Genetics and Primary Care_ Cystic Fibrosis and Ethnicity-Based ..

Genetics and Primary Care Cystic Fibrosis and Ethnicity-Based Carrier Screening 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 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 Outline • Principles of genetic carrier screening • Cystic fibrosis carrier screening • Screening guidelines for other ethnic groups • Ethical issues in carrier screening • Resource Information 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 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 Carrier Testing • To determine an individual’s carrier status for a specific genetic disease • Not usually offered on a population basis 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 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) Carrier Frequencies based on Ethnic Origin Population African-American Condition Sickle Cell Cystic Fibrosis Beta-Thalassemia Carrier Frequency 1 in 10 1 in 65 1 in 75 Ashkenazi Jewish Gaucher disease Cystic Fibrosis Tay-Sachs disease Dysautonomia Canavan disease Alpha-Thalassemia Beta-Thalassemia Cystic Fibrosis Tay Sachs disease Cystic Fibrosis Beta-Thalassemia Beta-Thalassemia Cystic Fibrosis Sickle Cell 1 in 15 1 in 26 - 1 in 29 1 in 30 1 in 32 1 in 40 1 in 20 1 in 50 1 in 25 - 1 in 29 1 in 30 1 in 46 1 in 30 - 1 in 50 1 in 25 1 in 29 1 in 40 Asian European American French Canadian, Cajun Hispanic Mediterranean 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 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 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 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 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 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 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 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. 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 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 Carrier Rates: Cystic Fibrosis Ethnic Group Northern European Caucasian Ashkenazi Jewish Southern European Caucasian Hispanic African American Asian Carrier Frequency 1/25 – 1/29 1/26 – 1/29 1/29 1/46 1/65 ~1/90 (?) Detection Rate 85-90% 97% 70-80% 57% 72% ~30% (?) Carrier risk after negative test ~1 in 250 ~1 in 930 ~1 in 97 to 1 in 140 ~1 in 105 ~1 in 232 Not available 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) 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 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. 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) 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 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?” 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 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 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 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 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 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 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) 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 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 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 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 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) How, When, Where • How? Give a center a call • When? ASAP • Where? Oregon Genetics Clinics Contact List 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 ADDITIONAL INFORMATION Family History Questionnaire • Screens for reproductive genetic risks • Appropriate for patients considering pregnancy or already pregnant • Contains referral guidelines for genetic services Assessment Areas • Maternal age • Family medical history (both sides) • Current pregnancy/pre-pregnancy history • Ethnic background (both sides) 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 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