Download CYSTIC FIBROSIS CARRIER SCREENING

CYSTIC FIBROSIS CARRIER SCREENING
CLINICAL BACKGROUND
Facts
Cystic fibrosis (CF) affects at least 30,000 people in the United States, with between 900 and 1,000 new cases diagnosed
every year. In the US, most cases of CF are now identified through neonatal screening tests. Cystic fibrosis is one of the
most common life-shortening genetic diseases in Caucasians, and one in 29 Caucasians is an unaffected carrier of CF.
What is Cystic Fibrosis?
Most of the other signs and symptoms of cystic fibrosis affect the respiratory system or the digestive system. Affected
individuals have persistent lung infections and difficulty breathing due to mucus buildup in the lungs. Many other
symptoms are associated with CF, including infertility in men, wheezing, shortness of breath, inflamed/stuffy nose,
decreased weight gain and stunted growth, intestinal blockage and severe constipation. The severity of symptoms varies
from one individual to another, but the life expectancy of individuals with CF has increased to an average of 37 years
with the help of new medicines to manage these symptoms. There is currently no cure for this disease.
What Causes Cystic Fibrosis?
CF is an autosomal recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane regulator (CFTR)
gene. Certain mutations in CFTR cause a defective CFTR protein to be produced, resulting in abnormal transport of salt
(sodium and chloride) and water across cells that line the respiratory, digestive, and genital tracts. CF is inherited when
two parents that are carriers (i.e., they have one normal allele and one allele with a mutation) each contribute an
abnormal allele to their child. Thus, the likelihood that two carrier parents will have an affected child is 1 in 4 for each
pregnancy. Carriers do not usually have symptoms of CF, but carrier status can be detected through genetic testing.
What does Cystic Fibrosis Carrier Screening Involve?
Once a DNA sample is collected from a patient, the laboratory runs the test using commercially available molecular
diagnostic platforms. The laboratory then uses Translational Software’s cloud-based technology and clinical decision
support tools to interpret and report the results to healthcare providers.
The American College of Medical Genetics (ACMG) and the American Congress of Obstetricians and Gynecologists
(ACOG) recommend screening for 23 common CFTR mutations that were chosen primarily based on their frequency in
Ashkenazi Jewish and non-Hispanic Caucasian populations1. CF is more common in these ethnic groups, and the 23
mutations account for 94% of mutant alleles in Ashkenazi Jews and 88% in non-Hispanic Caucasians. Depending on the
laboratory’s diagnostic platform and testing panel, the test may only focus on the 23 recommended CF-causing variants
or include other CF-causing variants which may occur at lower frequencies (table 1).
Translational Software
12410 SE 32nd Street, Suite 250
Bellevue, WA 98040
www.translationalsoftware.com
Table 1: Example of CFTR mutations supported by TSI
1717-1G>Aa
2184insA
D579G
Q525X
Q1313X
1898+1G>Aa
2307insA
D614G
Q552X
Q220X
2184delAa
2347delG
D836Y
Q890X
Q359K/T360K
2789+5G>Aa
2585delT
delF311
Q98R
Q39X
3120+1G>Aa
2622+1G>A
E1104X
Q98X
Q493X
3659delCa
2711delT
E1371X
R1066C
W846X
3849+10kbC>Ta
2789+2insA
E585X
R1066H
Y1092X(c.3276C>A)
621+1G>Ta
2869insG
E60X
R1070Q
Y1092X(c.3276C>G)
711+1G>Ta
2942insT
E822X
R1070W
Y122X
A455Ea
3007delG
E831X
R1158X
Y569D
F508dela
3120G>A
E92K
R117C
D110H
G542Xa
3121-1G>A
E92X
R1283M
D1152H
G551Da
3171delC
F508CR
R170H
2143delT
G85Ea
3199del6
G1069R
R334L
2183AA>G
I507dela
3272-26A>G
G1244E
R347H
2183delAA
N1303Ka
3667del4
G1349D
R352Q
CFTRdele2.3
R1162X
3791delC
G178R
R352W
CFTRdele22.23
R117Ha
3821delT
G330X
R560G
2105-2117del13insAGAAA
R334Wa
3876delA
G480C
R560K
R347Pa
3905insT
G551S
R709X
R553Xa
394delTT
G622D
R75X
R560Ta
4005+1G>A
G970R
R764X
W1282Xa
405+1G>A
H199Y
R851X
1078delT
405+3A>C
I1234V
S1196X
1154insTC
406-1G>A
I336K
S1251N
1213delT
4209TGTT>AA
I506VR
S1255P
1248+1G>A
4382delA
I507VR
S1255X
1259insA
444delA
K710X
S341P
1288insTA
457TAT>G
L1065P
S364P
2055del9>A
CFTRdele2.3
Q1238X
2108delA
1461ins4
5TR
L206W
S466X(c.1397C>G)
1471delA
663delT
L227R
S489X
1525-1G>A
711+3A>G
L467P
S492F
1548delG
711+5G>A
L558S
S549N
1677delTA
712-1G>T
L732X
S549R(c.1645A>C)
1717-8G>A
852del22
L927P
S549R(c.1647T>G)
1811+1.6kbA>G
935delA
L967S
S945L
1812-1G>A
936delTA
M1101K
T338I
1833delT
7T/9TR
1949del84
T351S
1898+3A>G
A559T
P1013H
V520F
1898+5G>T
c.1486T>G
P205S
W1089X
1924del7
c.3297C>A
P574H
W1204X
a: Variant required by the American College of Medical Genetics (ACMG) for CFTR carrier screening.
R: Reflex tests that are not part of ACMG carrier screen but are required when certain mutations are detected.
Translational Software
12410 SE 32nd Street, Suite 250
Bellevue, WA 98040
www.translationalsoftware.com
What do the results of the CF screening test mean?
 A Carrier: Of the CF-causing mutations tested by the laboratory, the individual carries one copy of a CF-causing
mutation in the CFTR gene. This individual is not affected by CF but is a carrier of the disease. For pregnancy
planning, it is recommended that the individual’s partner be tested as well in order to determine the risk for
their child to be affected by CF.
 A Non-Carrier: Of the CF-causing mutations tested by the laboratory, the test has not identified any CF-causing
mutation. However, the individual may carry other CF-causing mutations in the CFTR gene that were not
included in the test, and therefore the results do not rule out the possibility of the individual being a carrier. As
most tests focus on the most common CF-causing mutations, a negative test result reduces but does not
eliminate the risk of an individual being a carrier of CF.
Who Should Have Cystic Fibrosis Carrier Screening?
CF carrier testing is recommended for Caucasian women who are considering pregnancy or who are pregnant.
Regulatory guidelines recommend individuals with a family history of CF to be screened for the disease. CF has also
historically been seen in certain ethnicities; non-Hispanic white (Caucasian) and Ashkenazi Jewish individuals are more
likely to be carriers of CF. The test can also be used in individuals with a family history of known CFTR mutations.
TRANSLATIONAL SOFTWARE’S SOLUTION
Product Components and Benefits
Translational Software Inc.’s (TSI) interpretative cloud-based solution allows molecular diagnostic labs to review, analyze
and interpret results of their CF carrier screening panels. This process enables timely, cost-efficient, and scalable delivery
of results in a form accessible and useful to both healthcare providers and patients.
The current system supports CFTR genetic test results from three different genotyping platforms and vendors: Thermo
Fisher (Open Array), Luminex (xTAG Cystic Fibrosis Kit) and Autogenomics (INFINITI CFTR-31 Assay). Efforts are in process
to include results from additional platforms and vendors such as Illumina and Agena.
TSI’s end-to-end solution includes the following components:
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A web-based portal for results review by the laboratory personnel
An annotated knowledge base of CF-causing mutations (table 1)
Algorithms for results capture and translation
Clinical decision support
Automated reporting
Report delivery to Laboratory Information Systems
Technology and Workflow
When a healthcare provider orders a CF carrier screening test, the laboratory runs the test and submits patient
information and raw genetic data to TSI’s cloud-based technology for interpretation. TSI’s proprietary knowledge
platform generates a tailored, clinically meaningful report. The laboratory director uses the TSI portal to review, approve
and release the report to the healthcare provider (physician or genetic counselor), who uses it to manage the patient.
The interpretive report for CF carrier screening specifies the mutations screened, mutations identified, and interpretive
information. Our variant annotations and interpretation principles have been reviewed by an expert with extensive
experience in interpreting and reporting results for CF carrier screening.
Translational Software
12410 SE 32nd Street, Suite 250
Bellevue, WA 98040
www.translationalsoftware.com
Interpretation of CF results from a carrier screening test can be complex because the mutation detection rate is less than
100%. Moreover, in the presence of certain mutations such as R117H, additional testing and interpretation of results is
required. R117H mutation on its own has low penetrance and the effect on the function of CFTR depends upon presence
of other mutations known as the poly-T (see figure 1, adapted from Bean et al.3). Similarly, detection of a homozygous
mutation in deltaF508 is consistent with a diagnosis of CF and requires reflex testing variants I506V and I507V in order to
rule out false positive. These different and complex scenarios are already accounted for during the interpretation of CF
carrier screening by the TSI platform. In summary, TSI CF interpretation provides a complete and reliable pipeline for
interpreting CF carrier screening data and accounts for complex genotypes that could potentially be seen during testing.
Figure 1 – Possible results from a CF carrier screen.
Getting Started
Whether you are an existing customer or newly considering genetic reporting services, TSI can provide you with
information about using your existing equipment and laboratory infrastructure for CF screening. Our services span the
selection or definition of a testing panel, report creation and branding, support and integration into laboratory
environments.
References
1: American College of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 486: Update on carrier screening for cystic fibrosis.
Obstet Gynecol. 2011 Apr;117(4):1028-31.
2: Strom CM, Janeszco R, Quan F, Wang SB, Buller A, McGinniss M, Sun W. Technical validation of a TM Biosciences Luminex-based multiplex assay for detecting the
American College of Medical Genetics recommended cystic fibrosis mutation panel. J Mol Diagn. 2006 Jul;8(3):371-5.
3: Bean, Lora J. H., Pratt V.M. “Cystic Fibrosis.” Molecular Pathology in Clinical Practice. 2nd Ed. Debra G.B. Leonard. Springer International Publishing. 189-196. Print.
Contact Us
Please contact Rick Shigaki at 206-777-4396 for more information.
Translational Software
12410 SE 32nd Street, Suite 250
Bellevue, WA 98040
www.translationalsoftware.com