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  • The Human Genome Project, completed on April 14, 2003, With collaboration from genetics specialists, genetic risk assessment, screening and testing can become an important part of primary medical care
  • Consultation with genetics specialiists is critical as the field is advancing at a rapid pace and genetic tests and interpretation of results are complex.
  • Purpose: To detect couples at risk of having children with prenatally diagnosable genetic diseases Guides to screening are in Genetics Resource Packet March of Dimes Genetic Screening Pocket Facts Preconception/prenatal family history assessment guide Insurance coverage for ethnicity-based carrier screening tests: Some insurers and some plans will cover testing, others will not. Each patient needs to check their personal plan prior to screening.
  • Appropriate carrier tests should be offered to each patient based on his/her ethnic background & family history Counseling before screening should include: Purpose of screening, voluntary nature of testing Range of symptoms and severity of each disease being screened for Risk of carrier status and affected offspring based on ethnicity Meaning of positive and negative results Factors to consider in deciding to have or not have testing
  • ACOG guidelines, Oct. 2001 recommend pffeing CF screening to: Persons with a family history of CF Reproductive partners of carriers or persons with CF Couples in whom one or both partners are Caucasian and are planning a pregnancy or seeking prenatal care AND “ Making CF screening available” to couples in other racial or ethnic groups at lower risk
  • Cannot emphasize enough that different mutations confer different risks! Know the details about a given mutation before talking to a patient. Consult with genetics or call the testing laboratory to get the most up-to-date information. Genetic counseling is available prior to testing should a couple want to discuss each of these disorders in more depth before making decisions about testing.
  • Standard of care to offer to persons of AJ background or their partners prior to conception or during 1 st trimester: Tay-Sachs disease Cystic Fibrosis Canavan disease
  • Make sure that if the patient is already pregnant, that screening is performed by leukocyte or platelet assay. This necessitates special drawing and handling which should be set up in advance. Make sure you send to a lab that offers this type of testing. Otherwise, look for such a lab on
  • Detection rate much lower in non-AJ persons. Incidence of the disease in non-AJ population is very low as is carrier rate. Find testing labs through
  • See GENETIC CARRIER SCREENING : OPTIONS FOR PERSONS OF ASHKENAZI JEWISH ANCESTRY in the resource packet. This fact sheet can be given to patients of AJ background Some genetics labs offer “AJ carrier panels” with various tests on them. Labs will also often have patient education materials. Be aware that different labs test for different mutations or panels of mutations and will have different detection rates.
  • See Sample Family History Questionnaire in resource packet Use for patients considering pregnancy or already pregnant Screens for patients who may have reproductive genetic risks. Not comprehensive – captures only genetic and maternal health information relevant to current/future offspring
  • Transcript

    • 1. Genetics and Primary Care Cystic Fibrosis and Ethnicity-Based Carrier Screening
    • 2. Genetics in Health Care: the 21 st Century
      • The Human Genome Project has brought inherited health factors to the forefront
      • Genetic risk assessment, screening and testing is becoming part of primary medical care
      • Clinical genetics and primary care need to work together to offer appropriate services
    • 3. We are Working Together
      • Risk assessment for common genetic conditions
        • likely to be performed in the primary care/prenatal setting
      • Screening and testing for genetic conditions
        • increasingly performed in primary care/prenatal care
      • Patients with rare or more complex genetic conditions, risks, or family histories
        • likely continue to be served by genetics specialists
    • 4. Outline
      • Principles of genetic carrier screening
      • Cystic fibrosis carrier screening
      • Screening guidelines for other ethnic groups
      • Ethical issues in carrier screening
      • Resource Information
    • 5. Genetics Review
      • Most carrier tests are for autosomal recessive conditions (some for X-linked)
      • In general, carriers of autosomal recessive conditions do not have symptoms and remain unaffected
      • Both partners must be carriers to have a child with an autosomal recessive condition
      • Review of autosomal recessive inheritance
    • 6.  
    • 7. Carrier Screening
      • Population-based screening:
        • Particular genetic carrier tests offered to everyone in the general population
      • Targeted population-based screening:
        • Carrier screening limited to particular groups of people determined to be at higher risk for specific genetic disorders
        • e.g. Ethnicity-based carrier screening
    • 8. Carrier Testing
      • To determine an individual’s carrier status for a specific genetic disease
      • Not usually offered on a population basis
    • 9. Carrier Testing
      • Available to clients with a family history of an autosomal recessive or X-linked genetic condition for which carrier testing available
        • e.g. Fragile X syndrome, Duchenne muscular dystrophy, Hemophilia A or B
        • e.g. PKU, Alpha-1-antitrypsin deficiency, Galactosemia
    • 10. Ethnicity-Based Genetic Carrier Screening
      • Purpose: To detect couples at risk for prenatally diagnosable genetic diseases
      • Types of tests offered based on clients’ ethnic background
      • Offered to all individuals of that ethnic background (targeted population screening)
    • 11. Population Condition Carrier Frequency Carrier Frequencies based on Ethnic Origin 1 in 25 1 in 29 1 in 40 Beta-Thalassemia Cystic Fibrosis Sickle Cell Mediterranean 1 in 46 1 in 30 - 1 in 50 Cystic Fibrosis Beta-Thalassemia Hispanic 1 in 30 Tay Sachs disease French Canadian, Cajun 1 in 25 - 1 in 29 Cystic Fibrosis European American 1 in 20 1 in 50 Alpha-Thalassemia Beta-Thalassemia Asian 1 in 15 1 in 26 - 1 in 29 1 in 30 1 in 32 1 in 40 Gaucher disease Cystic Fibrosis Tay-Sachs disease Dysautonomia Canavan disease Ashkenazi Jewish 1 in 10 1 in 65 1 in 75 Sickle Cell Cystic Fibrosis Beta-Thalassemia African-American
    • 12. Principles of Carrier Screening
      • Should be offered to patients:
        • Seeking preconception counseling, OR
        • Seeking infertility care, OR
        • During the first or early second trimester of pregnancy
    • 13. Timing
      • Offering screening prior to pregnancy allows client more reproductive choices
      • Screening during pregnancy:
        • Depends on gestational age
        • If early in pregnancy, can do sequential screening
        • Concurrent testing is an option if later gestational age
    • 14. Informed consent
      • Counseling before screening should include:
        • Purpose, voluntary nature of screening
        • Range of symptoms and severity of each disease
        • Risk of carrier status and affected offspring
        • Meaning of positive and negative results
        • Factors to consider in decision-making
        • Further testing would be necessary for prenatal diagnosis
    • 15. Informed consent
      • Utilize patient resources materials
        • Patient brochures about CF and other ethnicity-based genetic screening available from multiple sources
        • Carrier screening videos can be shown in office settings
      • Document informed consent discussion and patient decision
    • 16. Carrier Screening Resources
      • March of Dimes Genetic Screening Facts
      • Patient brochures:
        • CF screening, Ashkenazi Jewish ethnicity based carrier screening, MOD fact sheets
      • - list of labs offering carrier testing for specific genetic disorders
    • 17. Important Points
      • Carrier screening is optional
      • Patient education/informed decision-making is essential
      • Most tests detect a majority but not all carriers
      • Screening may or may not be covered by insurance ( not covered by OHP and some other major insurers )
      • Genetic counseling is available and advised for carriers and carrier/carrier couples
    • 18. Cystic Fibrosis
      • Chronic lung disease with GI malabsorption
      • Incidence of 1/3300 in Caucasian and AJ populations
      • Age of onset early childhood. Variable symptoms. Life expectancy now 20-35 years
      • Treatment: daily respiratory therapy, digestive enzymes, medication to promote lung function
    • 19. CF Carrier Screening
      • 1/25-1/29 carrier rate in general Caucasian population
        • Same in Ashkenazi Jewish population
      • Carrier screening by DNA mutation analysis. ACOG suggests panel of 25 most common mutations*
        • Some labs do additional mutations but at higher cost
      • Detection rate in AJ population is 97%
      • Detection rate in Caucasian population is 80-90%
      • * Preconception and Prenatal Carrier Screening for Cystic Fibrosis: The American College of Obstetricians and Gynecologists, Oct. 2001.
    • 20. CF Carrier Screening
      • ACOG guidelines, Oct. 2001
      • Offer CF screening to:
        • Individuals with a family history of CF
        • Reproductive partners of carriers/persons with CF
        • Couples in whom one or both partners are Caucasian and are planning a pregnancy or seeking prenatal care
      • “ Make CF screening available” to couples in other racial or ethnic groups at lower risk
    • 21. CF Carrier Results
      • Many tests detect a majority but not all carriers
        • Detection rates differ by ethnicity
        • Negative results do not eliminate risk
      • Different mutations may confer different risks
        • Example: CFTR R117H mutation and 5T allele
      • Genetic consultation is available to carriers and strongly advised for carrier/carrier couples
    • 22. Carrier Rates: Cystic Fibrosis Not available ~30% (?) ~1/90 (?) Asian ~1 in 232 72% 1/65 African American ~1 in 105 57% 1/46 Hispanic ~1 in 97 to 1 in 140 70-80% 1/29 Southern European Caucasian ~1 in 930 97% 1/26 – 1/29 Ashkenazi Jewish ~1 in 250 85-90% 1/25 – 1/29 Northern European Caucasian Carrier risk after negative test Detection Rate Carrier Frequency Ethnic Group
    • 23. Issues in CF Screening
      • Variable severity and symptoms; mild vs. classic mutations
        • Know the details about the mutation before discussing results with the patient
      • Potential to detect an “affected” person through screening (i.e. person having two mutations and mild or no symptoms)
    • 24. Issues in CF Screening
      • Congenital absence of the vas deferens (CAVD) as a mild manifestation of CF
        • Should this be discussed with clients? Tested for?
      • Prenatal testing for women who are carriers when father of baby not available for carrier testing – risks/benefits
      • Rare chance of uncovering non-paternity
    • 25. CF screening case study
      • Marcia is a 25 year old Caucasian woman who comes to her first prenatal visit at 9 weeks gestation. Her husband, Mark, age 28, also Caucasian, attends the visit with her. There is no family history of significance.
      • Her prenatal care provider, Ann Smith, NP, discusses the option of CF carrier screening with the couple.
    • 26. Case Study: Informed Consent
      • NP Smith discusses:
        • The symptoms and natural history of CF
        • The risk of being a CF carrier is ~1/29 for individuals of Caucasian ancestry
        • The risk of both members of this couple being CF carriers is ~1/840
        • The risk of having an affected child is ~1/3300 (before testing)
    • 27. Case Study: Informed Consent
        • The risk of the fetus having CF if both are carriers is 25%. Options in this case:
          • amniocentesis to determine the status of the fetus
          • waiting until birth
        • The risk of the fetus having CF if one is a carrier and the other has a negative screen is ~1/560*
        • The risk of the fetus having CF if both have negative screen results is ~1/78,400*
        • *Preconception and Prenatal Carrier Screening for Cystic Fibrosis: ACOG/ACMG, Oct 2001
    • 28. Case Study: Informed Consent
        • Carrier screening is optional
        • Insurance may or may not cover CF screening
        • Their gestational age is early enough that they have the option of sequential vs. concurrent screening
      • Ms. Smith gives the couple the PacNoRGG brochure entitled “ Should I Have a Cystic Fibrosis Carrier Test?”
    • 29. CF Case Study – Results
      • Marcia and Mark decide to have CF screening
      • Results
        • Marcia has a deltaF508 mutation and is a CF carrier
        • Mark is negative for the 25 mutation panel
      • NP Smith informs couple of results
        • Marcia is a carrier of a common CF mutation. It will not affect her health
        • Mark has a negative screen; residual carrier risk is ~1/140
    • 30. Case Study: Results Counseling
        • The residual risk of CF in this fetus and in future pregnancies of theirs is ~1/560
        • The chance for each of Marcia’s siblings to be carriers of the same mutation is 50%
      • The couple is given the PacNoRGG brochure entitled “So I Have a Cystic Fibrosis Gene, But My Partner’s Test was Negative”
      • NP Smith encourages Marcia to inform her siblings and parents of her carrier status
    • 31. Ashkenazi Jewish patients
      • Standard of care to offer to persons of AJ background and/or their partners :
        • Tay-Sachs disease
        • Cystic Fibrosis
        • Canavan disease
        • Familial Dysautonomia
      • All autosomal recessive genetic conditions
    • 32. Tay-Sachs Carrier Testing
      • Progressive, fatal neurodegenerative condition with no treatment
      • 1 in 30 carrier rate (AJ)
      • Carrier screening:
        • Enzyme based (Hex A) – 98% detection rate
          • pregnant women: leukocyte or platelet test
        • DNA based – 94% carrier detection rate
    • 33. Canavan Carrier Testing
      • Progressive neurodegenerative disease; Onset infancy/childhood; Usually fatal by 10 yr; No treatment or cure
      • 1 in 40 carrier rate (AJ)
      • Carrier screening by DNA mutation analysis
        • 98% carrier detection rate in persons of AJ ancestry
    • 34. Familial Dysautonomia
      • Sensory and autonomic neuropathy (AR):
        • Lack of tears; decreased reaction to pain and taste; abnormal temperature and blood pressure control; GI dysmotility; dysphagia; excessive sweating; motor coordination problems
        • Normal intelligence
      • 1 in 27 carrier rate in AJ population
      • Now part of the standard panel offered to people of Ashkenazi ancestry*
      • * Obstet Gynecol 2004 Aug; 104(2):425-8. ACOG Committee Opinion Number 298
    • 35. Other Carrier Tests Available to Persons of AJ Descent
      • Bloom syndrome
      • Fanconi anemia group C
      • Gaucher disease, type 1
      • Niemann-Pick, type A
      • Mucolipidosis IV
      • Others? (Von Gierke disease, hereditary deafness, torsion dystonia)
    • 36. Hispanic/Latino patients
      • No standard protocol for carrier testing
        • Cystic Fibrosis: carrier rate 1/46
        • Beta-thalassemia: carrier rate 1/30 to 1/50
        • Sickle cell or other hemoglobin trait:
          • Carrier rate 1/30 (Caribbean) to 1/200
    • 37. Asian patients
      • Standard to review MCV. If <80, screen for thalassemia w/quantitative Hb electrophoresis:
        • Alpha-thalassemia carrier rates up to 1/20
        • Beta-thalassemia carrier rates 1/30 (SE Asian) to 1/50
      • Cystic fibrosis –carrier rate 1/90 or less
        • Detection rate is very low (~ 30%)
        • Not standard to do CF screening
        • Make available upon patient request
    • 38. African-American patients
      • Standard to offer Sickle Cell screening
        • Sickle cell carrier rate about 1/10 to 1/12
        • Use Hb electrophoresis (NOT sickle dex)
      • Standard to review MCV
        • Beta-thalassemia carrier rate about 1/75
        • If MCV <80, offer thalassemia screen w/quantitative Hb electrophoresis
      • CF carrier rate about 1/65 –
        • no standards re: offering CF carrier screening
    • 39. Who to Refer to Genetics
      • Individuals with a family history of cystic fibrosis or other autosomal recessive disease
      • Couples where both members are known carriers for an autosomal recessive disease
      • Couples where one member is a carrier and has additional questions
      • Pregnant carriers who do not have results on the father of baby
    • 40. Oregon Genetics Providers
      • Portland
        • Oregon Health & Science University
        • Legacy Health Care
        • Northwest Perinatal Services
        • Kaiser-Permanente
      • Eugene
        • Center for Genetics & Maternal Fetal Medicine
      • Bend
        • Genetic Counseling of Central Oregon (cancer only)
    • 41. How, When, Where
      • How? Give a center a call
      • When? ASAP
      • Where? Oregon Genetics Clinics Contact List
    • 42. Resource Information
      • Provider and patient education materials
        • Genetic Web Site Reference List
        • Patient brochures
      • - list of labs offering carrier testing for specific genetic disorders
    • 44. Family History Questionnaire
      • Screens for reproductive genetic risks
      • Appropriate for patients considering pregnancy or already pregnant
      • Contains referral guidelines for genetic services
    • 45. Assessment Areas
      • Maternal age
      • Family medical history (both sides)
      • Current pregnancy/pre-pregnancy history
      • Ethnic background (both sides)
    • 46. Who To Refer – Prenatal Genetic Services
      • Advanced maternal age
      • Abnormal serum marker screening results
      • Fetal abnormalities on prenatal ultrasound
      • Personal or family history of a known or suspected genetic disorder, birth defect, or chromosome abnormality
      • Family history of mental retardation of unknown etiology
      • Patient with a medical condition known or suspected to affect fetal development
    • 47. Who to refer (cont)
      • Exposure to a known or suspected teratogen
      • Either parent or family member with a chromosome rearrangement
      • Parent a known carrier or has a family history of a disorder for which prenatal testing is available
      • Unexplained infertility or multiple pregnancy losses or previous stillbirths
      • Absence of the vas deferens
      • Premature ovarian failure