National Medical Policy
Subject:
Genetic Testing for Cystic Fibrosis
Policy Number:
NMP132
Effective Date*:
April 2004
Updated:
February 2017
This National Medical Policy is subject to the terms in the
IMPORTANT NOTICE
at the end of this document
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manual(s), publication(s), citation(s), and documented guidance for
coverage criteria and benefit guidelines prior to applying Health Net
Medical Policies
The Centers for Medicare & Medicaid Services (CMS)
For Medicare Advantage members please refer to the following for coverage
guidelines first:
Use
X
Source
National Coverage Determination
(NCD)
National Coverage Manual Citation
Local Coverage Determination
(LCD)*
Article (Local)*
Other
Reference/Website Link
MLN Matters Number: MM7745
Related Change Request (CR) #: CR 7745
March 23, 2012. April Update to the Calendar
Year (CY) 2012 Medicare Physician Fee Schedule
Database (MPFSDB). Provider Types Affected:
http://www.cms.gov/Outreach-andEducation/Medicare-Learning-NetworkMLN/MLNMattersArticles/downloads/MM7745.pdf
Palmetto. MolDX. CFTR Gene Analysis Coding
and Billing Guidelines (M00076). Effective for
DOS 1/1/2013:
http://www.palmettogba.com/palmetto/MolDX.n
sf/docsCat/MolDx%20Website~MolDx~Browse%
20By%20Topic~Excluded%20Tests~CFTR%20G
Genetic Testing for Cystic Fibrosis Feb 17
1
ene%20Analysis%20Coding%20and%20Billing
%20Guidelines%20(M00076)?open
None
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Current Policy Statement
In accordance with the American Congress of OB/GYN (ACOG) and the American
College of Medical Genetics (ACMG) recommendations, Health Net, Inc. considers
genetic testing for cystic fibrosis (CF) medically necessary for any of the following:
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Reproductive partners of persons with known CF; or
Family history of cystic fibrosis; or
First degree relative who has been identified as a CF carrier; or
Couples seeking prenatal diagnosis and/or care; or
Couples planning a pregnancy; or
Confirmation of a diagnosis of cystic fibrosis when the diagnosis is in doubt,
e.g., those who have a negative sweat chloride test, but have the symptoms
of CF; or
Diagnosis for otherwise healthy men with infertility due to congenital absence
of the vas deferens (CBAVD); or
Follow-up study of newborn with an elevated level of immunoreactive
trypsinogen (IRT) on dry blood spot screening test; or
Prenatal diagnosis where ultrasound indicates fetal meconium ileus, echogenic
bowel, or obstructed bowel.
Note: In accordance with recommendations set forth by The American College of
Medical Genetics, only a core mutation panel of 25 mutations for general population
CF carrier screening are medically necessary. An extended panel or complete
analysis (i.e., CFTR, CFnxt) should not be offered routinely to couples testing
positive/negative with the standard panel.
Codes Related To This Policy
NOTE:
The codes listed in this policy are for reference purposes only. Listing of a code in
this policy does not imply that the service described by this code is a covered or non-
Genetic Testing for Cystic Fibrosis Feb 17
2
covered health service. Coverage is determined by the benefit documents and
medical necessity criteria. This list of codes may not be all inclusive.
On October 1, 2015, the ICD-9 code sets used to report medical diagnoses and
inpatient procedures have been replaced by ICD-10 code sets.
ICD-9 Codes
277.00 –
277.09
V83.81
Cystic fibrosis
Cystic fibrosis carrier testing
ICD-10 Codes
E84.0E84.8
Z31.430
Cystic fibrosis
Encounter of female for testing for genetic disease carrier status for
procreative management
Encounter of male for testing for genetic disease carrier status for
procreative management
Z31.440
CPT Codes
81220
81221
81222
81223
81224
CFTR (cystic fibrosis transmembrane conductance regulator)(eg, cystic
fibrosis) gene analysis; common variants(eg,ACMG/ACOG guidelines)
CFTR (cystic fibrosis transmembrane conductance regulator)(eg, cystic
fibrosis) gene analysis; known familial variants
CFTR (cystic fibrosis transmembrane conductance regulator)(eg, cystic
fibrosis) gene analysis; duplication/deletion variants
CFTR (cystic fibrosis transmembrane conductance regulator)(eg, cystic
fibrosis) gene analysis; full gene sequence
CFTR (cystic fibrosis transmembrane conductance regulator)(eg, cystic
fibrosis) gene analysis; intron 8 poly-T analysis(eg, male infertility)
HCPCS Codes
S3835
Complete gene sequence analysis for cystic fibrosis (code deleted 12/2012)
Scientific Rationale – Update February 2016
Loukas et al. (2015) A 23-mutation panel for CFTR carrier screening is recommended
to women of reproductive age by the American College of Obstetricians and
Gynecologists. In this study the optimized efficiency regarding the carrier rate of
Next-Generation sequencing (NGS) technology is compared to the one of limited
mutation detection panels. A total of 824 consequent cases were subjected to the
commercial Cystic Fibrosis Genotyping Assay. Some 188 negative samples randomly
selected from the initial group of probands were further subjected to an extended
mutation panel characterized by 92% detection rate, as well as to massive
parallel sequencing. Twenty-two probands subjected to the commercial assay proved
to carry one mutation included in the ACOG panel (carrier rate 0.0267). The
latter panels revealed the presence of mutations not included in the ACOG panel
in four probands, resulting to an increase of carrier rate of 0.0106 in the case
of in-house panel and an increase of rate of 0.0213 if NGS was used. The above
data seem to support the implementation of NGS in the routine CFTR carrier
screening.
Genetic Testing for Cystic Fibrosis Feb 17
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McKone et al. (2015) analyzed the US Cystic Fibrosis Foundation Patient Registry
data using Cox regression to examine the relationship between sweat chloride
concentration (<60, 60-<80, ≥80mmol/L), CFTR genotype (high and lower risk for
lung function decline), and survival and mixed linear regression to examine the
relationship between sweat chloride, CFTR genotype, and measures of lung function
and growth. When included in the same model, CFTR genotype, but not sweat
chloride, was independently associated with survival and with lung function, height,
and BMI. Among patients with unclassified CFTR genotype, sweat chloride was an
independent predictor of survival (<60 HR 0.53 [0.37, 0.77], 60-<80 0.51 [0.42,
0.63]). Sweat chloride concentration may be a useful predictor of mortality
and clinical phenotype when CFTR genotype functional class is unclassified.
Baker et al. (2015) Many regions have implemented newborn screening (NBS) for
cystic fibrosis (CF) using a limited panel of cystic fibrosis transmembrane regulator
(CFTR) mutations after immunoreactive trypsinogen (IRT) analysis. The authors tried
to determine the feasibility of further improving the screening using next-generation
sequencing (NGS) technology. A NGS assay was used to detect 162 CFTR
mutations/variants characterized by the CFTR2 project. 67 dried blood spots (DBSs)
were used, containing 48 distinct CFTR mutations to validate the assay. NGS assay
was retrospectively performed on 165 CF screen-positive samples with one CFTR
mutation. The NGS assay was successfully performed using DNA isolated from DBSs,
and it correctly detected all CFTR mutations in the validation. Among 165 screenpositive infants with one CFTR mutation, no additional disease-causing mutation was
identified in 151 samples consistent with normal sweat tests. Five infants had a CFcausing mutation that was not included in this panel, and nine with two CF-causing
mutations were identified. The NGS assay was 100% concordant with traditional
methods. Retrospective analysis results indicate an IRT/NGS screening algorithm
would enable high sensitivity, better specificity and positive predictive value (PPV).
This study lays the foundation for prospective studies and for introducing NGS in NBS
laboratories.
Giardet et al. (2015) This study provides an overview of 10years of experience of
preimplantation genetic diagnosis (PGD) for cystic fibrosis (CF) in our center. Owing
to the high allelic heterogeneity of CF transmembrane conductance regulator (CFTR)
mutations in south of France, we have set up a powerful universal test based on
haplotyping eight short tandem repeats (STR) markers together with the major
mutation p.Phe508del. Of 142 couples requesting PGD for CF, 76 have been so far
enrolled in the genetic work-up, and 53 had 114 PGD cycles performed. Twenty-nine
cycles were canceled upon in vitro fertilization (IVF) treatment because of hyper- or
hypostimulation. Of the remaining 85 cycles, a total of 493 embryos were biopsied
and a genetic diagnosis was obtained in 463 (93.9%), of which 262 (without or
with a single CF-causing mutation) were transferable. Twenty-eight clinical
pregnancies were established, yielding a pregnancy rate per transfer of 30.8% in
the group of seven couples with one member affected with CF, and 38.3% in the
group of couples whose both members are carriers of a CF-causing mutation
[including six couples with congenital bilateral absence of the vas deferens
(CBAVD)]. So far, 25 children were born free of CF and no misdiagnosis was
recorded. Our test is applicable to 98% of couples at risk of transmitting CF.
Marson et al. (2015) completed a retrospective study of the demographic, clinical,
and laboratory markers for CF treatment at a CF referral center, that was performed
during two decades: 2000 (DI, 1990-2000, n = 104 patients) and 2010 (DII, 2000-
Genetic Testing for Cystic Fibrosis Feb 17
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2010, n = 181 patients). The following variables were less common in DI than in DII:
(i) pancreatic insufficiency, (ii) meconium ileus, (iii) diabetes mellitus, (iv)
Burkholderia cepacia colonization, (v) moderate and severe Shwachman-Kulczycki
score (SKS), (vi) F508del mutation screening, (vii) patients without an
identified CFTR mutation (class IV, V, or VI mutation), (viii) patients above the
10th percentile for weight and height, (ix) restrictive lung disease, and (x)
older patients (p < 0.01). The following variables were more common in DI than in
DII: (i) excellent and good SKS, (ii) F508del heterozygous status, (iii)
colonization by mucoid and nonmucoid Pseudomonas aeruginosa, (iv) obstructive
lung disease, and (v) minimal time for CF diagnosis (p < 0.01). Clinical outcomes
differed between the two decades. Demographic, clinical, and laboratory markers in
patients with CF are useful tools and should be encouraged in CF referral centers to
determine the results of CF management and treatment, enabling a better
understanding of this disease and its clinical evolution. Early diagnosis and
management of CF will improve patients' quality of life and life expectancy until
personalized drug therapy is possible for all patients with CF.
Lim et al. (2015) Cystic fibrosis transmembrane regulator (CFTR) allele and genotype
frequencies were obtained from a non-patient cohort with more than 60,000
unrelated personal genomes collected by the Exome Aggregation Consortium. Likely
disease-contributing mutations were identified with the use of public database
annotations and computational tools. The authors identified 131 previously described
and likely pathogenic variants and another 210 untested variants with a high
probability of causing protein damage. None of the current genetic screening panels
or existing CFTR mutation databases covered a majority of deleterious variants in
any geographical population outside of Europe. Both clinical annotation and mutation
coverage by commercially available targeted screening panels for CF are strongly
biased toward detection of reproductive risk in persons of European descent. South
and East Asian populations are severely underrepresented, in part because of a
definition of disease that preferences the phenotype associated with European-typical
CFTR alleles.
Scientific Rationale – Update February 2015
Cystic fibrosis is caused by presence of a variant on both copies of the cystic fibrosis
transmembrane conductance regulator (ATP-binding cassette sub-family C, member
7) (CFTR) gene. Variants in this gene result in impairment of the CFTR protein. More
than 1900 variants have been described in the CFTR gene, however, most of the
variants are rare. Genetic testing for CFTR includes carrier testing and screening,
prenatal diagnosis, preimplantation genetic diagnosis (PGD), newborn screening, and
identification of individuals who will benefit from specific drug therapies. A number of
clinical laboratories in the United States offer testing for CFTR variants. Laboratories
typically offer a panel of 23 common CFTR variants that is recommended by the
American College of Medical Genetics (ACMG), as well as testing for additional
variants depending upon the laboratory. Full gene sequencing, deletion analysis, and
targeted testing for known familial variants are also available.
The Progenity CFnxt is a next-generation sequencing test for 149 disease-causing
CFTR variants that is intended to be used for carrier screening. The panel may be
expanded to 600 variants upon request. Acceptable samples include whole blood,
buccal cells, and mouthwash. However, there is a paucity of published peerreviewed literature on the CFnxt test, as well as insufficient data on analytical
validity, clinical validity, and clinical utility. In accordance with recommendations set
Genetic Testing for Cystic Fibrosis Feb 17
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forth by The American College of Medical Genetics, only a core mutation panel of 25
mutations for general population CF carrier screening are medically necessary. An
extended panel (i.e., CFTR, CFnxt) should not be offered routinely to couples testing
positive/negative with the standard panel.
Per ACOG Committee Opinion, ‘Preconception and Prenatal Carrier Screening for
Genetic Diseases in Individuals of Eastern European Jewish Descent’ (Number 442,
October 2009, Reaffirmed 2014):
“Certain autosomal recessive disease conditions are more prevalent in
individuals of Eastern European Jewish (Ashkenazi) descent. Previously, the
American College of Obstetricians and Gynecologists recommended that
individuals of Eastern European Jewish ancestry be offered carrier screening for
Tay–Sachs disease, Canavan disease, and cystic fibrosis as part of routine
obstetric care. Based on the criteria used to justify offering carrier screening for
Tay–Sachs disease, Canavan disease, and cystic fibrosis, the American College
of Obstetricians and Gynecologists' Committee on Genetics recommends that
couples of Ashkenazi Jewish ancestry also should be offered carrier screening
for familial dysautonomia. Individuals of Ashkenazi Jewish descent may inquire
about the availability of carrier screening for other disorders. Carrier screening
is available for mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia
group C, Bloom syndrome, and Gaucher disease”.
Scientific Rationale – Update February 2012
In April 2011, the American College of Obstetricians and Gynecologists' (ACOG)
Committee on Genetics updated current guidelines for cystic fibrosis screening
practices among obstetrician–gynecologists. The committee notes the following
various carrier screening scenarios with associated management guidelines:
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A woman is a carrier of a CF mutation and her partner is unavailable for testing
or paternity is unknown. Genetic counseling to review the risk of having an
affected child and prenatal testing options and limitations may be helpful.
Prenatal diagnosis is being performed for other indications and CF carrier status
is unknown. Cystic fibrosis screening can be performed concurrently on the
patient and partner. Chorionic villi or amniocytes may be maintained in culture
by the diagnostic laboratory until CF screening results are available for the
patient or couple. If both partners are carriers, the sample can then be tested
for CF.
Both partners are CF carriers. Genetic counseling is recommended to review
prenatal testing and reproductive options. Prenatal diagnosis should be offered
for the couple's known specific mutations.
Both partners are unaffected but one or both has a family history of CF. Genetic
counseling and medical record review should be performed to identify if CFTR
mutation analysis in the affected family member is available.
A woman's reproductive partner has CF or apparently isolated congenital
bilateral absence of the vas deferens. The couple should be referred to a
genetics professional for mutation analysis and consultation.
An individual has two CF mutations but has not previously received a diagnosis
of CF. A mild form of the disease is present and should be referred to a specialist
for further evaluation. Genetic counseling is recommended.
The committee made the following recommendations:
Genetic Testing for Cystic Fibrosis Feb 17
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It is important that CF screening continues to be offered to women of
reproductive age. It is becoming increasingly difficult to assign a single ethnicity
to individuals. It is reasonable, therefore, to offer CF carrier screening to all
patients. Screening is most efficacious in the non-Hispanic white and Ashkenazi
Jewish populations.
It is prudent to determine if the patient has been previously screened before
ordering CF screening that may be redundant. If a patient has been screened
previously, CF screening results should be documented but the test should not
be repeated.
Complete analysis of the CFTR gene by DNA sequencing is not appropriate for
routine carrier screening.
Newborn screening panels that include CF screening do not replace maternal
carrier screening.
If a woman with CF wants to become pregnant, a multidisciplinary team should
be considered to manage issues regarding pulmonary function, weight gain,
infections, and the increased risks of diabetes and preterm delivery.
For couples in which both partners are carriers, genetic counseling is
recommended to review prenatal testing and reproductive options.
For couples in which both partners are unaffected but one or both has a family
history of CF, genetic counseling and medical record review should be performed
to identify if CFTR mutation analysis in the affected family member is available.
If a woman's reproductive partner has CF or apparently isolated congenital
bilateral absence of the vas deferens, the couple should be referred to a genetics
professional for mutation analysis and consultation
Scientific Rationale Update – April 2010
(2009) American Congress of Obstetricians and Gynecologists (ACOG) published an
ACOG Committee Opinion, Number 442, on October 2009. In their recommendations
for ‘Preconception and Prenatal Carrier Screening in Individuals of Eastern European
Jewish Descent’, the ACOG Committee on Genetics states:
“Carrier screening for cystic fibrosis should be offered to Ashkenazi Jewish
individuals before conception or during early pregnancy so that a couple has
an opportunity to consider prenatal diagnostic testing options. If the woman
is already pregnant, it may be necessary to screen both partners
simultaneously so that the results are obtained in a timely fashion to ensure
that prenatal diagnostic testing is an option. If only one of the couple is
Ashkenazi Jew, that person should be screened first. Carrier screening should
be offered if there is a positive family history of CF.”
Scientific Rationale Initial
Cystic fibrosis (CF) is an inherited disease that most commonly affects the
respiratory and digestive systems in children and young adults. Advances in medical
treatment continue to improve the outlook for affected children and adults. However,
there is no cure and most affected individuals survive to about age 30, though some
die in childhood and others live to age 40 or beyond. According to the data collected
by the Cystic Fibrosis Foundation, there are about 30,000 Americans and 20,000
Europeans with CF. The disease occurs mostly in whites whose ancestors came from
northern Europe, although it affects all races and ethnic groups. Accordingly, it is
less common in African Americans, Native Americans, and Asian Americans.
Approximately 2,500 babies are born with CF each year in the United States. Also,
Genetic Testing for Cystic Fibrosis Feb 17
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about 1 in every 20 Americans is an unaffected carrier of an abnormal "CF gene."
These 12 million people are usually unaware that they are carriers.
The abnormal gene that causes CF was discovered in 1989. This discovery led to the
development of tests that can help determine whether or not couples carry an
abnormal gene that can cause CF in their children. Testing usually is offered to
couples with a family history of this disease, though now health care providers also
are offering this test to couples without a family history of CF who are planning
pregnancy or who are already pregnant. Couples will be better able to decide
whether they want to have the carrier test if they understand the medical problems
that CF can cause and what the tests can and cannot tell them.
The normal gene product of cystic fibrosis is a transmembrane conductance regulator
(CFTR) that allows the normal passage of chloride, along with sodium to make a salt,
into and out of certain cells, including those that line the lungs and pancreas.
Mutations in the normal gene protein can affect the CFTR protein quantitatively,
qualitatively, or both. As a result, these cells produce thick, sticky mucus and other
secretions. The mucus clogs the lungs, causing breathing problems. Affected
individuals also have frequent lung infections, which eventually damage the lungs
and contribute to early death. The thickened digestive fluids made by the pancreas
are prevented from reaching the small intestine, where they are needed to digest
food.
According to the NIH Consensus Development Conference Statement on genetic
testing for cystic fibrosis (1997), individuals with a family history of CF and partners
of those with CF should be offered genetic testing. As a group, individuals with a
family history have relatively high frequencies of mutations in the CFTR gene.
Members of this group have increased awareness of their risk of being carriers, as
well as increased familiarity with the disease and its impact on the family. Testing
can be helpful with regard to reproductive decision making and informative regarding
family health. CF genetic testing should be offered to the prenatal population and
couples currently planning a pregnancy, particularly those in high-risk populations.
There is little justification of CF testing for the general population given the low
incidence and prevalence of CF and the demonstrable lack of interest in the general
population. Neither is routine genetic screening for CF in newborns based on
available data. Studies have not provided sufficient evidence that identifying CF
patients earlier than the current average age of diagnosis improves outcomes.
CF does not follow the same pattern in all patients but affects different people in
different ways and to varying degrees. However, the basic problem is the same - an
abnormality in the glands which produce or secrete sweat and mucus. Sweat cools
the body; mucus lubricates the respiratory, digestive, and reproductive systems, and
prevents tissues from drying out, protecting them from infection. People with CF lose
excessive amounts of salt when they sweat. This can upset the balance of minerals
in the blood, which may cause abnormal heart rhythms. Going into shock is also a
risk. Mucus in CF patients is very thick and accumulates in the intestines and lungs.
The result is malnutrition, poor growth, frequent respiratory infections, breathing
difficulties, and eventually permanent lung damage. They may develop repeated lung
infections, such as pneumonia. Many of these infections are caused by Pseudomonas
aeruginosa, which rarely causes problems in healthy people. Lung disease is the
usual cause of death in most patients.
Genetic Testing for Cystic Fibrosis Feb 17
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The most common test for CF is called the sweat test. It measures the amount of
sodium chloride in the sweat. In this test, an area of the skin (usually the forearm) is
made to sweat by using a chemical called pilocarpine and applying a mild electric
current. To collect the sweat, the area is covered with a gauze pad or filter paper and
wrapped in plastic. After 30 to 40 minutes, the plastic is removed, and the sweat
collected in the pad or paper is analyzed. Higher than normal amounts of sodium and
chloride suggest that the person has cystic fibrosis. The sweat test may not work
well in newborns because they do not produce enough sweat. In that case, another
type of test, such as the immunoreactive trypsinogen test (IRT), may be used. In the
IRT test, blood drawn 2 to 3 days after birth is analyzed for a specific protein called
trypsinogen. Positive IRT tests must be confirmed by sweat and other tests. Also, a
small percentage of people with CF have normal sweat chloride levels. They can only
be diagnosed by chemical tests for the presence of the mutated gene. Some of the
other tests that can assist in the diagnosis of CF are chest X-rays, lung function tests,
and sputum (phlegm) cultures. Stool examinations can help identify the digestive
abnormalities that are typical of CF.
There are a number of medications that can help affected individuals breath better
and prevent infections. The medications recommended for a child or adult with CF
will depend on the person’s symptoms and their severity. These medications include
a mucus-thinning drug called Pulmozyme and an antibiotic called TOBI (tobramycin
solution) that is inhaled in vapor form. One study also suggested that the antiinflammatory drug ibuprofen, when given in high doses, can help prevent lung
inflammation, which is common in individuals with CF, and can make breathing more
difficult. When infections occur, they are treated at home or in the hospital with a
number of antibiotics, which can be given orally, intravenously, or by inhalation.
Unfortunately, as the individual gets older, infections tend to get worse and more
difficult to treat, and lung damage becomes more serious
Since CF is a genetic disease, the only way to prevent or cure it would be with gene
therapy at an early age. Ideally, gene therapy could repair or replace the defective
gene. Another option for treatment would be to give a person with CF the active
form of the protein product that is scarce or missing. At present, neither gene
therapy nor any other kind of treatment exists for the basic causes of CF, although
several drug-based approaches are being investigated. In the meantime, treatment
is centered on easing the symptoms of CF and slowing the progress of the disease so
the patient's quality of life is improved. This is achieved by antibiotic therapy
combined with treatments to clear the thick mucus from the lungs. The therapy is
tailored to the needs of each patient. For patients whose disease is very advanced,
lung transplantation may be an option.
Review History
April 2004
April 2006
March 2007
April 2008
April 2010
April 2011
February 2012
February 2013
February 2014
December 2014
Medical Advisory Council
Update - no changes
Code Updates
Update – no revisions. Codes updated
Update. No revisions. Codes updated.
Added Medicare table, no other changes
Update – no revisions
Update – no revisions. Code updates
Update – no revisions. Codes reviewed.
Clarified criteria for carrier testing and removed
paragraph on population screening
Genetic Testing for Cystic Fibrosis Feb 17
9
February 2015
February 2016
February 2017
Update – no revisions. Codes reviewed.
Update – no revisions. Codes updated.
Update – no revisions. Codes updated.
This policy is based on the following evidence-based guidelines:
1.
2.
3.
4.
5.
6.
7.
8.
American College of Medical Genetics. Cystic Fibrosis Population Carrier
Screening: 2004 Revision of American College of Medical Genetics Mutation
Panel. 2004, Reaffirmed 2013. Genet Med 6:5:387-391. Available at:
http://www.acmg.net/StaticContent/StaticPages/CF_Mutation.pdf
Moskowitz S, Chmiel J, Sternen D, et al. Gene Reviews. CFTR-Related Disorders.
Last updated Feb 2008.
Comeau A, Accurso F, White T. et al. Guidelines for Implementation of Cystic
Fibrosis Newborn Screening Programs: Cystic Fibrosis Foundation Workshop
Report. Pediatrics Vol. 119 No. 2 February 2007, pp. e495-e518. Available
at:http://pediatrics.aappublications.org/cgi/content/full/119/2/e495
American College of Obstetricians and Gynecologists. (ACOG). Committee on
Genetics. ACOG Committee Opinion No. 442: Preconception and prenatal carrier
screening for genetic diseases in individuals of Eastern European Jewish descent.
Obstet Gynecol. 2009 Oct; 114 (4): 950-3. (Replaces No. 298, August 2004).
Reaffirmed 2014.
American College of Obstetricians and Gynecologists. (ACOG). Committee
Opinion #486, Apr.2011. Update on Carrier Screening for Cystic Fibrosis.
Replaces #325, Dec 2005. Reaffirmed 2014.
Hayes GTE Overview. Cystic Fibrosis Transmembrane Regulator (CFTR) for
Cystic Fibrosis. May 30, 2013. Updated May 20, 2014. Updated May 13, 2015.
Hayes GTE Overview. CFTR Testing for Diagnosis, Carrier Testing and Newborn
Screening for Cystic Fibrosis. 2013.
Hayes. CFnxt for Cystic Fibrosis Carrier Screening (Progenity Inc.). October 9,
2014.
References – Update February 2016
1.
2.
3.
4.
5.
6.
Baker MW, Atkins AE, Cordovado SK, et al. Improving newborn screening for
cystic fibrosis using next-generation sequencing technology: a technical
feasibility study. Genet Med. 2015 Feb 12. doi: 10.1038/gim.2014.209. [Epub
ahead of print]
Giardet A, Ishmukhametova A, Willems M, et al. Preimplantation genetic
diagnosis for cystic fibrosis: the Montpellier center's 10-year experience. Clin
Genet. 2015 Feb;87(2):124-32. doi: 10.1111/cge.12411. Epub 2014 May 20.
Lim RM, Silver AJ, Silver MJ, et al. Targeted mutation screening panels expose
systematic population bias in detection of cystic fibrosis risk. Genet Med. 2015
Apr 16. doi: 10.1038/gim.2015.52. [Epub ahead of print].
Loukas YL, Thodi G, Molou E, et al. Clinical diagnostic Next-Generation
sequencing: The case of CFTR carrier screening. Scand J Clin Lab Invest. 2015
Apr 15:1-8. [Epub ahead of print].
Marson FA, Hortencio TD, Aguiar KC, et al. Demographic, clinical, and laboratory
parameters of cystic fibrosis during the last two decades: a comparative
analysis. BMC Pulm Med. 2015 Jan 15;15(1):3. [Epub ahead of print]
McKone EF, Velentgas P, Swenson AJ, et al. Association of sweat chloride
concentration at time of diagnosis and CFTR genotype with mortality and cystic
fibrosis phenotype. J Cyst Fibros. 2015 Feb 3. pii: S1569-1993(15)00007-7.
doi: 10.1016/j.jcf.2015.01.005. [Epub ahead of print]
Genetic Testing for Cystic Fibrosis Feb 17
10
7.
Salinas DB, Sosnay PR, Azen C, et al. Benign outcome among positive cystic
fibrosis newborn screen children with non-CF-causing variants. J Cyst Fibros.
2015 Mar 28. pii: S1569-1993(15)00061-2. doi: 10.1016/j.jcf.2015.03.006.
[Epub ahead of print].
References – Update February 2015
1.
2.
3.
4.
Girardet A, Ishmukhametova A, Willems M, et al. Preimplantation Genetic
Diagnosis for Cystic Fibrosis: the Montpellier centre's 10-year experience. Clin
Genet. 2014 Apr 25. doi: 10.1111/cge.12411. [Epub ahead of print.
Ioannou L, McClaren BJ, Massie J, et al. Population-based carrier screening for
cystic fibrosis: a systematic review of 23 years of research. Genet Med. 2014
Mar;16(3):207-16. doi: 10.1038/gim.2013.125. Epub 2013 Sep 12.
Langfelder-Schwind E(1), Karczeski B, Strecker MN, et al. Molecular testing for
cystic fibrosis carrier status practice guidelines: recommendations of the
National Society of Genetic Counselors. J Genet Couns. 2014 Feb;23(1):5-15.
doi: 10.1007/s10897-013-9636-9. Epub 2013 Sep 7.
Ziętkiewicz E, Rutkiewicz E, Pogorzelski A, et al. CFTR mutations spectrum and
the efficiency of molecular diagnostics in Polish cystic fibrosis patients. PLoS
One. 2014 Feb 26;9(2):e89094. doi: 10.1371/journal.pone.0089094. eCollection
2014.
References – Update February 2014
1. Antunovic SS, Lukac M, Vujovic D. Longitudinal cystic fibrosis care. Clin
Pharmacol Ther. 2013;93(1):86-97.
2. Davies JC, Wainwright CE, Canny GJ, et al. Efficacy and safety of ivacaftor in
patients aged 6 to 11 years with cystic fibrosis with a G551D mutation. Am J
Respir Crit Care Med. 2013. Epub ahead of print. April 3, 2013. Available at:
http://www.atsjournals.org/doi/abs/10.1164/rccm.2013010153OC?url_ver=Z39.882003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed&.
3. De Oronzo, M.A., Hyperechogenic fetal bowel: an ultrasonographic marker for
adverse fetal and neonatal outcome?. Journal of Prenatal Medicine 2011; 5 (1):
9-13
4. Katkin JP. Cystic fibrosis: Genetics and pathogenesis. UpToDate. October 2, 2013.
5. Raby BA, Kohlmann W, Venne V. Genetic counseling and testing. UpToDate.
December 11, 2013.
6. Rechitsky S, Verlinsky O, Kuliev A. PGD for cystic fibrosis patients and couples at
risk of an additional genetic disorder combined with 24-chromosome aneuploidy
testing. Reprod Biomed Online. 2013;26(5):420-430.
7. Simmonds NJ. Cystic fibrosis presenting in adulthood: when to think of it and
what to do. Clin Pulm Med. 2013;20(1):1-5.
8. Veenstra DL, Piper M, Haddow JE, et al. Improving the efficiency and relevance of
evidence-based recommendations in the era of whole-genome sequencing: an
EGAPP methods update. Genet Med. 2013;15(1):14-24.
References – Update February 2013
1. Field PD, Martin NJ. CFTR mutation screening in an assisted reproductive clinic.
Aust N Z J Obstet Gynaecol. 2011 Dec;51(6):536-9.
2.
Stahl PJ, Schlegel PN. Genetic evaluation of the azoospermic or severely
oligozoospermic male. Curr Opin Obstet Gynecol. 2012 Aug;24(4):221-8.
References – Update February 2012
Genetic Testing for Cystic Fibrosis Feb 17
11
1.
2.
3.
Darcy D, Tian L, Taylor J, Schrijver I. Cystic fibrosis carrier screening in
obstetric clinical practice: knowledge, practices, and barriers, a decade after
publication of screening guidelines. Genet Test Mol Biomarkers. 2011 JulAug;15(7-8):517-23.
Maclean JE, Solomon M, Corey M, Selvadurai H. Cystic fibrosis newborn
screening does not delay the identification of cystic fibrosis in children with
negative results. J Cyst Fibros. 2011 Sep;10(5):333-7.
Sanak M. Newborn screening for cystic fibrosis, a clinical geneticist perspective.
Przegl Lek. 2011;68(1):14-6.
References Updated-April 2010
1.
2.
3.
National Newborn Screening Status Report. Dec 4. 2009. Updated 3/1/2010.
Southern KW, Mérelle MME, Dankert-Roelse JE, et al. Newborn screening for
cystic fibrosis. Cochrane Database of Systematic Reviews 2009, Issue 1. Art.
U.S. Food and Drug Administration (FDA). Tag-It Cystic Fibrosis Kit - K043011.
Updated Jul 8, 2009. Available at:
http://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/DeviceAppro
valsandClearances/Recently-ApprovedDevices/ucm078613.htm
References – Initial
1. Mekus F, Tummler B. Genes, environment, ion transport, and cystic fibrosis.
Am J Respir Crit Care Med. 2004 Mar 15;169(6):770; author reply 770.
2. Strom CM. Current challenges in cystic fibrosis screening. Arch Pathol Lab Med.
2004 Mar;128(3):366; author reply 366.
3. Han EE, Beringer PM, Louie SG, Gill MA, Shapiro BJ. Pharmacokinetics of
Ibuprofen in children with cystic fibrosis. Clin Pharmacokinet. 2004;43(3):145-56.
4. Henneman L, Bramsen I, van der Ploeg HM, ten Kate LP. Preconception cystic
fibrosis carrier couple screening: impact, understanding, and satisfaction. Genet
Test. 2002 Fall;6(3):195-202.
5. Bombieri C, Pignatti PF. Cystic fibrosis mutation testing in Italy. Genet Test. 2001
Fall;5(3):229-33.
6. Delvaux I, van Tongerloo A, Messiaen L, et al. Carrier screening for cystic fibrosis
in a prenatal setting. Genet Test. 2001 Summer;5(2):117-25.
7. Doksum T, Bernhardt BA, Holtzman NA. Carrier screening for cystic fibrosis
among Maryland obstetricians before and after the 1997 NIH Consensus
Conference. Genet Test. 2001 Summer;5(2):111-6.
8. Guilloud-Batailler M, De Crozes D, Rault G, Degioanni A, Feingold J. Cystic fibrosis
mutations: report from the French Registry. Hum Hered 2000;50:142-145.
9. Cystic Fibrosis Foundation. Cystic Fibrosis Foundation Patient Registry Annual
Data Report, 1998. Bethesda, MD: Cystic Fibrosis Foundation.
10. NIH Consensus Development Conference Statement. Genetic testing for cystic
fibrosis. April 14-16, 1997. Arch Intern Med 1999;159:1529-1539.
11. Mennuti MT, Thomson E, Press N. Screening for cystic fibrosis carrier state.
Obstet Gynecol 1999;93:456-461.
12. Macek M, Mackova A, Hamosh A, et al. Identification of common cystic fibrosis
mutations in African-Americans with cystic fibrosis increases the detection rate to
75%. Am J Hum Genet 1997;60:1122-1127.
13. Estivill X, Bancells C, Ramos C. Geographic distribution and regional origin of 272
cystic fibrosis mutations in European populations. The Biomed CF Mutation
Analysis Consortium. Hum Mutat 1997;10:135-154.
Genetic Testing for Cystic Fibrosis Feb 17
12
14. Grody WW, Dunkel-Schetter C, Tatsugawa ZH, et al. PCR-based screening for
cystic fibrosis carrier mutations in an ethnically diverse pregnant population. Am
J Hum Genet 1997;60:935-947.
15. Eng CM, Schechter C, Robinowitz J, et al. Prenatal genetic carrier testing using
triple disease screening. JAMA 1997;278:1268-1272.
16. Rowley PT, Loader S, Levenkron JC. Cystic fibrosis carrier population screening: a
review. Genet Test. 1997;1(1):53-9.
17. Kerem B, Chiba-Falek O, Kerem E. Cystic fibrosis in Jews: frequency and
mutation distribution. Genet Test. 1997;1(1):35-9.
18. Döork T, Dworniczak B, Aulehis-Schotz C, et al. Distinct spectrum of CFTR gene
mutations in congenital absence of vas deferens. Hum Genet 1997;100:367-377.
19. Witt DR, Hallam P, Wi S, et al. Cystic fibrosis heterozygote screening in 5,161
pregnant women. Am J Hum Genet 1996;58:823-835.
20. DeMarchi JM, Caskey CT, Richards CS. Screening for diseases frequent in the
Ashkenazi Jewish population. Hum Mutat 1996;8:116-125.
21. Chillon M, Casals T, Mercier B, et al. Mutations in the cystic fibrosis gene in
patients with congenital absence of the vas deferens. N Engl J Med
1995;332:1475-1480.
22. Cystic Fibrosis Genetic Analysis Consortium. Population variation of common
cystic fibrosis mutations. Hum Mutat 1994;4:167-177.
23. Super M, Schwarz MJ, Malone G, et al. Active cascade testing for carriers of cystic
fibrosis gene. BMJ 1994;308:1462-1468.
24. Mercier B, Raguenes O, Estivill X, et al. Complete detection of mutations in cystic
fibrosis of Native American origin. Hum Genet 1994;94:629-632.
25. Gregg R, Wilfond BS, Farrell PM, et al. Application of DNA analysis in a
population-screening program for neonatal diagnosis of cystic fibrosis (CF):
comparison of screening protocols. Am J Hum Genet 1993;52:616-626.
26. Kiesewetter S, Macek M, Davis C, et al. A mutation in CFTR produces different
phenotypes depending on chromosomal background. Nat Genet 1993;5:274-277.
27. Gervais R, Dumur V, Rigot M-M, et al. High frequency of the R117H cystic fibrosis
mutation in patients with congenital absence of the vas deferens. N Engl J Med
1993;328:446-447.
28. Abeliovich D, Lavon IP, Lerer I, et al. Screening for five mutations detects 97% of
cystic fibrosis (CF) chromosomes and predicts a carrier frequency of 1:29 in the
Jewish Ashkenazi population. Am J Hum Genet 1992;51:951-956.
29. Anguiano A, Oates RD, Amos JA, et al. Congenital bilateral absence of the vas
deferens: a primarily genital form of cystic fibrosis. JAMA 1992;267:1794-1797.
30. Wald NJ. Couple screening for cystic fibrosis. Lancet 1991;338:1318-1319.
31. Rommens JM, Iannuzzi MC, Kerem B-S, et al. Identification of the cystic fibrosis
gene: chromosome walking and jumping. Science 1989;245:1059-1065.
32. Riordan JR, Rommens JM, Kerem B-S, et al. Identification of the cystic fibrosis
gene: cloning and characterization of complementary DNA. Science
1989;245:1066-1073.
33. Kerem B-S, Rommens JM, Buchanan JA, et al. Identification of the cystic fibrosis
gene: genetic analysis. Science 1989;245:1073-1080.
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