Cystic Fibrosis Testing. clinician guide

Transcription

1 Cystic Fibrosis Testing clinician guide

2 Ambry s test offerings are designed to provide flexible, comprehensive options tailored to your patients personal and family histories Genetic Testing for Cystic Fibrosis Identifying and understanding the genetic cause of cystic fibrosis (CF) allows for individualized disease management, and provides insight into familial reproductive risks for CF. Advances in medicine and genetics mean that pinpointing a diagnosis of CF (based on the exact mutations within the CFTR gene) can identify medications and other treatments to improve symptoms at the cellular level. Thus, genetic testing may drastically change the way a patients are cared for, and improve their overall quality of life. Ambry s History We are proud to be the first lab to offer clinical sequencing of the CFTR gene in 1999, and our experience allows us to continue offering gold-standard diagnostic solutions for CF. We are now recognized as a global leader in providing cutting-edge, comprehensive, accurate genetic testing services, and remain committed to offering the most up-to-date analysis of CFTR. Our experienced team of Board-certified genetic counselors, geneticists, and scientists has designed our comprehensive reports to provide clear results, interpretations, and when applicable, details about any mutations or variants of unknown significance identified.

3 About Cystic Fibrosis Cystic fibrosis (CF) is a relatively common genetic condition that affects about 30,000 children and adults in the U.S, and about 70,000 worldwide. About 1 in 25 non-hispanic Caucasians is a CF carrier, and this frequency is typically lower in other ethnic groups. People with the most common type of CF have two CFTR gene mutations, which usually cause the body to produce mucus that clogs the lungs and leads to lifethreatening lung infections. Thick mucus secretions can also obstruct the pancreas and prevent natural digestive enzymes from reaching the intestines to help break down and absorb food. This can cause pancreatitis, pancreatic insufficiency, and poor weight gain % of newborns with CF have meconium ileus found at birth. In addition, babies with echogenic bowel on ultrasound have a higher risk of having CF (the risks increase as the degree of echogenicity increases). People with CF often have other symptoms including high sweat chloride levels, chronic sinus disease, and an excessive appetite but low weight gain. CFTR mutations may also lead to congenital absence of the vas deferens (CAVD) and infertility in males, who may not have pulmonary or gastrointestinal symptoms of CF. This wide variability in symptoms is, in part, due to the large size of the CFTR gene and the more than 1,900 different CFTR mutations and variants described to date. Treatment/prevention of complications may be implemented if a diagnosis is suspected or confirmed, and these treatments can involve many organ systems, and in some cases can be mutation-specific. In addition, regularly scheduled visits to CF care providers (if available) for ongoing surveillance and management are critical for those with the condition. Why Ambry for CF Testing? We were the first commercial laboratory to offer clinical genetic testing for cystic fibrosis using gene sequencing technology. Since then, we have analyzed the complete CF gene (CFTR) for more than 35,000 patients. As a result, we have the most robust single-laboratory database in the world from which to accurately and carefully interpret patient results. Due to CFTR s large size and the wide genetic heterogeneity seen in CF, this powerful database is highly valuable to clinicians like you. In addition, we have an ongoing variant assessment and reclassification program, which is continually updated with the latest in clinical and research information related to CF. This gives you confidence that we are giving you the most accurate and up-to-date interpretation of your patient s results. Ambry is also dedicated to supporting the CF community, through the Mauli Ola Foundation and various outreach activities.

4 Mauli Ola Foundation Ambry leadership created the Mauli Ola Foundation in 2006 to promote awareness of genetic diseases. Mauli Ola raises funds to support programs for those with life-threatening illnesses and provide direct, immediate ways for children with genetic disorders to enjoy healthy lives through natural treatments. Those with CF typically have chronic pulmonary and gastrointestinal complications, resulting in frequent hospitalizations for them. Mauli Ola Surf Experience and Ocean Experience Days get kids with CF into the ocean (high in saline) to experience what natural therapies can do for their lungs. The saline breaks down lung congestion and is a healthy, fun alternative to the typical regimens for CF. To learn more about the Mauli Ola Foundation, visit

5 Our Cystic Fibrosis Testing Options We have developed a range of genetic testing options to meet several clinical needs. CF AMPLIFIED is the most comprehensive testing option, detecting >99% of disease-causing CFTR changes (or mutations), gross deletions and duplications. CF AMPLIFIED may be optimal for: Confirming a diagnosis in patients known or suspected to have CF Testing newborns found to have one CFTR mutation on a newborn screen Carrier testing for high-risk individuals and partners of CF carriers CF 102 screens for >100 CFTR mutations carefully selected to provide the highest detection rate (91% in Caucasians) of any screening option. It includes the 23 common mutations as defined by the American College of Medical Genetics and Genomics (ACMG). CF 102 may be optimal for: Confirming a diagnosis in patients known or suspected to have CF Carrier screening for relatives of those with CF Carrier testing or testing for at-risk relatives Meeting the American Congress of Obstetrics and Gynecologists (ACOG s)1 and the National Society of Genetic Counselors (NSGC s)2 CF carrier screening recommendations 508 FIRST is a quick and cost-effective screen for deltaf508, the most common CFTR mutation, with a potential reflex to sequence and deletion/duplication analysis. 508 FIRST may be optimal for: Confirming a diagnosis in those suspicious for CF, with no prior genetic testing 508 ONLY analyzes only the deltaf508 mutation. 508 ONLY may be optimal for: Those with a known family history of CF due to the delta F508 mutation Ambry also offers Specific Site Analysis (SSA) for known familial CFTR mutations or alterations. 1. American Congress (formerly College) of Obstetricians and Gynecologists Committee on Genetics. ACOG Committee Opinion No. 486: Update on carrier screening for cystic fibrosis. Obstet Gynecol Apr;117(4): Langfelder-Schwind E, et al. Molecular testing for cystic fibrosis carrier status practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns Feb;23(1):5-15.

6 Our Experience With CF Testing cystic fibrosis: cftr mutation detection rate by testing option (%) % clinically affected individuals CF AMPLIFIED CF102 ACMG-defined common mutation 0 CFTR overall mutation detection rate by test type 79% of patients clinically affected with CF carry at least one mutation that is not in ACMG s list of common mutations. 41% of patients carry at least one mutation that would only be picked up by full gene sequencing and deletion/duplication analysis, such as our CF AMPLIFIED test. (Based on internal data, 2015) CF Carrier Risks and CFTR Mutation/Alteration Detection Rates Individuals with CF and Ethnic Group Estimated Detection Rate*** CF Gene Sequence CF Gene Sequence & Del/Dup Carrier Risk Before Tests Carrier Risk** After Negative Test CF Gene Sequence CF Gene Sequence & Del/Dup No CF Mutations One CF Mutation CF Gene Sequence & Del/Dup Ashkenazi Jewish Non- Hispanic Caucasian African American Hispanic American* Asian American 97-98% >99% 1/24 ~1 in 959 ~1 in 2301 ~0.01% ~2% 97-98% >99% 1/25 ~1 in 1001 ~1 in 2401 ~0.01% ~2% 97-98% >99% 1/61 ~1 in 2501 ~1 in 6001 ~0.01% ~2% 97-98% >99% 1/58 ~1 in 2376 ~1 in 5701 ~0.01% ~2% 97-98% >99% 1/94 ~1 in 3876 ~1 in 9301 ~0.01% ~2% * This is a pooled set of data and requires additional information to predict risk accurately for specific Hispanic populations. ** Based on a negative family history. *** Based on Ambry s empirical data.

7 Genetic Test Results Explained A patient undergoing genetic testing will receive one of four possible results: positive, carrier, negative, or inconclusive (i.e. variant of unknown significance or VUS). RESULTS EXPLANATION Positive Two mutations (or variants, likely pathogenic) were found in the CFTR gene. Diagnosis of CF may be confirmed. Familial testing may be indicated to determine whether mutations are on the same or different chromosomes. This changes clinical interpretation of results. Treatment may be altered, depending on the mutations identified. Testing at-risk relatives for specific mutations may be considered. Carrier One mutation (or variant likely pathogenic) was found in the CFTR gene. Confirmed carrier of CF. While it is unlikely the patient will have symptoms of classic CF, they may show mild symptoms. Genetic screening/testing at-risk relatives (including reproductive partner) may be recommended. Negative No clinically significant genetic changes identified in the CFTR gene. Consideration of other genetic testing may be warranted. Risk for medical issues based on personal and family history. Screening and recommendations based on personal and family history. Carrier testing for familial CFTR mutations in family members is not indicated. Inconclusive A genetic change (or changes) identified, but current knowledge cannot predict if the change is disease-causing or benign. These are known as variants of unknown significance (VUS). Family studies may help to classify the VUS. Risk for medical issues based on personal and family history. Screening and recommendations based on personal and family history. Benefits of Testing Confirming a diagnosis of cystic fibrosis by identifying causative mutations can direct medical management. For example: Tailoring clinical management and medication options to the gene mutation identified Specific drug treatment for those that have particular CFTR mutations, including deltaf508, G551D, and many more Specific drug treatment for those with CFTR nonsense mutations. A comprehensive CFTR analysis (like CF AMPLIFIED) is the most thorough way to know if individuals have a premature stop codon (a nonsense mutation) as one of their mutations. Identifying at-risk family members suitable for genetic testing for familial gene mutation Helping couples when discussing reproductive concerns (including prenatal diagnosis)

8 Our Comprehensive Pulmonology Genetic Testing Menu We have a longstanding commitment to inherited pulmonary disorders. We offer several flexible molecular testing options to aid in diagnostic assessment, confirmation, and identification of at-risk family members. CONDITION NAME GENES TECHNIQUE(S) Alpha-1 antitrypsin deficiency SEPINA1 Gene Sequence Analysis, Deletion/Duplication Congenital central hypoventilation syndrome PHOX2B Gene Sequence Analysis Cystic fibrosis CFTR Gene Sequence Analysis, Deletion/Duplication Hereditary angioedema SERPING1 Gene Sequence Analysis, Deletion/Duplication Pancreatitis PRSS1, SPINK1, CFTR, CTRC Gene Sequence Analysis, Deletion/Duplication Primary ciliary dyskinesia and related disorders Telomere-related pulmonary fibrosis Surfactant dysfunction (respiratory distress syndrome) CFTR, DNAAF1, DNAAF2, DNAH5, DNAH11, DNAI1, DNAI2, OFD1, RPGR, RSPH4A, RSPH9, TXNDC3 TERC, TERT ABCA3, SFTPB, SFTPC Gene Sequence Analysis Gene Sequence Analysis Gene Sequence Analysis

9 VUS Rates and Family Studies Program Variants of unknown significance (VUS) may be identified by sequencing the CFTR gene. As information is accumulated, updated VUS rates will be made readily available. The possibility of inconclusive results warrants careful discussion in preand post-test counseling sessions. Detailed interpretation of any VUS identified is included in the test report. We are committed to careful analysis and timely reclassification of VUS. If a VUS is identified, complimentary testing of informative relatives may be offered through our Family Studies Program. Familial tracking (segregation studies) can assist in clarifying the nature of a VUS. When enough evidence has been accumulated to reclassify the VUS as either disease-causing or benign, you will be automatically notified. We have invested heavily in both research and clinical collaborations to ensure the quality and accuracy of our variant analyses and interpretations. For more information, please visit: ambrygen.com/variantclassification Specimen Requirements Blood: Collect 6-10cc (adult) or at least 2cc (children) in purple top EDTA tube (preferred) or yellow top citric acetate tube. Storage: 2-8 C and do not freeze. Shipment: Room temperature for two-day delivery. Blood Spot: Blood spots are accepted for all CF testing options except CF102. Saliva: Fill 1 tube (2 tubes for pediatric patients) with saliva up to black line (1cc of saliva) in Oragene Self Collection container. After tube is closed, 1cc of buffer will mix with saliva for a total volume of 2cc. Store at room temperature in sterile bag. Shipment: Room temperature for two-day delivery. DNA: 20 μg of DNA in TE (10mM Tris-Cl ph 8.0, 1mM EDTA); preferred 200 μl at ~100 ng/μl. Please provide DNA OD ratio (preferred ) and send agarose picture with high mw genomic DNA, if available. Store at -20 C. Ship frozen on dry ice (preferred) or ice. It is recommended if DNA has undergone multiple freeze/thaw cycles that it not be submitted. Cultured Cells: We accept cultured cells from fibroblasts. Prefer two T25 cell flasks (one flask is acceptable) or suitable alternative at 80% confluence. Store at 2-8 C in tissue culture incubator up to 72 hours. Do not freeze. Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor at (949) to discuss your case. Saliva Samples Blood draws on pediatric patients can be challenging. Fortunately, Ambry accepts saliva samples for many pediatric genetic tests. Please visit ambrygen.com/forms for complete specimen requirements.

10 Ambry Expertise support Board-certified genetic counselors, laboratory directors, and medical directors are readily available to assist with test selection, case reviews, and result interpretation. insurance We are contracted with the majority of commercial insurances and Medicare. All out-of-network patients are treated as in-network to minimize out-of-pocket costs. Insurance, Medicare, and Medicaid coverage varies; preverification is recommended. patient protection plan Ambry s billing policy is to preverify insurance coverage (with or without patient sample) for genetic testing. We will contact the patient after their sample is received, if their out-of-pocket cost is estimated to exceed $100. We are committed to working with you and your patients to make the genetic testing process as simple and cost-effective as possible, and our Billing Department is available to answer any questions your patient may have. Our Billing Department can be reached by phone at or billing@ambrygen.com. progeny s family history questionnaire (fhq) With Progeny s FHQ, patients can complete their family health history at their own pace. Pedigrees are automatically generated and managed along with all submitted data. With no re-entry of data, referral and clinical decisions can be made immediately. Template FHQs are available for use in your clinic at no cost, or custom questionnaires can be designed for you. Visit progenygenetics.com/clinical/trial for more. about ambry genetics Ambry Genetics is a privately-held healthcare company with the most comprehensive suite of genetic testing solutions for inherited and non-inherited diseases. Since 1999, Ambry has tested approximately half a million patient samples benefiting 90% of all U.S. patients covered by public and private insurers. Ambry is dedicated to scientific collaboration by offering its rapidly growing database of anonymized genomic data (variant frequencies) free to the global medical research community to fulfill the promise of the human genome to cure or manage all human disease. Ambry is dedicated to the belief that human health should not be patented or owned, and genomic data should be freely shared so we can try to understand all human disease. To order your complimentary sample submission kits, please contact: Ambry Genetics 15 Argonaut Aliso Viejo, CA USA +1 (866) info@ambrygen.com For more details about these tests, visit ambrygen.com References used to develop clinical content are available at ambrygen.com

11 Order. Track. Review. AmbryPort2.0 AmbryPort2.0 is an online customer interface, which includes features such as: Insurance preverification and order submission Ability to get status updates and track samples Ability to print and/or download patient reports Patient-specific auto-generation of letters of medical necessity Patient signature form to easily obtain patient signature during clinic Ability to upload insurance paperwork, medical records and other patient-specific documents current ambry customers If you currently use Ambry and have an on file with us, please attempt to login to your account by going to ambrygen.com and clicking the AmbryPort 2.0 login link on the upper right corner of any screen. Click reset password and insert your address. If successful, a password reset will be sent to your account. You can then change your password. If you have any questions or concerns, please contact our Client Services department at user guide A user guide is available and can be found here at ambrygen.com/ap2 system requirements Compatible with: desktop, tablet and mobile devices AmbryPort 2.0 works with: Safari, Chrome, Firefox, and Internet Explorer Version 8 or higher We recommend using the most current browser version to insure full functionality of the AmbryPort 2.0 interface Now available: new enhancements to Patient List Screen and secure document downloading through AP2 -- visit ambrygen.com/ap2 for more details

12 ambrygen.com 15 Argonaut, Aliso Viejo, CA USA Toll Free Fax _v4 CFCBRO