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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: 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