Genetics and Primary Care

1. Genetics and Primary Care Cystic Fibrosis and Ethnicity-Based Carrier Screening

2. Genetics in Health Care: the 21st 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

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. Carrier Frequencies based on Ethnic Origin Condition Carrier Frequency Population

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 • www.genetests.com - 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

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 • www.ntsad.org

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 • www.ntsad.org

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 • www.genetests.com - list of labs offering carrier testing for specific genetic disorders

43. ADDITIONAL INFORMATION

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