It has been estimated that at least one in ten of the patients seen in primary care has a disorder with a genetic component. There are three main themes of genetics in primary care: identifying patients with, or at risk of, a genetic condition; clinical management of genetic conditions; communicating genetic information. Taking and considering a genetic family history is a key skill in identifying families with Mendelian disorders and clusters of common conditions such as cancer, cardiovascular disease and diabetes. General practitioners (GPs) have a key role in identifying patients and families who would benefit from being referred to appropriate specialist genetic services. General practice plays a key part in discussing results from the antenatal and newborn screening programs which are identifying carriers and people affected with genetic conditions. Information about genetic susceptibility in common conditions (currently being gathered through research studies) is likely to offer additional information about risk factors to aid management. Genomic information is currently being utilized in the stratified use of certain medicines.

1. Primary Care & Genetics
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. 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 26 - 1 in 29
1 in 30
1 in 32
1 in 40
Asian Alpha-Thalassemia
Beta-Thalassemia
1 in 20
1 in 50
European American Cystic Fibrosis 1 in 25 - 1 in 29
French Canadian,
Cajun
Tay Sachs disease 1 in 30
Hispanic Cystic Fibrosis
Beta-Thalassemia
1 in 46
1 in 30 - 1 in 50
Mediterranean Beta-Thalassemia
Cystic Fibrosis
Sickle Cell
1 in 25
1 in 29
1 in 40
Population Condition Carrier Frequency
Carrier Frequencies based on Ethnic Origin

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
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

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. 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

41. Family History Questionnaire
• Screens for reproductive genetic risks
• Appropriate for patients considering
pregnancy or already pregnant
• Contains referral guidelines for genetic
services

42. Assessment Areas
• Maternal age
• Family medical history (both sides)
• Current pregnancy/pre-pregnancy history
• Ethnic background (both sides)

43. 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

44. 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

45. ADDITIONAL
INFORMATION
www.maximedrx.com