Genetic Counseling Student Version F2024 PDF

Genetic Counseling Dr. Guri Tzivion Office: GC18 [email protected]  Learning Objectives GEM.6. Apply the principles of genetic counselling to risk assessment in medical genetics. Given a clinical scenario, students should be able to: GEM.6.1. Apply the principles of...

Genetic Counseling Dr. Guri Tzivion Office: GC18 [email protected]  Learning Objectives GEM.6. Apply the principles of genetic counselling to risk assessment in medical genetics. Given a clinical scenario, students should be able to: GEM.6.1. Apply the principles of genetic inheritance to counsel patients. GEM.6.2. Assess genetic risk based on an elicited family history, using a genetic pedigree. GEM.6.3. Recognize the benefits and risks of genetic testing. GEM.6.4. Recognize the legal and ethical responsibilities of physicians related to genetic testing. Textbook Reading: Human Genetics: From Molecules to Medicine. Chapter 12: The Diagnostic Approach for a Child with Multiple Anomalies or Dysmorphic Features Section:  “Family Medical History and Pedigree Analysis Chapter 18: Ethical Concerns in Medical Genetics  Entire chapter Textbook Reading: Thompson & Thompson – Genetics and Genomics in Medicine, 9th ed. Chapter 17. Genetic Counseling and Risk Assessment  Entire chapter Chapter 19: Ethical and Social Issues in Genetics and Genomics  Entire chapter  What Do Medical Geneticists Do?  Diagnosis and treatment of genetic diseases  Pre-symptomatic testing for genetic diseases  Carrier testing, especially for high-risk people  Genetic counseling during pregnancy  Definition of Genetic counseling An educational counseling process for individuals and families who have a genetic disease or who are at risk for such a disease.  Genetic counseling: What should we do? The medical diagnosis The mode of inheritance and its implications in of the disorder and the terms of prognosis and risk of developing and treatment. transmitting it. The choice or option available for dealing with the risk.  Genetic counseling: What should we do? Evaluation of the Discussion of the family history importance of testing other family members who are at risk of developing the disease or of being a carrier. Establishing the diagnosis Investigation Taking a history Examination laboratory tests  Family history Taking a history Personal medical history Genetic counseling: physical examination  Genetic counseling: laboratory tests  Prenatal diagnosis: Cytogenetics, biochemistry, DNA, and/or other testing;  Neonatal screening  Factors in genetic counseling Genetic defects that occur frequently in certain populations Either parent already has a child/children with birth defects or genetic disorders Relatives (parents or siblings) having genetic disorders  Factors in genetic counseling Delayed age of onset Penetrance (the proportion of individuals with the mutation who exhibit clinical symptoms) Expressivity (the proportion of individuals with a given genotype who also possess the associated phenotype: quantitative) Phenocopy (Mimicking of a genetic phenotype caused by environmental conditions) Pleiotropy (one gene influences multiple, seemingly unrelated phenotypic traits)  Genetic counseling: Genetic heterogeneity A similar phenotype being caused by more than one genetic mechanism. Most commonly used for a similar phenotype being caused by mutations in different genes. Allelic heterogeneity refers to different mutations in the same gene.  Genetic counseling example Chances of having a child with Down syndrome increase with the mother's age a woman has a 1 in 350 chance of conceiving a child with Down syndrome at age 35, a 1 in 110 chance at age 40, and a 1 in 30 chance at age 45. Aged-associated increased risk of genetic disorders  Factors in genetic counseling  Genetic defects that occur frequently in certain populations  Either parent already has a child/children with birth defects or genetic disorders  Relatives (parents or siblings) having genetic disorders  Genetic counseling: calculating and presenting the risk 1 ． Genotype – Known: estimating the probability of recurrence risk by Mendelian principals. Examples: AD: (Alzheimer’s disease). Affected genes: APP, PSEN1, or PSEN2 AR: (androgen insensitivity syndrome). Affected genes: AR, x-linked 2. Genotype – Unknown: estimating the probability of recurrence risk (conditional probability or Bayes principal).  Genetics Across the Life Span  Pre-implantation Screening/Diagnosis (PGS/PGD)  Carrier screening  Testing for lethal diseases/gender  Prenatal  MSAFP/Ultrasound  Amniocentesis/CVS  Neonatal  Inborn errors of metabolism  Adolescents and adults  Carrier screening  Pre-symptomatic testing  Predictive testing  Therapies Enhancement therapies Individualized medicine  Indications for genetic counselling  Previous child with multiple congenital anomalies, intellectual disability, or an isolated birth defect such as neural tube defect or cleft lip and palate  Personal history or family history of a hereditary condition, such as cystic fibrosis, fragile X syndrome, congenital heart defect, hereditary cancer, or diabetes  Pregnancy at risk for a chromosomal or hereditary disorder  Consanguinity  Teratogen exposure, such as to occupational chemicals, medications, alcohol  Repeated pregnancy loss or infertility  Newly diagnosed abnormality or genetic condition  Before undertaking genetic testing and after receiving results, particularly in testing for susceptibility to late-onset disorders, such as hereditary cancer syndromes or neurological disease  As follow-up for a positive result of a newborn test, as with phenylketonuria; a heterozygote (preconception carrier) screening test, such as Tay-Sachs; or a positive first- or second-trimester maternal serum screen, a noninvasive prenatal screen by free fetal DNA analysis or abnormal fetal ultrasound examination results Types of Genetic Testing and Screening  Carrier Screening  Carrier screening determines whether an individual carries a copy of an altered gene for a particular recessive disease even though they do not show the trait phenotypically  Carrier screening is often used if a particular disease is common in a couple’s ethnic background or if there is a family history of the disease  Examples of carrier tests include those for Tay-Sachs disease or sickle cell disease  Carrier Screening Ashkenazi Jewish Population Tay-Sachs (1/30), Canavans Disease (1/40), and Gaucher Disease (1/15) Caucasian Population Cystic Fibrosis (1/25) African-American Population Sickle Cell Anemia (1/10) Greek/Mediterranean/Asian Population Thalassemias Pre-implantation Genetic Diagnosis (PGD)  PGD is used following in vitro fertilization to diagnose a genetic disease or condition before the embryo is implanted in the uterus.  A single cell is removed from an embryo and examined for chromosome abnormalities or genetic changes.  Parents and doctors can then choose which embryos to implant.  Fetal Screening/Prenatal Diagnosis  Prenatal diagnosis allows parents to diagnose a genetic condition in their developing fetus  Techniques such as amniocentesis, chorionic villi sampling (CVS), and regular scheduled ultrasound allow parents to monitor the health of the growing fetus Prenatal diagnostic Techniques  Amniocentesis: Chromosomes, Enzymes DNA Testing AFP- protein made by  Chorionic Villi liver Sampling (CVS): Chromosomes, Enzymes  Ultrasound: DNA  Maternal blood Fetal Anatomy multiple marker screening: Down syndrome, Neural Tube Defects, trisomy 18  Newborn Screening The most widespread type of genetic screening, newborn screening is used to detect genetic or metabolic conditions for which early diagnosis and treatment are available State-mandated newborn tests in the US typically screen anywhere from 4 to over 30 genetic or metabolic disorders Testing protocols and mandates vary from State to State The goal of newborn screening is to identify affected newborns quickly in order to provide early treatment and care  Newborn Screening - PKU Phenylketonuria (PKU) is the prototype of genetic diseases for which mass newborn screening is justified (see Chapter 19 ) because: 1. It is relatively common in some populations (up to ~1 in 2,900 live births) 2. Mass screening is feasible 3. Failure to treat has severe consequences (profound intellectual disability) 4. Treatment is effective if begun early in life  Newborn Screening - PKU  To allow time for the postnatal increase in blood phenylalanine levels, the test is performed after 24 hours of age.  Central laboratories assay blood from a heel prick for blood phenylalanine levels and phenylalanine-to-tyrosine ratio.  Positive test results must be confirmed quickly because delays in treatment beyond 4 weeks postnatally have profound effects on intellectual outcome.  The current recommendation is to initiate treatment within the first week of life  Testing methodologies  Biochemical genetic testing: assay for specific metabolites that indicate a genetic disease  Cytogenetic testing: examination of the chromosomes for visible alterations that indicate a genetic defect  Direct genetic testing: examination of DNA to determine if mutations are present Before DNA testing, diagnostic genetic testing relied on the detection of phenotypes and/or metabolites as well as the visualization of chromosomes. In some cases, these tests are still used today 1. Taste test - baby with salty-tasting skin - cystic fibrosis 2. Color of urine - black urine disease - alkaptonuria 3. Green ring around iris - copper build up - Wilson’s disease 4. Blood test for high levels of phenylalanine - PKU 5. Chromosomal abnormalities - Down Syndrome (trisomy chr 21), XXY, XO etc.  Examples of disorders that can be detected using enzyme- activity assays  Galactosemia – galactose metabolism - galactose-1- phosphate uridylyltransferase (type 1 galactosemia)  PKU – phenylalanine metabolism - phenylalanine hydroxylase  Lesch-Nyhan - purine metabolism - hypoxanthine guanine phosphoribosyltransferase (HPRT)  Maple syrup urine disease – amino acid metabolism - proteins of the branched-chain alpha-keto acid dehydrogenase complex  Examples of disorders that can be detected using enzyme- activity assays  Tay Sachs Disease – build up of GM2 gangliosides - DNA test is available but does not detect all of the known alleles.  By performing a test for the enzyme that is deficient in Tay Sachs patients, beta-hexosaminidase A, more cases can be detected than through DNA testing.  Cytogenetic Testing Used to detect visible chromosomal abnormalities. Visible alterations in the structure of chromosomes can include:  Large Deletions  Inversions  Translocations Alterations in the number of chromosomes  Down syndrome  Direct genetic testing examination of DNA (or RNA) for the presence of mutations Direct genetic testing analyzes the sequence of a person’s DNA to determine if a mutation is present.  Creating a Pedigree International standards should be followed when creating a pedigree  start with the indexed patient or the consultand and then proceed on both sides of the family over three generations. The consultands are marked with an arrow.  list the men (and the paternal family line) on the left and the women (and the maternal line) on the right. Siblings in a family are listed chronologically by birth from left to right.  the symbols for affected individuals are shaded.  Sample question John and Jessica are planning a family, but since each has a brother who has Sickle Cell anemia (Autosomal Recessive disease), they are concerned that their children may develop the disease. Neither, John or Jessica, nor their respective parents have the disease. They consult a genetic counselor that tells them: A. There is very little chance that any of their children will have sickle-cell disease B. That all of their children will have sickle-cell disease C. That one out of four of their children could be expected to have sickle cell- disease D. That its possible that none of their children will have the disease but blood tests on them both will be required to make sure Creating a pedigree  Family History use in Risk Assessment  High Risk  Age at onset of a disease in a first-degree relative relatively early compared to the general population  Two affected first-degree relatives  One first-degree relative with late or unknown disease onset and an affected second-degree relative with premature disease from the same lineage  Two second-degree maternal or paternal relatives with at least one having premature onset of disease  Three or more affected maternal or paternal relatives  Presence of a “moderate-risk” family history on both sides of the pedigree  Moderate Risk  One first-degree relative with late or unknown onset of disease  Practice Questions Instructions: Go to https://socrative.com/ Log in using your Student Login Room Name: TZIVIONMD1 Break  Learning Objectives GEM.6. Apply the principles of genetic counselling to risk assessment in medical genetics. Given a clinical scenario, students should be able to: GEM.6.1. Apply the principles of genetic inheritance to counsel patients. GEM.6.2. Assess genetic risk based on an elicited family history, using a genetic pedigree. GEM.6.3. Recognize the benefits and risks of genetic testing. GEM.6.4. Recognize the legal and ethical responsibilities of physicians related to genetic testing.  The Benefits and Harms of Genetic Testing – Informed Consent Patients must give informed consent to all procedures, including tests – This is because of the importance of patient autonomy In order to give informed consent, patients must be informed about: – The reasons for a procedure – The relevant benefits and risks of a procedure – Alterative procedures along with their relevant benefits and risks  The Benefits and Harms of Genetic Testing – Possible Benefits Often the relevant possible benefits and harms associated with a medical procedure are physical benefits and harms. With genetic testing, however, there are also potential psychological and social benefits and harms. Patients must understand these benefits and risks before they can give informed consent to a test. Possible Benefits: Allows for additional screening tests to detect a disease earlier Earlier and hopefully more effective treatment of a disease Allows for planning to deal with a possible disease Allows planning for decisions about having children One should, of course, consider the analytic validity, clinical validity,  Possible Harms of Genetic Testing Patient confusion about the meaning of test results:  Confusion about predisposition vs. guaranteed determinism  Difficulty in the interpretation of percentage risks, relative risks, absolute risk etc. Psychological distress, anxiety, and worry  May be made worse if no treatment or cure exists  Would you want to know that you are highly likely to get early onset Alzheimer’s? “Nocebo” effect, where a patient’s condition worsens more  Possible Harms of Genetic Testing Concerns about abnormality vs. perfection: Particularly for prenatal testing Social stigma if the information is released: Family and friends may treat one differently Would you still marry someone who carries the gene for Huntington’s disease? Employers and insurers might want to discriminate Discrimination by employers or insurers based on genetic information is illegal through the U.S. 2008 Genetic Information Nondiscrimination Act  Tests for predisposition (or carriage) of a genetic disease Scenarios about informing family members:  If a patient tests positive for having a gene that predisposes the patient to have a disease (for example colorectal cancer), then the patient’s family members may also have that gene, and if so, they could be screened more often for that disease  If a patient tests positive for having a gene for a recessive disease (for example cystic fibrosis), then other family members might also have that gene, and if so, that could influence their choices about whether to have children  Do the patient’s family members deserve to know that they  Should patients’ families be informed about risks revealed by genetic tests?  There are two conflicting values: Confidentiality Preventing harm  Ideally, the physician would get the patient to inform the patient’s family, such that patient confidentiality would not be breached But what if the patient is unwilling (or unable) to inform their family? Should a physician directly inform the patient’s genetic family of that risk?  First, we need some background on confidentiality and duties to warn in order to prevent harm…  Four Principles of Medical Ethics Non-maleficence (do no harm) and Beneficence (doing good) What counts as benefit and harm is not always obvious, and often depends on a particular patient’s personal values Patient Autonomy safeguarding an individual’s rights to control his or her medical care and medical information, free of coercion Justice - ensuring that all individuals are treated equally and fairly Justice can be defined as the fair distribution and equal availability of health care and genetic testing for all of  Confidentiality Confidentiality is presumed to be the patient’s choice, and is therefore justified by patient autonomy Patients may be harmed or stigmatized by the release of information Patients can, of course, provide specific waivers to confidentiality (which is a choice to allow the physician Confidentiality also to share information) encourages patients to share information with physicians, and sharing of information is necessary for treatment and diagnosis generally HIPAA and Breaching Confidentiality to Prevent Harm The U.S. law requiring confidentiality is called HIPAA (the Health Insurance Portability and Accountability Act of 1996) Confidentiality is justified by patient autonomy, but patient autonomy is limited such that one need not respect choices that will harm others, so confidentiality can be breached to prevent harm to others HIPAA allows for a breach of confidentiality to prevent harm if a physician, “has a good faith belief that the disclosure: (1)is necessary to prevent or lessen a serious and imminent threat to the health or safety of the patient or others  Breaching Confidentiality in Genetic Testing Is the duty to warn people to prevent harm applicable to the families of patients who are known to have genes related to a disease.  Reasons to Breach Confidentiality  Harm may be prevented In cases of genetic predisposition to diseases, harm might be prevented by additional screening tests which might lead to earlier diagnosis and more effective treatment But if there is no effective treatment for a disease, then there would be no reason to breach confidentiality HIPAA requires that breaches of confidentiality must be in cases where someone is “reasonably able to prevent or lessen the threat”  In cases of carriage of a recessive gene, harm might be prevented through a choice to not have children, or to do specific prenatal or IVF testing Reasons to Preserve Confidentiality In general, there should be a high standard to be met for breaching confidentiality Breaches of confidentiality may result in psychological and social harm Breaches of confidentiality may lessen the patient’s trust in a doctor If doctors breach confidentiality of genetic tests, patients may be less likely to have genetic tests done (and hence, less likely to receive appropriate treatment) The harm may not be likely enough Consider carriage of a recessive gene for a disease. If Joe has that recessive gene, then his brother Bob has roughly a 50% chance of having that gene (absent other information). So if Bob has a child, there is only a 25% chance that the child will have the gene. And the child will only be harmed if the child got the second recessive gene from the other parent. (This is, of course, oversimplified.) HIPAA requires that breaches of confidentiality be in cases of serious and  American Medical Association Suggested Policy  The AMA suggests that physicians should tell patients that they expect the patient to inform their genetic family members who are subject to a preventable risk - So the AMA suggests that physicians should maintain confidentiality  The AMA also suggests that physicians should tell patients of a possible duty that the patient may have to inform family members about risks before the patient consents to genetic testing  American Society of Human Genetics Suggested Policy The physician can notify members of the patient’s family if the following four factors are all present: – Attempts to encourage disclosure on the part of the patient have failed – The harm is highly likely to occur and is serious and foreseeable – The at-risk relative is identifiable – The disease is preventable, treatable, or medically accepted standards indicate that early monitoring will reduce the genetic risk  Court Case 1. Pate v. Threlkel Florida Supreme Court - 1995 Marianne New was diagnosed and treated for medullary thyroid carcinoma Three years later, New’s daughter, Heidi Pate was diagnosed with advanced medullary thyroid carcinoma Pate sued New’s physician, Dr. Threlkel, claiming that the physician should have warned Pate that she might have the genetic predisposition to the disease The Supreme Court of Florida ruled that a physician has a duty to warn patients about the genetically transferable nature of conditions they are treated for, and that the physician also has a duty to make sure relatives are warned of the risk. However, the court ruled that the physician should only pass on information to relatives by encouraging the patient to inform their relatives. So, Pate v. Threlkel ruled that confidentiality should be maintained because having the patient inform their family was  Court Case 2. Safer v. Estate of Pack New Jersey Supreme Court - 1996  When Donna Safer was 10-years old, her father died of colorectal cancer, under the care of Dr. Pack  26-years later, Safer was diagnosed with colorectal cancer that had spread to an ovary  Safer sued the estate of the late Dr. Pack on the grounds that colorectal cancer was known to have a hereditary component, and that Pack should have warned her (Safer’s father couldn’t have warned her because he died when she was a child)  The New Jersey Supreme Court ruled that Pack should have personally informed Safer, and that the duty to warn justified a breach of confidentiality for avertable risk from genetic causes  Summary Legalities  Informed consent conversations for genetic testing must ensure that the patient has a good understanding of the risks and benefits specific to genetic testing  There is no clear consensus on whether there is a duty for the physician to warn family members of possible risks  Minimally, you should urge patients to disclose the information to their family  For a recent discussion on legal issues around genetic testing: https://www.sciencemag.org/news/2019/04/medical-dna-sequencing-leads-lawsuits-and-legal-qu estions?fbclid=IwAR2rED87swSWvlb8KC4h31CT2Ezi0NIjilA2l1YDzGy5zOLcwv1kcDxV26I  Also, for more detailed information on laws around genetic testing and Questions?