Transcript Carrier Screening for Cystic Fibrosis

Genetic Testing for
Cystic Fibrosis
Dee Quinn, MS, CGC
August, 2006
“Gene Testing Going
Mainstream”
Cystic Fibrosis Gene Test Offered
By Lauran Neergaard
AP Medical Writer
Monday, Oct. 1, 2001; 9:53 p.m. EDT
WASHINGTON –– Gene testing is going
mainstream: Starting this month, tens of
thousands of white Americans will be offered
testing to see if they carry a gene mutation that
causes cystic fibrosis even if no one in their
family has the disease.
CFTR Gene
Identified in 1989
 Cystic Fibrosis Transmembrane
Conductance Regulator (CFTR)
 27 exons, 250kB of genomic DNA
 Chromosome 7q

CFTR Gene
 cAMP-dependent
chloride channel
 Expressed in epithelial cells of:
respiratory tract
sweat and salivary glands
pancreas
intestine
reproductive tract
Clinical Phenotype



Respiratory
GI, pancreas
Reproductive
CFTR Mutations
 Over 1,000 mutations identified
 Most labs test for 25-87 mutations
 13 of the identified CF mutations occur in



more than 1% of CF chromosomes
72% of whites with CF are homozygous or
heterozygous for 8 mutations
5 classes of CFTR mutations
Genotype/phenotype correlations may not
be helpful
CFTR Mutations- ΔF508
Most common mutation in North America,
70-75% of the mutations
 Deletion of codon 508  Results in
shortening of the protein product
 Protein product still functioning as Cl
channel, but is retained in the
endoplasmic reticulum
 ΔF508 (homozygosity): classical
phenotype

Epidemiology
One of the most common autosomal
recessive diseases in Caucasians
 Occurs in 1 in 3300 births
 30,000 affected persons in the United
States

Recessive Pedigree
Epidemiology
Group
Incidence
Carrier
Frequency
Sensitivity
Caucasians
(United States)
1/3,300
1/29
80-90
Ashkenazi Jews
1/3,300
1/29
97
1/8-9,000
1/46
57
Native Americans
1/3,970-1/1,500
1/52
80-90
African Americans
1/15,300
1/60-65
69
Asian
Americans
1/32,100
1/90
30
Hispanics
Congenital Bilateral Absence of the Vas
Deferens (CBAVD)





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Vas deferens – carries sperm from the
epididymis to the ejaculatory ducts
Absence of vas occurs in 95% of males with CF
CBAVD: distinct genetic disorder which overlaps
with CF and causes infertility
Noncoding region of CFTR gene involved: intron
8 with thymidine tracts (5T/7T/9T)
60-70% of men with CBAVD carry one mutation
in the CFTR gene.
5T reduces the number of functional Cl
channels
Congenital Bilateral Absence of the Vas
Deferens (CBAVD)
Genotype - Phenotype
Correlation
CFTR Genotype
First Allele
Second Allele
Phenotypes
Range of
Classic (e.g., F508) Classic
Classic >> nonclassic
Mild (e.g., A455E) Classic or mild
Nonclassic > classic
R117H/5T
Classic or mild
Nonclassic > classic
R117H/7T
Classic or mild
Asymptomatic female or
CBAVD > nonclassic
5T/TG13 or TG12
>>
Classic or mild
CBAVD or nonclassic CF
asymptomatic carrier
5T/TG11
Classic or mild
Asymptomatic > CBAVD
7T or 9T
Classic or mild
Asymptomatic
Newborn Screening
 Blood
spots from infants taken within
days of birth to identify infants at
increased risk for a specific genetic
disorders
 Justifications:
– Early treatment of respiratory illnesses
– Evidence for nutritional benefit
 Currently
offered or in planning in
many states – AZ to begin newborn
screening by 9/07
Newborn Screening
Initial screen tests levels of IRT
(immunoreactive trypsinogen)
 Screening program should include:

– Specific provider and patient educational
materials
– Protocol for addressing positive screening
results
 Sweat
chloride
 DNA testing
– Development of systems in collaboration with
specialty care providers to track short-term
and long-term child outcomes and identify
resources to support this activity
Carrier Screening for CF
1997- NIH convened a Consensus
Conference
 1998- ACOG/ACMG formed Steering
Committee
 10/2001- “Preconception and Prenatal
Carrier Screening for Cystic Fibrosis”

ACOG/ACMG
Recommendations

Offer screening to:
– Individuals with a family history of CF
– Reproductive partners of individuals
with CF
– Couples in whom one or both are
Caucasian and are planning a
pregnancy or seeking prenatal care
– Other individuals must be given
written information
ACOG/ACMG
Recommendations

Provider’s Role:
–
–
–
–
–
–
Purpose of screening
Voluntary nature of screening
Symptoms of CF, treatment and
prognosis
Genetics of CF and population
frequencies
Meaning of positive and negative test
results
Factors to consider in deciding to have
or not to have screening
Additional Indications for Screening
 Echogenic
bowel detected on
prenatal ultrasound
 Infertility in males
Diagnostic Prenatal Tests

Testing offered when:
– When both members of a couple are carriers,
ie: 25% risk of having a baby with CF
– When one member of a couple is carrier and
other member not available for testing
– Testing options:
 Chorionic
villus sampling (CVS)
– 9-11 weeks
 Amniocentesis
– After 14 weeks
Other Approaches

Procedure
– In vitro fertilization
– One cell removed from early embryo to test for
mutations which were found in parents
– Cell without a CF genotype transferred to
mother’s uterus

Caveats
–
–
–
–
Technically demanding and complex procedure
Available on a limited basis
Expensive: $4,000 - $12,000
Ethical implications
ACOG/ACMG
Recommendations

Laboratory’s Role:
Reports should include results of
screening and an interpretation:
 Negative  Residual risk given
 Positive  Test other partner
Limitations of CF Screening
Does not detect all carriers
 Estimate of residual risk applies only when
family history is negative and to the
current pregnancy
 Cannot make reliable predictions for
outcome based on mutations
 Non-paternity

Genetic Counseling

Various outcomes of prenatal and
newborn will generate need for genetic
counseling:
–
–
–
–
Newly diagnosed child with CF
Healthy males who carry mutations
associated with infertility
Identification of positive/negative couples
who request additional mutational analyses
or counseling to clarify residual risk
Positive/positive couples
Ethical, Legal, and Social
Implications of CF Screening

Ethical
Unnecessary anxiety created
Inadequate pretest information

Legal
Informed Consent
Insurance discrimination

Social
Expense swell health costs
Societal pressure not to bear affected offspring
Resources
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Cystic Fibrosis Foundation
http://www.cff.org
http://cysticfibrosis.com
GeneTests and GeneReviews
http://www.genetests.org
National Society of Genetic Counselors
http://www.nsgc.org
Mountain States Genetics Network
http://www.mostgene.org
Conclusions
“It will be very important to see how
this goes. Certainly it requires the
obstetricians to become more
familiar with genetics than many of
them have previously had occasion
to do.”
-Francis Collins