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

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

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)

African-American Sickle Cell Cystic Fibrosis Beta-Thalassemia 1 in 10 1 in 65 1 in 75 Ashkenazi Jewish Gaucher disease Cystic Fibrosis Tay-Sachs disease Dysautonomia Canavan disease 1 in 15 1 in in 29 1 in 30 1 in 32 1 in 40 Asian Alpha-Thalassemia Beta-Thalassemia 1 in 20 1 in 50 European AmericanCystic Fibrosis1 in in 29 French Canadian, Cajun Tay Sachs disease1 in 30 Hispanic Cystic Fibrosis Beta-Thalassemia 1 in 46 1 in in 50 Mediterranean Beta-Thalassemia Cystic Fibrosis Sickle Cell 1 in 25 1 in 29 1 in 40 Population ConditionCarrier Frequency Carrier Frequencies based on Ethnic Origin

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 - list of labs offering carrier testing for specific genetic disorderswww.genetests.com

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 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

CF Carrier Screening ACOG guidelines, Oct 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 GroupCarrier Frequency Detection RateCarrier risk after negative test Northern European Caucasian 1/25 – 1/ %~1 in 250 Ashkenazi Jewish1/26 – 1/2997%~1 in 930 Southern European Caucasian 1/ %~1 in 97 to 1 in 140 Hispanic1/4657%~1 in 105 African American1/6572%~1 in 232 Asian~1/90 (?)~30% (?)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

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

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): 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 - list of labs offering carrier testing for specific genetic disorderswww.genetests.com

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