Posted April 1, 2005
Cystic fibrosis (CF) is the most common inherited disease that is
fatal among Caucasian people in the United States. The incidence
is estimated to be 1/3,000 live Caucasian births and approximately
1/29 Caucasians in the United States carry a single copy of the abnormal
CF gene or are carriers. These rates are lower in non-Caucasians.
Carriers are healthy individuals, usually unaware of their status
unless they have an affected relative or undergo genetic testing.
When one parent is a CF carrier, 50% of their offspring will also
be carriers. Couples, in whom both partners carry a CF mutation,
have a 25% chance of having an affected child with each pregnancy
and a 66.6% chance that unaffected children will be carriers.
The gene that causes CF is located on chromosome
7 and directs the synthesis of cystic fibrosis transmembrane conductance
regulator (CFTR). CFTR is a cAMP-regulated chloride channel in the
apical membrane of epithelial cells. More than 1,000 different disease-causing
mutations have been identified and are classified as severe or mild.
Compounding the problem is the same CFTR genotypes may show variable
expression in different patients, making it difficult to predict
the phenotype. The most common mutation, seen in 70% of cases in
Caucasians of northern European descent, is a 3-base pair deletion
resulting in the loss of amino acid 508 (DF508del).
Diagnostic testing is offered to patients with symptoms of CF and
has been added to the newborn screening programs in 8 states. About
two thirds of new cases in the US are in individuals who are <1
year old. A sweat chloride test, nasal potential difference and/or
immunoreactive trypsinogen test (used in newborns who may not produce
enough sweat), in conjunction with DNA studies, is used to confirm
the diagnosis. Prenatal diagnosis using DNA studies can be performed
with chorionic villus sampling or amniocentesis at 10-12 or 15-20
weeks of gestation, respectively. Evidence suggests that treating
the condition from birth may improve disease management and lung
In 2001, the American College of Medical Genetics and the American
College of Obstetricians and Gynecologists issued a policy statement
regarding screening for CF. Carrier screening should be offered to
the following: (1) individuals with a family history of CF, (2) reproductive
partners of individuals with CF and (3) couples in whom one or both
partners are Caucasian (of northern European or Ashkenazi Jewish
decent) and are planning a pregnancy or seeking prenatal care. This
allows CF carriers to choose whether or not to conceive biological
children and provides them the opportunity to pursue prenatal diagnosis
with the option of terminating the pregnancy. Couples should understand
that the DNA test cannot detect all mutations; therefore a negative
screen reduces, but does not eliminate, the risk of being a carrier.
A multiethnic standard screening panel of 23 CFTR mutations with
a US population frequency ≥1/1000 is recommended. Additional mutations
can be added or removed if they reach or fall below this frequency.
The screening panel is expected to have a sensitivity of 80% in Caucasians
of European decent, 90% in Caucasians of northern European descent
and 97% in Ashkenazi Jews. Detection rate in African-Americans and
Hispanics is 69% and 57%, respectively. The data for Asian-Americans
is unknown. Adding less common mutations results in only very small
increases in the sensitivity of screening.
When certain methods are used, the presence of normal genetic variants
can cause false positives. To eliminate false positive results, laboratories
will perform “reflex” testing for certain positive mutations.
These tests are done automatically and do not require additional
requests by the referring provider.
It is important to provide the laboratory with the appropriate information,
so they can provide the most accurate results. The minimum required
data includes: (1) if the test is being ordered to determine affected
or carrier status, (2) if there is a family history and (3) the patient’s
ethnicity. Diagnostic testing requires the laboratory to identify
2 mutations. If only 1 is found using a screening assay, further
testing may be warranted, depending on symptoms and ethnicity.
The issues surrounding CF screening remain complex. There are limitations
to the testing itself, as well as in predicting the severity of the
disease from the genotype. Despite this there is strong support for
screening and early intervention.
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NewsPath® Editor: Megan
J. DiFurio, MD, FCAP
This newsletter is produced in cooperation with the College of American
Pathologists Public Affairs Committee and may be reproduced in whole or
in part as a service to the medical community. Copyright © 2006 by
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