Intervention Program www.cdc.gov/ncbddd/ehdi March of Dimes www.marchofdimes.com National Newborn Screening and Genetics Resource Center genes-r-us.uthscsa.edu A N e w Yo r k – M i d - A t l a n t i c G u i d e f o r P at i e n t s a n d H e a lt h P r o f e s s i o n a l s  Chapter 5 : Genetic Counseling As members of a healthcare team, genetic counselors provide information and support to families affected by or at risk for a genetic disorder. They serve as a central resource of information about genetic disorders for other healthcare professionals, patients, and the general public. This chapter provides an overview of the role of genetic counselors and their approach to educating patients and identifying individuals/families at risk of a genetic disorder. Patient resources are also provided. 26 5.1 Role of Genetic Counseling Genetic counselors help identify families at possible risk of a genetic condition by gathering and analyzing family history and inheritance patterns and calculating chances of recurrence. They provide information about genetic testing and related procedures. They are trained to present complex and difficult-to-comprehend information about genetic risks, testing, and diagnosis to families and patients. Genetic counselors can help families understand the significance of genetic conditions in relation to cultural, personal, and familial contexts. They also discuss available options and can provide referrals to educational services, advocacy and support groups, other health professionals, and community or state services. Genetic counselors can serve as a central resource of information about genetic conditions for other healthcare professionals, patients, and the general public. (See Appendix O for Making Sense of Your Genes: A Guide to Genetic Counseling.) 5.2 Process of Genetic Counseling In general, a genetic counseling session aims to: Increase the family’s understanding of a genetic condition Discuss options regarding disease management and the risks and benefits of further testing and other options