egov.oregon.gov

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)

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

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