Genetics and Primary Care

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Genetics and Primary Care

• Cystic Fibrosis and Ethnicity-Based
• Carrier Screening

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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

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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

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Outline

• Principles of genetic carrier screening
• Cystic fibrosis carrier screening
• Screening guidelines for other ethnic groups
• Ethical issues in carrier screening
• Resource Information

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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

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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

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Carrier Testing

• To determine an individuals carrier status for a
  specific genetic disease
• Not usually offered on a population basis

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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

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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)

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Carrier Frequencies based on Ethnic Origin
Condition
Carrier Frequency
Population
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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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Carrier Rates Cystic Fibrosis
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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)

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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

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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.

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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)

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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

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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?

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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

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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 Marcias 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 Partners Test was Negative
• NP Smith encourages Marcia to inform her siblings
  and parents of her carrier status

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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

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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

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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

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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

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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)

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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

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Asian patients

• Standard to review MCV. If 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

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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 w/quantitative Hb electrophoresis
• CF carrier rate about 1/65
• no standards re offering CF carrier screening

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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

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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)

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How, When, Where

• How? Give a center a call
• When? ASAP
• Where? Oregon Genetics Clinics Contact List

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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

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ADDITIONAL INFORMATION
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Family History Questionnaire

• Screens for reproductive genetic risks
• Appropriate for patients considering pregnancy or
  already pregnant
• Contains referral guidelines for genetic services

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Assessment Areas

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

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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

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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