Carrier Screening for Cystic Fibrosis

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Transcript Carrier Screening for Cystic Fibrosis

Dee Quinn, MS, CGC
August, 2009
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.
One of the most common autosomal
recessive diseases in Caucasians
Occurs in 1 in 3300 births
30,000 affected persons in the United
Sensitivity of
Mutation Analysis
(United States)
Ashkenazi Jews
Native Americans
African Americans
O'Sullivan, B, Freedman, S.
Cystic Fibrosis. Lancet 2009;
CFTR - cystic fibrosis transmembrane
conductance regulator
Chromosome 7q31.2
Identified in 1989
Composed of 27 exons, 250kB of genomic
Gene product is a 1480-amino acid membrane
protein that functions as a regulated chloride
channel in epithelial cells
More than 1500 mutations have been found in
this gene
Expressed in epithelial cells of:
respiratory tract
sweat and salivary glands
reproductive tract
Responsible for:
◦ CF
◦ Chronic sinusitis
Ratjen, F. Cystic fibrosis:
Pathogenesis and future
treatment strategies. Respir
Care 2009; 54(5): 595-602.
GI, pancreas
Current life expectancy 31-37 years
UK study estimated life expectancy
for child born today with CF is 50
 Most labs test for 25-97 mutations
 10 of the identified CF mutations occur in
more than 1% of CF chromosomes
 Most common mutation (Δ F508) found in
66% of individuals with CF
 5 classes of CFTR mutations
 Genotype/phenotype correlations may be
helpful in predicting pancreatic sufficiency
Class I, II and III mutations are more common
and associated with pancreatic insufficiency
Class IV and V are less common and usually
associated with pancreatic sufficiency
CFTR gene interacts with other intracellular
proteins which may affect clinical symptoms
Most common mutation in North America
Deletion of phenylalanine in codon 508  misfolded protein
Protein product still functioning as Cl channel, but is
degraded in the endoplasmic reticulum
ΔF508 (homozygosity): classical phenotype
Moskowitz, SM, Clinical practice and genetic counseling for cystic
fobrosis and CFTR_related disorders. Genet Med 2008; 10(12): 851-868
Gene therapy
◦ uses viral vector
◦ Still being developed
Ataluren trial
◦ Drug which “reads through” stop codons
◦ Currently beginning phase 3 trials
◦ Can only be used for individuals who have CF
mutation as result of nonsense mutations (Class I)
◦ Ataluren is designed to allow the ribosome to
ignore the premature stop signal and continue
translation of the mRNA, resulting in formation of a
functioning protein.
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
Screening program should include:
◦ Specific provider and patient educational
◦ Protocol for addressing positive screening results
◦ 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
Blood spots from infants taken within days
of birth to identify infants at increased risk
for a specific genetic disorders
Tests for immunoreactive trypsinogen (IRT),
repeat IRT if elevated
Trypsinogen is synthesized in the pancreas
Individuals with CF have elevated levels of
trypsinogen, regardless of pancreatic sufficiency
Currently offered in most states – AZ began
newborn screening in 11/07
Important for:
◦ Early treatment of respiratory illnesses
◦ Evidence for nutritional benefit
Diagnostic test is sweat chloride test
DNA testing is important for family planning
and new treatments
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
Additional indications for screening
Echogenic bowel detected on prenatal ultrasound (15%
of infants with CF have meconium ileus)
Infertility in males
Provider’s Role:
Purpose of screening
Voluntary nature of screening
Symptoms of CF, treatment and
Genetics of CF and population
Meaning of positive and negative test
Factors to consider in deciding to have
or not to have screening
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
◦ 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
Technically demanding and complex procedure
Available on a limited basis
Expensive: $4,000 - $12,000
Ethical implications
Does not detect all carriers
Estimate of residual risk applies only when
family history is negative and to the current
Cannot make reliable predictions for
outcome based on mutations
Various outcomes of prenatal and
newborn testing 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
◦ Unnecessary anxiety created
◦ Inadequate pretest information
◦ Informed consent
◦ Insurance discrimination
◦ Expense swell health costs
◦ Societal pressure not to bear affected offspring
Cystic Fibrosis Foundation
GeneTests and GeneReviews
National Society of Genetic Counselors
Mountain States Genetics Network
“It will be very important to see how this goes.
Certainly it requires primary care providers to
become more familiar with genetics than
many of them have previously had occasion
to do.”
-Francis Collins