primary care and genetic testing
TRANSCRIPT
Primary Care & Genetics
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)
African-American Sickle CellCystic FibrosisBeta-Thalassemia
1 in 101 in 651 in 75
Ashkenazi Jewish Gaucher diseaseCystic FibrosisTay-Sachs diseaseDysautonomiaCanavan disease
1 in 151 in 26 - 1 in 291 in 301 in 321 in 40
Asian Alpha-ThalassemiaBeta-Thalassemia
1 in 201 in 50
European American Cystic Fibrosis 1 in 25 - 1 in 29
French Canadian, Cajun
Tay Sachs disease 1 in 30
Hispanic Cystic FibrosisBeta-Thalassemia
1 in 461 in 30 - 1 in 50
Mediterranean Beta-ThalassemiaCystic FibrosisSickle Cell
1 in 251 in 291 in 40
Population Condition Carrier 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
• 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 Carrier Frequency
Detection Rate Carrier risk after negative test
Northern European Caucasian
1/25 – 1/29 85-90% ~1 in 250
Ashkenazi Jewish 1/26 – 1/29 97% ~1 in 930
Southern European Caucasian
1/29 70-80% ~1 in 97 to 1 in 140
Hispanic 1/46 57% ~1 in 105
African American 1/65 72% ~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
• 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
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
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