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MEDICAL POLICY – 12.04.518 Preconception Testing for Carrier Status of Genetic Diseases BCBSA Ref. Policies: 2.04.104, 2.04.83 Effective Date: Aug. 1, 2016 RELATED MEDICAL POLICIES: Last Revised: July 12, 2016 12.04.93 Replaces: 12.04.107 12.04.519 Genetic Testing for Alpha –Thalassemia Genetic Cancer Susceptibility Panels Using Next Generation Sequencing Select a hyperlink below to be directed to that section. POLICY CRITERIA | CODING | RELATED INFORMATION EVIDENCE REVIEW | REFERENCES | HISTORY ∞ Clicking this icon returns you to the hyperlinks menu above. Introduction Genetic tests are laboratory tests that measure changes in human DNA, chromosomes, genes or gene products (proteins). Blood, skin, cheek swabs, and amniotic fluid are some common samples that can be tested. Genetic testing for carrier status is done on people planning a pregnancy. The goal is to see if they have a potential disease that could be passed onto their offspring. For certain disorders a carrier state exists where a person has no symptoms of the disease, but has the potential to pass the disease onto their children, because they carry a gene for the disease. Often it takes at least two copies of the gene for the disease to cause symptoms. Usually carrier testing is done before conception when individuals are planning a pregnancy, but may also be done in the early stages of pregnancy. Note: The Introduction section is for your general knowledge and is not to be taken as policy coverage criteria. The rest of the policy uses specific words and concepts familiar to medical professionals. It is intended for providers. A provider can be a person, such as a doctor, nurse, psychologist, or dentist. A provider also can be a place where medical care is given, like a hospital, clinic, or lab. This policy informs providers about when a service may be covered. Policy Coverage Criteria Expanded Carrier Test Type Medical Necessity Expanded Carrier Expanded carrier screening panels which test for mutations on Screening Panels many different genes are considered not medically necessary. Based on the individual tested, a subset of the panel may be covered when the policy criteria are met. Expanded carrier panel test names, and their individual mutation components, are rapidly evolving. Examples of tests addressed in this policy include but are not limited to: Counsyl™ (Counsyl) GoodStart Select™ (GoodStart Genetics) Inherigen™ (GenPath) InheriGen Plus Inheritest™ (LabCorp) Natera One™ Disease Panel (Natera) Notes: For GoodStart Select the provider may select/limit mutations to those which are targeted to a specific population and in some instances this would not be considered an expanded panel. American College of Medical Genetics (ACMG) defines expanded panels as those that use next generation sequencing to screen for mutations in many genes, as opposed to gene-by-gene screening (e.g., ethnic-specific screening or pan-ethnic testing for cystic fibrosis). An ACMG position statement states that although commercial laboratories offer expanded carrier screening panels, there has been no professional guidance as to which disease genes and mutations to include.1Expanded panels may include the diseases that are present with increased frequency in specific populations, but typically include testing for a wide range of diseases for which the patient is not at risk of being a carrier. Page | 2 of 30 ∞ The General Population Genetic Disease Coverage Criteria Cystic Fibrosis Covered for all individuals with a panel that tests the most common genes (CPT 81220) Note: Carrier testing for cystic fibrosis using CPT 81223 “CFTR (e.g. cystic fibrosis) gene analysis; full gene sequence” is considered not medically necessary for carrier testing. Spinal Muscular Atrophy Covered for all individuals Specific Groups or Populations The following genetic testing may also be considered medically necessary due to an increased frequency of certain disorders in groups or populations: Genetic Disease Medical Necessity Ashkenazi Jewish Founder When the individual meets one of the following criteria: Mutations: Bloom syndrome Canavan disease Cystic fibrosis Familial dysautonomia Fanconi anemia (group C) Gaucher disease Mucolipidosis IV Niemann-Pick (type A) Tay-Sachs disease Ashkenazi Jewish ancestry consisting of a minimum of one Jewish grandparent. If the Jewish partner has a positive carrier test result, the other partner (regardless of ethnic background) should be screened only for that identified mutation. Genetic testing for Askenazi Jewish Founder mutation is considered not medically necessary for all other uses. FMR1 Mutations (Including When any of the following criteria are met: Fragile-X Syndrome) Individuals of either sex with intellectual disability, developmental delay, or autism spectrum disorder Individuals with a family history of fragile X syndrome or a family history of undiagnosed intellectual disability Mothers who are known carriers to determine whether the fetus inherited the normal or mutant FMR1 gene Page | 3 of 30 ∞ Genetic Disease Medical Necessity Affected individuals or relatives of affected individuals who have had a positive cytogenetic fragile X test (less accurate historic test) result who are seeking further counseling related to the risk of carrier status FMR1 Mutations (Including Fragile-X Syndrome) is considered not medically necessary for all other uses. Alpha-Thalassemia – When ALL of the following criteria are met: Preconception (Carrier) Testing At least one parent is of a high-risk ethnic group, such as Southeast Asian, African or Mediterranean ancestry At least one parent has had abnormal biochemical testing which may include ANY of the following: o Anemia o Microcytosis ( a low MCV – small blood cells) o Hypochromia (a low MCH or MCHC – red blood cells with less hemoglobin) o Abnormal hemoglobin electrophoresis Genetic testing for hemoglobinopathies, except for alpha thalassemia, is considered not medically necessary. Other Inherited Disorders Carrier testing may be considered medically necessary based on the following general criteria: Genetic Disease Medical Necessity Carrier Testing Specific When any of the following are present: Disorder One or both parents have a first- or second-degree relative who has the disorder: o 1st-degree relatives are parents, siblings, and children. o 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings. One parent is or both parents are a known carrier of the disorder. Page | 4 of 30 ∞ Genetic Disease Medical Necessity All of the following criteria must also be are met: The natural history of the disease is understood and the disease is likely to result in severe health problems in the homozygous or compound heterozygous state. Other biochemical or clinical tests to diagnose carrier status are not available, or provide an indeterminate result or are less accurate than genetic testing. The genetic test has adequate sensitivity and specificity to guide clinical decision making and residual risk is understood o The American College of Medical Genetics and Genomics (ACMG) recommends testing for specific mutations, which will result in carrier detection rate of 95% or higher for most disorders. A clear association of the genetic change with the disorder has been established Genetic testing for other specific disorders is considered not medically necessary when the criteria above are not met. Coding If CPT Tier 1 or Tier 2 molecular pathology codes are available for the specific test, they should be used. If the test has not been codified by CPT, the unlisted molecular pathology code 81479 would be used. CPT 81223 CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; full gene sequence 81412 Ashkenazi Jewish associated disorders genomic sequence panel- Must include at least 9 genes including ASPA, BLM, CFTR, FANCC, GBA, HEXA, IKBKAP, MCOLN1, and SMPD1 81257 HBA1/HBA2 ( alpha globulin 1 and alpha globulin 2) gene analysis Page | 5 of 30 ∞ CPT 81479 Unlisted molecular pathology procedure Related Information Definition of Terms 1st-, 2nd-, or 3rd-degree relative: For the purpose of familial assessment, 1st-, 2nd-, or 3rddegree relatives are blood relatives on the same side of the family (maternal or paternal).The maternal and paternal sides of the family should be considered independently for familial patterns of cancer. 1st-degree relatives are parents, siblings, and children. 2nd-degree relatives are grandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings. 3rd-degree relatives are great-grandparents, great-aunts, great-uncles, great-grandchildren, and first cousins Carrier testing: Carrier genetic testing is performed on people who display no symptoms for a genetic disorder but may be at risk for passing it on to their children. A carrier of a genetic disorder has one abnormal allele for a disorder. Carriers of an autosomal recessive mutation are typically unaffected. Offspring who inherit the mutation from both parents usually manifest the disorder. When associated with an autosomal dominant or an Xlinked dominant disorder, the individual may be affected with the disorder or at high risk of developing the disorder later in life. Women with an X-linked recessive mutation are usually unaffected. Males receiving a chromosome with an X-linked recessive mutation usually manifest the disorder. Compound heterozygous: The presence of two different mutant alleles at a particular gene locus, one on each chromosome of a pair. Expressivity/expression: The degree to which a penetrant gene is expressed within an individual. Genetic testing involves the analysis of chromosomes, DNA, RNA, genes, or gene products to detect inherited (germline) or non-inherited (somatic) genetic variants related to disease or health. Page | 6 of 30 ∞ Homozygous: Having the same alleles at a particular gene locus on homologous chromosomes (chromosome pairs). Penetrance: The proportion of individuals with a mutation that causes a particular disorder who exhibit clinical symptoms of that disorder. Residual risk: The risk that an individual is a carrier of a particular disease, but genetic testing for carrier status of the disease is negative (e.g., if the individual has a disease-causing mutation that wasn’t included in the test assay). Testing sequence: Testing sequence of carrier testing for genetic diseases is generally, the mother or affected partner is first, and if positive, the other parent is tested. Evidence Review Carrier testing is performed to identify couples at risk of having offspring with a genetic disease. Carriers are usually not at risk of developing the disease, but have a risk of passing a pathogenic gene mutation to their offspring. Carrier testing may be performed before conception or during a pregnancy. This policy offers a framework for evaluating the utility of carrier genetic testing. This policy applies only if there is not a separate policy that outlines specific criteria for carrier testing. If a separate policy exists, then criteria for medical necessity in that policy supersede the guidelines in this policy (see Related Policies). Specific Patient Populations Carrier screening may be performed for conditions that are found in the general population (pan-ethnic), for diseases that are more common in particular populations, or based on family history. Pan-ethnic (population) screening for carrier status is done for single-gene disorders that are common in the population, such as cystic fibrosis. Carrier screening for specific genetic conditions may be done in members of an ethnic group with a high risk of a specific genetic disorder. For example, certain autosomal recessive conditions are more prevalent in individuals of Eastern European Jewish (Ashkenazi) descent. Most individuals of Jewish ancestry in North America are descended from Ashkenazi Jewish Page | 7 of 30 ∞ communities and are therefore at increased risk of being carriers of one of these conditions. Many of these disorders are lethal in childhood or associated with significant morbidity. FMR1 Mutations/Fragile-X Syndrome Fragile-X syndrome is associated with the expansion of the CGG trinucleotide repeat in the fragile-X mental retardation 1 (FMR1) gene on the X chromosome. Fragile-X syndrome (FXS) is the most common cause of heritable intellectual disability, characterized by moderate intellectual disability in males and mild intellectual disability in females. FXS affects approximately 1 in 4000 males and 1 in 8000 females. In addition to intellectual impairment, patients present with typical facial features, such as an elongated face with prominent forehead, protruding jaw, and large ears. Connective tissue anomalies include hyperextensible finger and thumb joints, hand calluses, velvet-like skin, flat feet, and mitral valve prolapse. The characteristic appearance of adult males includes macroorchidism. Patients may show behavioral problems including autism spectrum disorders, sleeping problems, social anxiety, poor eye contact, mood disorders, and hand-flapping or biting. Another prominent feature of the disorder is neuronal hyperexcitability, manifested by hyperactivity, increased sensitivity to sensory stimuli, and a high incidence of epileptic seizures. Men who are premutation carriers are referred to as transmitting males. All of their daughters will inherit a premutation, but their sons will not inherit the premutation. Males with a full mutation usually have intellectual disability and decreased fertility. Alpha-Thalassemia Hemoglobin, is the major oxygen carrying protein molecule of red blood cells, consists of 2 alpha (α)-globin chains and 2 beta (β)-globin chains. Alpha-thalassemia refers to a group of syndromes that arise from deficient production of α-globin chains. Deficient α-globin production leads to an excess of β-globin chains, which results in anemia by a number of mechanisms: Ineffective erythropoiesis in the bone marrow. Production of nonfunctional hemoglobin molecules. Page | 8 of 30 ∞ Shortened survival of RBCs [red blood cells] due to intravascular hemolysis and increased uptake of the abnormal RBCs by the liver and spleen. The physiologic basis of α-thalassemia is a genetic defect in the genes coding for α-globin production. Each individual carries four genes that code for α-globin (2 copies each of HBA1 and HBA2, located on chromosome 16), with the wild genotype (normal) being aa/aa. Genetic mutations may occur in any or all of these 4 α-globin genes. The number of genetic mutations determines the phenotype and severity of the α-thalassemia syndromes. The different syndromes are classified as follows: Silent carrier (α-thalassemia minima): This arises from one of four abnormal alpha genes (aa/a-), and is a silent carrier state. A small amount of abnormal hemoglobin can be detected in the peripheral blood, and there may be mild hypochromia and microcytosis present, but there is no anemia or other clinical manifestations. Thalassemia trait (α-thalassemia minor): This is also called α-thalassemia trait and arises from the loss of 2 α-globin genes, resulting on one of two genotypes (aa/--, or a-/a-). There is a mild anemia present, and red blood cells are hypochromic and microcytic. Clinical symptoms are usually absent and in most cases, the Hg electrophoresis is normal. Hemoglobin H disease (α-thalassemia intermedia): This syndrome results from three abnormal α-globin genes (a-/--), resulting in a moderate to severe anemia. In HgH disease, there is an imbalance in α- and β-globin gene chain synthesis, resulting in the precipitation of excess β chains into the characteristic hemoglobin H, or β-tetramer. This condition has marked phenotypic variability, but most individuals have mild disease and live a normal life without medical intervention. A minority of individuals may develop clinical symptoms of chronic hemolytic anemia. These include neonatal jaundice, hepatosplenomegaly, hyperbilirubinemia, leg ulcers, and premature development of biliary tract disease. Splenomegaly can lead to the need for splenectomy, and transfusion support may be required by the third to fourth decade of life. It has been estimated that approximately 25% of patients with HgH disease will require transfusion support during their lifetime. In addition, increased iron deposition can lead to premature damage to the liver and heart. Inappropriate iron therapy and oxidant drugs should be avoided in patients with HgH disease. There is an association between genotype and phenotype among patients with HgH disease. Individuals with a nondeletion mutation typically have an earlier presentation, more severe anemia, jaundice, and bone changes, and more frequently require transfusions. Page | 9 of 30 ∞ Hemoglobin Bart syndrome (α-thalassemia major): This syndrome results from mutations in all 4 α-globin genes (--/--), resulting in absent production of α-globin chains. This condition causes hydrops fetalis, which often leads to intrauterine death, or death shortly after birth. There are also increased complications of pregnancy for a woman carrying a fetus with hydrops fetalis. These include hypertension, preeclampsia, antepartum hemorrhage, renal failure, premature labor, and abruption placenta. (See table for probability of Hoemoglobin Bart Syndrome.) Alpha-thalassemia is a common genetic disorder, affecting approximately 5% of the world’s population. The frequency of mutations is highly dependent on ethnicity, with the highest rates seen in Asians, and much lower rates in Northern Europeans. The carrier rate is estimated to be 1 in 20 in Southeast Asians, 1 in 30 for Africans, and between 1 in 30 and 1 in 50 for individuals of Mediterranean ancestry. In contrast, for individuals of northern European ancestry, the carrier rate is less than 1 in 1,000. Expanded Carrier Screening New technologies have made it possible to screen for mutations in many genes more efficiently than testing mutations in a single gene or a small number of population-specific mutations in several genes. Commercial laboratories offer expanded carrier screening (ECS) panels, which comprise a nontargeted approach to carrier screening. There is no standardization to the makeup of these genetic panels; panel composition varies among labs; and different commercial products for a single condition may test different sets of genes. Although ECS panels may include conditions that are routinely assessed in carrier testing, ECS panels include many conditions that are not routinely evaluated and for which there are no existing professional guidelines. FMR1 Mutation/Fragile-X Syndrome Evidence on the clinical benefit of testing for Fragile-X syndrome is largely anecdotal. Clinical utility of genetic testing can be considered in the following clinical situations: (1) individuals with a clinical diagnosis of intellectual disability, developmental delay, or autism, especially if they have any physical or behavioral characteristics of Fragile-X syndrome, a family history of Fragile X syndrome, or male or female relatives with undiagnosed intellectual disability, and (2) individuals seeking reproductive counseling. Page | 10 of 30 ∞ Clinical utility for these patients depends on the ability of genetic testing to make a definitive diagnosis and for that diagnosis to lead to management changes that improve outcomes. No studies were identified that described how a molecular diagnosis of Fragile-X syndrome changed patient management. Therefore there is no direct evidence for clinical utility of genetic testing in these patients. Because there is no specific treatment for Fragile-X syndrome, making a definitive diagnosis will not lead to treatment that alters the natural history of the disorder. There are several potential ways in which adjunctive management might be changed after confirmation of the diagnosis by genetic testing. The American Academy of Pediatrics (AAP)5 and the American Academy of Neurology (AAN) recommend cytogenetic evaluation in individuals with developmental delay to look for certain chromosomal abnormalities that may be causally related to their condition. AAN guidelines note that only in occasional cases will an etiologic diagnosis lead to specific therapy that improves outcomes but suggest more immediate and general clinical benefits of achieving a specific genetic diagnosis from the clinical viewpoint, as follows: Limit additional diagnostic testing; Anticipate and manage associated medical and behavioral comorbidities; Improve understanding of treatment and prognosis; and Allow counseling regarding risk of recurrence in future offspring and help with reproductive planning. AAP and AAN guidelines also emphasize the importance of early diagnosis and intervention in an attempt to ameliorate or improve behavioral and cognitive outcomes over time. Guidelines from AAP recommend against routine fragile X testing for children with isolated attentiondeficit/hyperactivity disorder. Alpha-Thalassemia Preconception (Carrier) Testing The major benefit of carrier testing is to define the likelihood of α-thalassemia major. Avoiding a pregnancy with α-thalassemia major is of benefit in that a prospective mother will avoid carrying a non-viable pregnancy, and will avoid the increased obstetrical complications associated with a fetus with α-thalassemia major. Page | 11 of 30 ∞ Carrier screening with biochemical testing is recommended for all patients who are from an ethnic groups with a high incidence of α-thalassemia. Biochemical screening consists of a CBC with peripheral smear analysis. If there are any abnormalities noted, such as anemia, microcytosis, or hypochromia, Hg electrophoresis is then performed to identify the specific types of Hg present and between HgH disease. As noted, the hemoglobin electrophoresis may be normal in the asymptomatic carrier and α-thalassemia trait states, but the states may be suspected based on CBC and peripheral smear analysis. Unlike for a clinical diagnosis, for carrier testing, it is important to distinguish between αthalassemia carrier (one abnormal gene) and α-thalassemia trait (two abnormal genes), and also important to distinguish between the two variants of α-thalassemia trait, that is the aa/-- (cis variant) and the a-/a- (trans variant). This is because only when both parents have the aa/-- cis variant is there a risk for a fetus with α-thalassemia major.17 When both parents are αthalassemia carriers (aa/--), there is a 1 in 4 likelihood that an offspring will have α-thalassemia major and hydrops fetalis. These parents may decide to pursue pre-implantation genetic diagnosis in conjunction with in vitro fertilization to avoid a pregnancy with hydrops fetalis. In this situation, genetic testing has incremental utility over biochemical testing. Whereas biochemical testing can determine whether a silent carrier/trail syndrome is present, and can distinguish those syndromes from HgH disease, it cannot provide a precise determination of the number or pattern of abnormal alpha genes. As a result, using biochemical screening alone, the probability of developing a hemoglobin Bart fetus cannot be accurately assessed. In contrast, genetic testing can delineate the number of abnormal genes with certainty. In addition, genetic testing can determine whether an α-thalassemia trait exists as the cis (aa/--) variant or the trans (a-/a-) variant. Using this information from genetic testing, the probability of hemoglobin Bart syndrome can be determined according to the table below. Clinical Diagnosis in Genotype Genotype Probability of Hg Bart Parents (Parent 1) (Parent 2) Syndrome, % Both parents silent carriers aa/a- aa/a- 0 One parent silent carrier, 1 aa/a- a-/a- 0 aa/a-- 0 aa/-- 25 a-/a- 0 aa/-- 0 a-/a- 0 parent trait Both parents trait aa/-- a-/a- Page | 12 of 30 ∞ One parent HgH, 1 parent a-/-- aa/a- 0 a-/-- aa/-- 25 a-/a- 0 a-/-- 25 silent carrier One parent HgH, 1 parent trait Both parents HgH a-/-- Hg: hemoglobin Parents can also determine the likelihood of HgH disease in an offspring through genetic testing. However, because this is in most cases a mild condition, it is less likely to be considered information that is actionable in terms of altering reproductive decision making. Preconception (carrier) testing is likely to have clinical utility by providing incremental diagnostic information over biochemical testing that can identify the pattern of abnormal alpha genes and estimate more precisely the risk of hydrops fetalis. Expanded Carrier Screening Panels Expanded carrier screening (ECS) panels may provide the opportunity to test carriers for a greatly expanded number of diseases for a lower cost than the conventional forms of carrier testing. However, current limitations of these expanded panels include technical and interpretive limitations and ethical and genetic counseling challenges, as outlined next. In 2015, a joint statement on ECS was issued by ACMG, ACOG, the National Society of Genetic Counselors, the Perinatal Quality Foundation and the Society for Maternal-Fetal Medicine.13 The statement was not meant to replace current screening guidelines but to demonstrate an approach for health care providers and laboratories that are seeking to or are currently offering ECS panels. Some of the points to consider include the following: ECS panels include most of the conditions recommended in current guidelines; however, molecular methods used in ECS are not as accurate as methods recommended in current guidelines for: the hemoglobinopathies, which require use of mean corpuscular volume and hemoglobin electrophoresis, and for Tay-Sachs disease. The detection rate for Tay-Sachs carrier status is low in non-Ashkenazi populations using molecular testing for the 3 common Ashkenazi mutations-currently, hexoaminidase An enzyme analysis on blood is the best method to identify carriers in all ethnicities. Page | 13 of 30 ∞ Patients should be aware that newborn screening is mandated by all states and can identify some of genetic conditions in the newborn. However, newborn screening may include a different panel of conditions than ECS. Newborn screening does not usually detect children who are carriers for the conditions being screened so will not necessarily identify carrier parents at increased risk. ECS can be performed by genotyping, which searches for known pathogenic and likely pathogenic variants, or by DNA sequencing, which analyzes the entire coding region of the gene and identifies alterations from the normal sequence. Genotyping includes selected variants, but sequencing has the potential to identify benign and likely benign variants and variants of unknown significance, in addition to pathogenic variants. Therefore, ECS panels should only include genes and variants with a well-understood relationship with a phenotype. When carrier frequency and detection rate are both known, residual risk estimation should be provided in the lab report. Conditions with unclear value on preconception and prenatal screening panels include alpha-1-antitrypsin (A1AT), methylene tetrahydrofolate reductase (MTHFR) and hereditary hemochromatosis (HH). There is currently little evidence that addresses reproductive outcomes using ECS. Future research needs in ECS should focus on data collection and development of a curated data repository, and education of health care providers and patients. To improve the predictive value of ECS, previously unreported and relatively rare variants and full phenotypes of homozygous and compound heterozygotes should be collected and made available. Determining the frequency of variants in previously untested ethnic and racial groups is required because risks associated with gene variants may vary with different genetic backgrounds and in different environmental situations. Collaborative analysis among laboratories is necessary to further understanding of ECS. A 2011 study by Bell et al., described the development of an ECS panel for 448 severe recessive diseases of childhood, using next generation sequencing (NGS).14 The authors tested 104 unrelated DNA samples. They noted that although technical standards and guidelines for laboratory-developed genetic testing for rare disorders in accredited laboratories have been established, there are several challenges in their adoption for NGS and for bioinformatic-based testing of many conditions. Specific national standards for quality assurance, quality control, test accessioning and reporting, and proficiency evaluation does not currently exist. Also, issues of specificity and false positives are complex when hundreds of genes are being sequenced simultaneously and need to be addressed. Page | 14 of 30 ∞ Lazarin et al. (2013) reported on carrier status from an ethnically diverse clinical sample of 23,452 individuals.15 Using the Counsyl test screening platform, they assayed 417 diseasecausing mutations associated with 108 recessive diseases. Of the individuals tested, 5,633 (24%) were heterozygous for at least one condition, and 5.2% were identified as carriers for multiple disorders. Of 127 carrier couples identified (i.e., pairs of individuals identified as partners by selfreport who were both found to share heterozygosity for at least one disease), 47 (37%) were for alpha-1 antitrypsin deficiency, a condition which has reduced penetrance, variable severity, and uncertain clinical presentation in the newborn period and into adulthood. The American Thoracic Society discourages genetic testing for alpha-1 antitrypsin deficiency in asymptomatic adults with no increased risk for this disease.16 In March 2011, 6 U.S. academic centers convened focus groups to examine genetics professionals’ views on ECS.17 Forty genetics professionals, including those specializing in medical genetics, pediatric genetics, genetic counseling, public health genetics, primary care, laboratory medicine, and law and bioethics, aimed to clarify how genetics professionals view potential benefits and challenges of ECS. Overall, participants agreed that there was financial value in ECS panels compared with conventional carrier screening. However, their findings highlighted major limitations of ECS. Concerns included the following: Use of ECS panels would be a significant departure from clinical practice guidelines in genetic and reproductive healthcare in the United States, and carrier screening guidelines currently exist for only a few of the genetic disorders evaluated by ECS panels. Technical limitations of ECS include the inability to fully rule out the possibility of severe recessive diseases due to rare mutations that could be identified by alternative methods such as DNA sequencing, and, there are gaps in coverage of both specific genes and individual mutations included in the ECS panels. Current ECS panels typically examine only a fraction of the many genes associated with genetic disorders and limit their evaluation to common genetic mutations within those genes. Reproductive healthcare providers might fail to recommend more conventional forms of targeted genetic evaluation, such as screening tests indicated by a couple’s ethnicity, based on erroneous perceptions about the coverage of ECS products being marketed as universal in scope. Less common mutations in specific ethnic populations may not be included, and couples may be falsely reassured by “negative” results. Page | 15 of 30 ∞ As the number of individual assays on a multiplexed genetic test increases, the likelihood of erroneous results (e.g., false positives) and clinically ambiguous findings (e.g., variants of unknown significance) increases significantly. As carrier screening panels expand to include less common genetic diseases, interpretation of mutation results is hindered by lack of data on clinical phenotypes associated with rare variants. In 2013, Wienke et al. issued a commentary on the limitations of using ECS panels.18 The authors stated that: Patients may not understand the nature of every disease on the panel, confounding the process of informed consent. In practice, it is infeasible to inform patients of the nature of each condition tested, and many healthcare providers are unfamiliar with some of the conditions tested, making it difficult to communicate residual risk and take action on the information obtained. Panels usually include diseases with decreased penetrance and variable expressivity that are unlikely to be life-threatening in a patient with a negative family history (e.g., Factor V Leiden thrombophilia, hemochromatosis, methylenetetrahydrofolate reductase [MTHFR] deficiency). Screening for mutations that have unclear clinical significance has unclear implications in reproductive decision making. It is possible that a test primarily designed to assess reproductive risk will inadvertently identify an asymptomatic individual with the disease, which poses many challenges. These include unanticipated psychosocial burden to patients, and a burden to the healthcare system in general as a person identified through this method may undergo additional baseline testing for the disease and receive follow-up for the disease that may otherwise have been unnecessary. Genetic Counseling Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The Interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, Page | 16 of 30 ∞ including the possible impact of the information on the individual’s family. Genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods. Ongoing and Unpublished Clinical Trials Some currently unpublished trials that might influence this review are listed in the Table 1below. Table 1: Summary of Key Trials NCT No. Trial Name Planned Completion Enrollment Date 400 May 2017 Ongoing NCT01902901 Clinical Implementation of Carrier Status Using Next Generation Sequencing NCT: National Clinical Trial Summary of Evidence The evidence for carrier testing in individuals who are asymptomatic but at risk for having an offspring with a genetic disease includes mutation prevalence studies, general principles of carrier testing and accepted practice guidelines from major medical societies, which provides a framework for evaluating these tests; direct evidence on outcomes with carrier testing is lacking. Relevant outcomes are test accuracy, test validity and changes in reproductive decision making. Reported analytic validity (technical accuracy) of targeted carrier screening tests is high. Changes in management involve family planning decisions. Results of genetic testing can be used to assist individuals with reproductive decisions such as avoidance of pregnancy, preimplantation genetic testing, adoption, etc. Therefore, the evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. The evidence for preconception (carrier) genetic testing for alpha-thalassemia includes case reports and case series that correlate pathogenic mutations with clinical disease. Relevant Page | 17 of 30 ∞ outcomes are test accuracy, test validity, and changes in reproductive decision making. Preconception carrier testing is intended to avoid the most serious form of α-thalassemia, hemoglobin Bart disease. This condition leads to intrauterine death or death shortly after birth and is associated with increased obstetrical risks for the mother. Screening of populations at risk is first done by biochemical tests, including hemoglobin electrophoresis and complete blood count and peripheral smear, but these tests cannot reliably distinguish between the carrier and trait syndromes and cannot determine which configuration of mutations is present in αthalassemia trait. They therefore cannot completely determine the risk of a pregnancy with hemoglobin Bart syndrome and hydrops fetalis. Genetic testing can determine with certainty the number of abnormal genes present, and therefore can more precisely determine the risk of hydrops fetalis. Therefore, the evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. The evidence for FMR1 mutation testing (including Fragile X) in individuals with intellectual disability, developmental delay, or autism spectrum disorder or in affected individuals or at-risk relatives in whom testing will affect reproductive decision making includes studies evaluating the analytic and clinical validity of FMR1 mutation testing and a chain of indirect evidence for demonstration of clinical outcome improvements. Relevant outcomes are test accuracy, test validity, resource utilization, and changes in reproductive decision making. Analytic sensitivity and specificity for diagnosing these disorders has been demonstrated to be sufficiently high. The evidence demonstrates that FMR1 mutation testing can establish a definitive diagnosis of FXS when the test is positive for a pathogenic mutation. Following a definitive diagnosis, there are a variety of ways management may change. Providing a diagnosis can eliminate the need for further clinical workup. For certain mutations, results may aid in management of psychopharmacologic interventions, assist in informed reproductive decision making, or both. Although direct evidence for improved outcomes is insufficient, there is a chain of indirect evidence that supports improvements in outcomes following FMR1 mutation testing. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. The evidence for expanded carrier testing in individuals who are asymptomatic but at risk for having an offspring with a genetic disease includes mutation prevalence studies; direct evidence is lacking. Relevant outcomes are test accuracy, test validity and changes in reproductive decision making. analytic validity of expanded carrier screening (ECS) panels is unknown. ECS panels have significant limitations, including increased false positives and variants of uncertain significance due to testing for many mutations, false negatives due to rare mutations not included in panel testing, the inclusion of diseases with decreased penetrance and variable Page | 18 of 30 ∞ expressivity that are unlikely to be life-threatening in a patient with a negative family history and difficulties with communicating residual risk and actionability of information obtained. Therefore, the evidence is insufficient to determine the effects of the technology on health outcomes. Practice Guidelines and Position Statements Ethnic groups with a higher carrier rate for a particular condition. Ashkenazi Jewish In 2014, the American Congress of Obstetricians and Gynecologists (ACOG) reaffirmed a 2009 committee opinion that carrier screening for Tay-Sachs disease, Canavan disease, cystic fibrosis, and familial dysautonomia should be offered to Ashkenazi Jewish individuals before conception or during pregnancy so that a couple has an opportunity to consider prenatal diagnostic testing options.4,5 The committee opinion stated that individuals of Ashkenazi Jewish descent may inquire about the availability of carrier screening for other disorders found among individuals of Eastern European Jewish descent, and that carrier screening is available for mucolipidosis IV, Niemann-Pick disease type A, Fanconi anemia group C, Bloom syndrome, and Gaucher disease, and that patient education materials can be made available so that interested patients can make informed decisions about having additional screening tests. When only one partner is of Ashkenazi Jewish descent, that individual should be screened first. If that individual is a carrier, the other partner should be offered screening; however, the couple should be informed that because carrier frequency and detection rate in non-Jewish individuals is unknown for all of these disorders (except for Tay-Sachs disease and cystic fibrosis), it is difficult to predict the couple’s risk of having a child with one of the disorders. If an individual has a positive family history for one of these disorders, he or she should be offered carrier screening for that specific disorder. When both partners are carriers of one of these disorders, they should be referred for genetic counseling and offered prenatal diagnosis. In 2013, The American College of Medical Genetics and Genomics (ACMG) reaffirmed a 2008 guideline that recommended carrier screening for cystic fibrosis, Canavan disease, familial dysautonomia, and Tay-Sachs disease be offered to all individuals of Ashkenazi Jewish descent who are pregnant, or considering pregnancy.2,3 ACMG also recommended that carrier screening Page | 19 of 30 ∞ be offered for Fanconi anemia (group C), Niemann-Pick (type A), Bloom syndrome, mucolipidosis IV, and Gaucher disease. According to ACMG, if only 1 member of the couple is Jewish, ideally, that individual should be tested first. If the Jewish partner has a positive carrier test result, the other partner (regardless of ethnic background) should be screened for that particular disorder. One Jewish grandparent is sufficient to offer testing. Hemoglobinopathies Society of Obstetricians and Gynaecologists of Canada The Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada published guidelines on carrier testing for thalassemia in 2008. These guidelines included the following recommendations: Carrier screening for α-thalassemia should be offered to all woman from ethnic groups with an increased prevalence of α-thalassemia. Initial screening should consist of CBC, Hg electrophoresis (or hemoglobin high performance liquid chromatography), ferritin testing and examination of peripheral smear for the presence of H bodies. If a woman is found to have abnormal results on initial screen, testing of the partner should be performed using the same battery of tests. If both partners are found to be carriers of thalassemia, or combination of a thalassemia and hemoglobin variant, they should be referred for genetic counseling. Additional molecular studies may be required to clarify the carrier status of the parents and thus the risk to the fetus. In 2013, ACOG reaffirmed a 2007 guideline for hemoglobinopathies in pregnancy, which included recommendations for carrier screening.6,7 For carrier screening, individuals of African, Southeast Asian, and Mediterranean descent are at risk for being carriers of hemoglobinopathies; ACOG recommended that individuals from these ethnic group should be offered carrier screening and, if both parents are determined to be carriers, genetic counseling. A complete blood count and hemoglobin electrophoresis are appropriate laboratory tests for screening for hemoglobinopathies. Page | 20 of 30 ∞ Cystic Fibrosis The initial ACMG Cystic Fibrosis Carrier Screening Working Group recommended that laboratories use a pan-ethnic panel of 25 mutations present in at least 0.1% of patients with classic cystic fibrosis (CF).19 Current guidelines, revised by ACMG in 2004 9 and reaffirmed in 2013,3 recommend a 23-mutation panel and were developed after assessing initial experiences on implementation of CF screening into clinical practice. CF screening also may identify 5T/7T/9T variants in the CFTR gene, which vary between individuals. Genetic counseling is important to discern whether the combination of mutations and variants would cause classic or atypical CF. Complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening because it may yield results that can be difficult to interpret. This type of testing is generally reserved for patients with CF, patients with a family history of CF, males with congenital bilateral absence of the vas deferens, or newborns with a positive newborn screening result when mutation testing, using the standard 23-mutation panel, has a negative result. Because carrier screening detects most mutations, sequence analysis should be considered only after discussion with a genetics professional to determine if sequencing will be informative after standard screening has been performed. In 2011, ACOG issued an update on carrier screening for CF, and the Committee on Genetics provided the following guidelines8: It is important that CF screening continue 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 whether 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. Page | 21 of 30 ∞ If a woman with CF wants to become pregnant, a multidisciplinary team should be consulted to manage issues regarding pulmonary function, weight gain, infections, and 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 whether 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. Spinal Muscular Atrophy Current practice guidelines for spinal muscular atrophy (SMA) carrier testing from ACMG and ACOG are in conflict. ACMG’s 2008 guideline, reaffirmed in 2013, recommends carrier testing for SMA in all couples regardless of race or ethnicity.3,10 ACOG’s 2009 Committee on Genetics opinion statement limits SMA carrier screening (1) to those with a family history of SMA or SMAlike disease, and (2) to those who request SMA carrier screening and have completed genetic counseling to review sensitivity, specificity, and limitations of screening.11 The genetics of SMA is complex, involving 2 genes; 95% of patients have a deletion in SMN1, but variable copy number of SMN2 affects phenotypic expression (greater copy number is associated with milder disease). Further, copy number of SMN1 can vary, confounding interpretation of a negative (normal) result, e.g., 2 SMN1 copies on 1 chromosome may mask SMN1 deletion from the other chromosome. Because of this complexity and residual risk with a negative result, ACOG opinion authors recommended pilot studies to determine best practices for pre- and posttest education and counseling before implementing pan-ethnic SMA carrier screening. Page | 22 of 30 ∞ FMR1 Mutations/Fragile X Syndrome American College of Medical Genetics American College of Medical Genetics’s (ACMG) Professional Practice and Guidelines Committee makes the following recommendations regarding diagnostic and carrier testing for FXS. The purpose of these recommendations is to provide general guidelines to aid clinicians in making referrals for testing the repeat region of the FMR1 gene. Individuals of either sex with intellectual disability, developmental delay, or autism, especially if they have (a) any physical or behavioral characteristics of fragile X syndrome, (b) a family history of fragile X syndrome, or (c) male or female relatives with undiagnosed intellectual disability. Individuals seeking reproductive counseling who have (a) a family history of fragile X syndrome or (b) a family history of undiagnosed intellectual disability. Fetuses of known carrier mothers. Affected individuals or their relatives in the context of a positive cytogenetic fragile X test result who are seeking further counseling related to the risk of carrier status among themselves or their relatives. The cytogenetic test was used before the identification of the FMR1 gene and is significantly less accurate than the current DNA test. DNA testing on such individuals is warranted to accurately identify premutation carriers and to distinguish premutation from full mutation carrier women. In the clinical genetics evaluation to identify the etiology of autism spectrum disorders, ACMG recommends testing for FXS as part of first tier testing. Academy of Pediatrics The Academy of Pediatrics recommends that, because children with FXS may not have apparent physical features, any child who presents with developmental delay, borderline intellectual abilities, or intellectual disability, or has a diagnosis of autism without a specific etiology should undergo molecular testing for FXS to determine the number of CGG repeats. Page | 23 of 30 ∞ American Congress of Obstetricians and Gynecologists The American Congress of Obstetricians and Gynecologists (Committee Opinion, 2010) recommends that prenatal testing for FXS should be offered to known carriers of the fragile X premutation or full mutation, and to women with a family history of fragile X‒related disorders, unexplained intellectual disability or developmental delay, autism, or premature ovarian insufficiency. European Molecular Genetic Quality Network In 2015, the European Molecular Genetic Quality Network issued best practice guidelines for the molecular genetic testing and reporting of FXS, fragile X‒associated primary ovarian insufficiency, and fragile X‒associated tremor/ataxia syndrome.20 The guidelines recommend “a method which detects the whole range of expansions when testing relatives (including prenatal diagnosis) in a family with any known fragile X disorder due to expansion.” Technical limitations of specific techniques, such as Southern blot and PCR‒based methods, are described. Expanded Panel Testing In 2013, ACMG issued a position statement on prenatal/preconception expanded carrier testing.1 For a particular disorder to be included in carrier screening, the following criteria should be met: 1. Disorders should be of a nature that most at-risk patients and their partners identified in the screening program would consider having a prenatal diagnosis to facilitate making decisions surrounding reproduction. a. The inclusion of disorders characterized by variable expressivity or incomplete penetrance and those known to be associated with a mild phenotype should be optional and made transparent when using these technologies for screening. This recommendation is guided by the ethical principle of nonmaleficence. 2. When adult-onset disorders (disorders that could affect offspring of the individual undergoing carrier screening once offspring reach adult life) are included in screening panels, patients must provide consent to screening for these conditions, especially when Page | 24 of 30 ∞ there may be implications for the health of the individual being screened or for other family members. a. This recommendation follows the ethical principles of autonomy and nonmaleficence. 3. For each disorder, the causative gene(s), mutations, and mutation frequencies should be known in the population being tested, so that meaningful residual risk in individuals who test negative can be assessed. a. Laboratories should specify in their marketing literature and test results how residual risk was calculated using pan-ethnic population data or a specific race/ethnic group. b. The calculation of residual risk requires knowledge of two factors: one is the carrier frequency within a population, the other is the proportion of disease-causing alleles detected using the specific testing platform. Laboratories using multiplex platforms often have limited knowledge of one or both factors. Laboratories offering expanded carrier screening should keep data prospectively and regularly report findings that allow computation of residual risk estimates for all disorders being offered. When data are inadequate, patient materials must stress that negative results should not be over interpreted. 4. There must be validated clinical association between the mutation(s) detected and the severity of the disorder. a. Patient and provider materials must include specific citations that support inclusion of the mutations for which screening is being performed. 5. ECS tests must comply with ACMG’s Standards and Guidelines for Clinical Genetics Laboratories, including quality control and proficiency testing. a. Quality control should include the entire test process, including preanalytical, analytical, and postanalytical phases. Test performance characteristics should be available to patients and providers accessing testing. A highly multiplexed approach will require a more generic consent process than is typically used for single-disease screening because it may be impractical for a clinician to discuss each disease included in a multidisease carrier screening panel. An appropriately tailored informational pamphlet or web site, containing a brief description of each disorder included in a test panel, should be available to patients undergoing or considering an expanded prenatal/preconception carrier screening panel. Genetic counseling before testing should be available to those Page | 25 of 30 ∞ who desire this, and posttest genetic counseling for those with positive screening results is recommended. U.S. Preventive Services Task Force Recommendations The U.S. Preventive Services Task Force (USPSTF) makes recommendations for carrier testing for BRCA-associated genetic diseases and for hereditary hemochromatosis, topics that are not included in this policy but in separate policies for each condition. Medicare National Coverage There is no national coverage determination (NCD). In the absence of an NCD, coverage decisions are left to the discretion of local Medicare carriers. Regulatory Status Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. There are a number of commercially available genetic tests for carrier screening, which range from testing for individual diseases, to small panels designed to address testing based on ethnicity as recommended by practice guidelines (American College of Obstetricians and Gynecologists [ACOG], American College of Medical Genetics and Genomics [ACMG]), to large expanded panels that test for numerous diseases beyond those recommended in practice guidelines. The following is not a comprehensive list of some of the available panels: Counsyl™ (Counsyl): Tests for more than 100 diseases, which, according to the manufacturer website, lead to shortened lifespan, have limited treatment or can lead to intellectual disability. Diseases tested for include those recommended by ACOG, ACMG, as well as an Ashkenazi Jewish panel, Fragile-X syndrome, a 100-mutation CF panel, sickle cell disease, and metabolic disorders. GoodStart Select™ (GoodStart Genetics): “Customizes” the testing panel for each patient based on ethnicity, family history, and provider testing preferences. The test menu includes Page | 26 of 30 ∞ several ethnic panels, and includes testing for hemoglobinopathies, Fragile-X syndrome, CF, metabolic disorders, and others. Inherigen™ (GenPath): A pan-ethnic test for over 160 inherited disorders, typically those with childhood onset and severe symptoms, such as immunodeficiencies and several metabolic diseases, such as Tay-Sachs disease, glycogen storage diseases, and fatty acid oxidation disorders. InheriGen Plus includes all InheriGen diseases plus CF, SMA, and FragileX syndrome. Inheritest™ (LabCorp): A pan-ethnic test for more than 90 autosomal recessive inherited diseases. The Inheritest Select Carrier Screen is a test that evaluates diseases for patients of Ashkenazi Jewish descent. Natera One™ Disease Panel (Natera): Tests for 13 diseases, which include ACMGrecommended tests for carrier screening, plus Fragile-X syndrome, sickle cell anemia, hemoglobin C trait, and SMA. Natera Horizon has 5 different panels that screen for as few as 4 and up to 274 autosomal and X-linked genetic conditions. The panels are pan-ethnic, ancestry-based or expanded. Two CLIA-certified laboratories, Progenity™ (Ann Arbor, Michigan; formerly aMDx Laboratory Sciences and Ascendant MDx) and Sequenom® Laboratories (San Diego, CA), offer both single disease carrier testing (cystic fibrosis [CFnxt cystic fibrosis and HerediT™ Cystic Fibrosis Carrier Screen, respectively], fragile X syndrome [Fragile X syndrome and HerediT™ Cystic Fibrosis Carrier Screen, respectively], SMA [SMAnxt spinal muscular atrophy and HerediT™ Spinal Muscular Atrophy Carrier Screen, respectively) and disease panels for Ashkenazi Jewish patients (AJPnxt Basic [9 diseases] or AJPnxt Expanded [19 diseases] and HerediT™ Ashkenazi Jewish Panel Carrier Screen [17 diseases], respectively). Progenity™ also offers nxtPanel for simultaneous CF, SMA, and fragile X syndrome testing. References 1. Grody WW, Thompson BH, Gregg AR, et al. ACMG position statement on prenatal/preconception expanded carrier screening. Genet Med. Jun 2013; 15(6):482-483. PMID 23619275 2. Gross SJ, Pletcher BA, Monaghan KG. Carrier screening in individuals of Ashkenazi Jewish descent. Genet Med. Jan 2008;10(1):54-56. PMID 18197057 Page | 27 of 30 ∞ 3. American College of Medical Genetics and Genomics Practice Guidelines. https://www.acmg.net/ACMG/Publications/Practice_Guidelines/ACMG/Publications/Practice_Guidelines.aspx?hkey=b5 e361a3-65b1-40ae-bb3e-4254fce9453a. Accessed April 2016. 4. ACOG Committee Opinion No. 442: Preconception and prenatal carrier screening for genetic diseases in individuals of Eastern European Jewish descent. Obstet Gynecol. Oct 2009;114(4):950-953. PMID 19888064 5. American Congress of Obstetricians and Gynecologists Committee Opinions. http://www.acog.org/Resources-AndPublications/Committee-Opinions-List. Accessed April 2016. 6. American Family Physician. Practice guidelines on heomglobinopathies in pregnancy. 2007; http://www.aafp.org/afp/2007/1015/p1229.html. Accessed April 2016. 7. ACOG. Practice bulletin number 78: hemoglobinopathies in pregnancy, January 2007; reaffirmed 2013. http://www.acog.org/Search?Keyword=hemoglobinopathy. Accessed April 2016. 8. ACOG Committee Opinion No. 486: Update on carrier screening for cystic fibrosis. Obstet Gynecol. Apr 2011;117(4):1028-1031. PMID 21422883 9. Watson MS, Cutting GR, Desnick RJ, et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med. Sep-Oct 2004;6(5):387-391. PMID 15371902 10. Prior TW. Carrier screening for spinal muscular atrophy. Genet Med. Nov 2008;10(11):840-842. PMID 18941424 11. ACOG Committee Opinion No. 432: spinal muscular atrophy. Obstet Gynecol. May 2009;113(5):1194-1196. PMID 19384151 12. Arup Laboratories. Ashkenazi Jewish diseases, common mutation panel. http://ltd.aruplab.com/tests/pub/0051415. Accessed April 2016. 13. Edwards JG, Feldman G, Goldberg J, et al. Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. Obstet Gynecol. Mar 2015;125(3):653-662. PMID 25730230 14. Bell CJ, Dinwiddie DL, Miller NA, et al. Carrier testing for severe childhood recessive diseases by next -generation sequencing. Sci Transl Med. Jan 12 2011; 3(65):65ra64. PMID 21228398 15. Lazarin GA, Haque IS, Nazareth S, et al. An empirical estimate of carrier frequencies for 400+ causal Mendelian variants: results from an ethnically diverse clinical sample of 23,453 individuals. Genet Med. Mar 2013; 15(3):178-186. PMID 22975760 16. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. Oct 1 2003; 168(7):818-900. PMID 14522813 17. Cho D, McGowan ML, Metcalfe J, et al. Expanded carrier screening in reproductive healthcare: perspectives from genetics professionals. Hum Reprod. Jun 2013; 28(6):1725-1730. PMID 23589535 18. Wienke S, Brown K, Farmer M, et al. Expanded carrier screening panels-does bigger mean better? J Community Genet. Sep 24 2013. PMID 24062228 19. Grody WW, Cutting GR, Klinger KW, et al. Laboratory standards and guidelines for population-based cystic fibrosis carrier screening. Genet Med. Mar-Apr 2001;3(2):149-154. PMID 11280952 20. Muncie HL, Jr., Campbell J. Alpha and beta thalassemia. Am Fam Physician. Aug 15 2009; 80(4):339-344. PMID 19678601 21. Galanello R, Cao A. Gene test review. Alpha-thalassemia. Genet Med. Feb 2011; 13(2):83-88. PMID 21381239 22. Vichinsky E. Complexity of alpha thalassemia: growing health problem with new approaches to screening, diagnosis, and therapy. Ann N Y Acad Sci. Aug 2010; 1202:180-187. PMID 20712791 Page | 28 of 30 ∞ 23. Origa R, Moi P, Galanello R, et al. Alpha-Thalassemia. GeneReviews 2005; http://www.ncbi.nlm.nih.gov/books/NBK1435/. PMID 20301608. Accessed April 2016. 24. Langlois S, Ford JC, Chitayat D, et al. Carrier screening for thalassemia and hemoglobinopathies in Canada. J Obstet Gynaecol Can. Oct 2008; 30(10):950-971. PMID 19038079 25. Schaefer GB, Mendelsohn NJ. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. May 2013;15(5):399-407. PMID 23519317 26. Miles JH. Autism spectrum disorders--a genetics review. Genet Med. Apr 2011;13(4):278-294. PMID 21358411 27. Hersh JH, Saul RA. Health supervision for children with fragile X syndrome. Pediatrics. May 2011;127(5):994-1006. PMID 21518720 28. Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. Oct 2005;7(8):584-587. PMID 16247297 29. Michelson DJ, Shevell MI, Sherr EH, et al. Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. Oct 25 2011;77(17):1629-1635. PMID 21956720 30. Subcommittee on Attention-Deficit/Hyperactivity Disorder SCoQI, Management. ADHD: Clinical Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics. November 1, 2011; 128(5):1007-1022. PMID 31. American Congress of Obstetricians and Gynecologis (ACOG). Committee opinion number 469: Carrier Screening for Fragine X Syndrome. 2010. http://www.acog.org/Resources_And_Publications/Committee_Opinions/Committee_on_Genetics/Carrier_Screening_for _Fragile_X_Syndrome. Accessed April 4, 2016. 32. Biancalana V, Glaeser D, McQuaid S, et al. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders. Eur J Hum Genet. Apr 2015;23(4):417-425. PMID 25227148 33. Blue Cross Blue Shield Association MPRM 2.04.83 Genetic Testing for FMR1 Mutations (Including Fragile X Syndrome). Last accessed March 5, 2016. History Date Comments 01/12/16 Annual review. Policy renumbered, replaces 12.04.107. Policy updated with literature review through August 31, 2015. Policy statement on personal/family history criteria consolidated to eliminate redundancies. Policy statement and Guidelines amended to include necessity statements on specific carrier tests – cystic fibrosis, spinal muscular atrophy, Ashkenazi Jewish Panel, hemoglobinopathies. Definitions of 1st, 2nd and 3rd degree relatives added. Reference added. 05/01/16 Interim update, approved April 12, 2016. Genetic Testing for Alpha-Thalassemia incorporated into this policy for ease of use. New policy statement added: Fragile-X Syndrome testing may be considered medically necessary when criteria are met. Page | 29 of 30 ∞ Date Comments 07/01/16 Policy moved to new format. No change in content or coverage. 08/01/16 Interim Update, approved July 12, 2016. Policy statement on genetic testing for FMR1 mutations changed from investigational to not medically necessary. Policy statements of not medically necessary added to testing for Ashkenazi Jewish Founder and Other Inherited Disorders when criteria are not met. Disclaimer: This medical policy is a guide in evaluating the medical necessity of a particular service or treatment. The Company adopts policies after careful review of published peer-reviewed scientific literature, national guidelines and local standards of practice. Since medical technology is constantly changing, the Company reserves the right to review and update policies as appropriate. Member contracts differ in their benefits. Always consult the member benefit booklet or contact a member service representative to determine coverage for a specific medical service or supply. CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). ©2016 Premera All Rights Reserved. Scope: Medical policies are systematically developed guidelines that serve as a resource for Company staff when determining coverage for specific medical procedures, drugs or devices. Coverage for medical services is subject to the limits and conditions of the member benefit plan. Members and their providers should consult the member benefit booklet or contact a customer service representative to determine whether there are any benefit limitations applicable to this service or supply. This medical policy does not apply to Medicare Advantage. 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If you believe that Premera has failed to provide these services or discriminated in another way on the basis of race, color, national origin, age, disability, or sex, you can file a grievance with: Civil Rights Coordinator - Complaints and Appeals PO Box 91102, Seattle, WA 98111 Toll free 855-332-4535, Fax 425-918-5592, TTY 800-842-5357 Email [email protected] You can file a grievance in person or by mail, fax, or email. If you need help filing a grievance, the Civil Rights Coordinator is available to help you. You can also file a civil rights complaint with the U.S. Department of Health and Human Services, Office for Civil Rights, electronically through the Office for Civil Rights Complaint Portal, available at https://ocrportal.hhs.gov/ocr/portal/lobby.jsf, or by mail or phone at: U.S. Department of Health and Human Services 200 Independence Avenue SW, Room 509F, HHH Building Washington, D.C. 20201, 1-800-368-1019, 800-537-7697 (TDD) Complaint forms are available at http://www.hhs.gov/ocr/office/file/index.html. Getting Help in Other Languages This Notice has Important Information. This notice may have important information about your application or coverage through Premera Blue Cross. There may be key dates in this notice. You may need to take action by certain deadlines to keep your health coverage or help with costs. You have the right to get this information and help in your language at no cost. Call 800-722-1471 (TTY: 800-842-5357). አማሪኛ (Amharic): ይህ ማስታወቂያ አስፈላጊ መረጃ ይዟል። ይህ ማስታወቂያ ስለ ማመልከቻዎ ወይም የ Premera Blue Cross ሽፋን አስፈላጊ መረጃ ሊኖረው ይችላል። በዚህ ማስታወቂያ ውስጥ ቁልፍ ቀኖች ሊኖሩ ይችላሉ። የጤናን ሽፋንዎን ለመጠበቅና በአከፋፈል እርዳታ ለማግኘት በተውሰኑ የጊዜ ገደቦች እርምጃ መውሰድ ይገባዎት ይሆናል። ይህን መረጃ እንዲያገኙ እና ያለምንም ክፍያ በቋንቋዎ እርዳታ እንዲያገኙ መብት አለዎት።በስልክ ቁጥር 800-722-1471 (TTY: 800-842-5357) ይደውሉ። ( العربيةArabic): قد يحوي ھذا اإلشعار معلومات مھمة بخصوص طلبك أو.يحوي ھذا اإلشعار معلومات ھامة قد تكون ھناك تواريخ مھمة.Premera Blue Cross التغطية التي تريد الحصول عليھا من خالل وقد تحتاج التخاذ إجراء في تواريخ معينة للحفاظ على تغطيتك الصحية أو للمساعدة.في ھذا اإلشعار اتصل. يحق لك الحصول على ھذه المعلومات والمساعدة بلغتك دون تكبد أية تكلفة.في دفع التكاليف 800-722-1471 (TTY: 800-842-5357)بـ 中文 (Chinese): 本通知有重要的訊息。本通知可能有關於您透過 Premera Blue Cross 提交的 申請或保險的重要訊息。本通知內可能有重要日期。您可能需要在截止日期 之前採取行動,以保留您的健康保險或者費用補貼。您有權利免費以您的母 語得到本訊息和幫助。請撥電話 800-722-1471 (TTY: 800-842-5357)。 037338 (07-2016) Oromoo (Cushite): Beeksisni kun odeeffannoo barbaachisaa qaba. Beeksisti kun sagantaa yookan karaa Premera Blue Cross tiin tajaajila keessan ilaalchisee odeeffannoo barbaachisaa qabaachuu danda’a. Guyyaawwan murteessaa ta’an beeksisa kana keessatti ilaalaa. Tarii kaffaltiidhaan deeggaramuuf yookan tajaajila fayyaa keessaniif guyyaa dhumaa irratti wanti raawwattan jiraachuu danda’a. Kaffaltii irraa bilisa haala ta’een afaan keessaniin odeeffannoo argachuu fi deeggarsa argachuuf mirga ni qabaattu. Lakkoofsa bilbilaa 800-722-1471 (TTY: 800-842-5357) tii bilbilaa. Français (French): Cet avis a d'importantes informations. Cet avis peut avoir d'importantes informations sur votre demande ou la couverture par l'intermédiaire de Premera Blue Cross. Le présent avis peut contenir des dates clés. Vous devrez peut-être prendre des mesures par certains délais pour maintenir votre couverture de santé ou d'aide avec les coûts. Vous avez le droit d'obtenir cette information et de l’aide dans votre langue à aucun coût. Appelez le 800-722-1471 (TTY: 800-842-5357). Kreyòl ayisyen (Creole): Avi sila a gen Enfòmasyon Enpòtan ladann. Avi sila a kapab genyen enfòmasyon enpòtan konsènan aplikasyon w lan oswa konsènan kouvèti asirans lan atravè Premera Blue Cross. Kapab genyen dat ki enpòtan nan avi sila a. Ou ka gen pou pran kèk aksyon avan sèten dat limit pou ka kenbe kouvèti asirans sante w la oswa pou yo ka ede w avèk depans yo. Se dwa w pou resevwa enfòmasyon sa a ak asistans nan lang ou pale a, san ou pa gen pou peye pou sa. Rele nan 800-722-1471 (TTY: 800-842-5357). Deutsche (German): Diese Benachrichtigung enthält wichtige Informationen. Diese Benachrichtigung enthält unter Umständen wichtige Informationen bezüglich Ihres Antrags auf Krankenversicherungsschutz durch Premera Blue Cross. Suchen Sie nach eventuellen wichtigen Terminen in dieser Benachrichtigung. Sie könnten bis zu bestimmten Stichtagen handeln müssen, um Ihren Krankenversicherungsschutz oder Hilfe mit den Kosten zu behalten. Sie haben das Recht, kostenlose Hilfe und Informationen in Ihrer Sprache zu erhalten. Rufen Sie an unter 800-722-1471 (TTY: 800-842-5357). Hmoob (Hmong): Tsab ntawv tshaj xo no muaj cov ntshiab lus tseem ceeb. Tej zaum tsab ntawv tshaj xo no muaj cov ntsiab lus tseem ceeb txog koj daim ntawv thov kev pab los yog koj qhov kev pab cuam los ntawm Premera Blue Cross. Tej zaum muaj cov hnub tseem ceeb uas sau rau hauv daim ntawv no. Tej zaum koj kuj yuav tau ua qee yam uas peb kom koj ua tsis pub dhau cov caij nyoog uas teev tseg rau hauv daim ntawv no mas koj thiaj yuav tau txais kev pab cuam kho mob los yog kev pab them tej nqi kho mob ntawd. Koj muaj cai kom lawv muab cov ntshiab lus no uas tau muab sau ua koj hom lus pub dawb rau koj. Hu rau 800-722-1471 (TTY: 800-842-5357). Iloko (Ilocano): Daytoy a Pakdaar ket naglaon iti Napateg nga Impormasion. Daytoy a pakdaar mabalin nga adda ket naglaon iti napateg nga impormasion maipanggep iti apliksayonyo wenno coverage babaen iti Premera Blue Cross. Daytoy ket mabalin dagiti importante a petsa iti daytoy a pakdaar. Mabalin nga adda rumbeng nga aramidenyo nga addang sakbay dagiti partikular a naituding nga aldaw tapno mapagtalinaedyo ti coverage ti salun-atyo wenno tulong kadagiti gastos. Adda karbenganyo a mangala iti daytoy nga impormasion ken tulong iti bukodyo a pagsasao nga awan ti bayadanyo. Tumawag iti numero nga 800-722-1471 (TTY: 800-842-5357). Italiano (Italian): Questo avviso contiene informazioni importanti. Questo avviso può contenere informazioni importanti sulla tua domanda o copertura attraverso Premera Blue Cross. Potrebbero esserci date chiave in questo avviso. Potrebbe essere necessario un tuo intervento entro una scadenza determinata per consentirti di mantenere la tua copertura o sovvenzione. Hai il diritto di ottenere queste informazioni e assistenza nella tua lingua gratuitamente. Chiama 800-722-1471 (TTY: 800-842-5357). 日本語 (Japanese): この通知には重要な情報が含まれています。この通知には、Premera Blue Cross の申請または補償範囲に関する重要な情報が含まれている場合があ ります。この通知に記載されている可能性がある重要な日付をご確認くだ さい。健康保険や有料サポートを維持するには、特定の期日までに行動を 取らなければならない場合があります。ご希望の言語による情報とサポー トが無料で提供されます。800-722-1471 (TTY: 800-842-5357)までお電話 ください。 Română (Romanian): Prezenta notificare conține informații importante. Această notificare poate conține informații importante privind cererea sau acoperirea asigurării dumneavoastre de sănătate prin Premera Blue Cross. Pot exista date cheie în această notificare. Este posibil să fie nevoie să acționați până la anumite termene limită pentru a vă menține acoperirea asigurării de sănătate sau asistența privitoare la costuri. Aveți dreptul de a obține gratuit aceste informații și ajutor în limba dumneavoastră. Sunați la 800-722-1471 (TTY: 800-842-5357). 한국어 (Korean): 본 통지서에는 중요한 정보가 들어 있습니다. 즉 이 통지서는 귀하의 신청에 관하여 그리고 Premera Blue Cross 를 통한 커버리지에 관한 정보를 포함하고 있을 수 있습니다. 본 통지서에는 핵심이 되는 날짜들이 있을 수 있습니다. 귀하는 귀하의 건강 커버리지를 계속 유지하거나 비용을 절감하기 위해서 일정한 마감일까지 조치를 취해야 할 필요가 있을 수 있습니다. 귀하는 이러한 정보와 도움을 귀하의 언어로 비용 부담없이 얻을 수 있는 권리가 있습니다. 800-722-1471 (TTY: 800-842-5357) 로 전화하십시오. Pусский (Russian): Настоящее уведомление содержит важную информацию. Это уведомление может содержать важную информацию о вашем заявлении или страховом покрытии через Premera Blue Cross. В настоящем уведомлении могут быть указаны ключевые даты. Вам, возможно, потребуется принять меры к определенным предельным срокам для сохранения страхового покрытия или помощи с расходами. Вы имеете право на бесплатное получение этой информации и помощь на вашем языке. Звоните по телефону 800-722-1471 (TTY: 800-842-5357). ລາວ (Lao): ແຈ້ ງການນ້ີ ມີຂ້ໍ ມູ ນສໍາຄັ ນ. ແຈ້ ງການນ້ີ ອາດຈະມີຂ້ໍ ມູ ນສໍາຄັ ນກ່ ຽວກັ ບຄໍາຮ້ ອງສະ ໝັ ກ ຫື ຼ ຄວາມຄຸ້ ມຄອງປະກັ ນໄພຂອງທ່ ານຜ່ ານ Premera Blue Cross. ອາດຈະມີ ວັ ນທີສໍາຄັ ນໃນແຈ້ ງການນີ້. ທ່ ານອາດຈະຈໍາເປັນຕ້ ອງດໍາເນີນການຕາມກໍານົ ດ ເວລາສະເພາະເພື່ອຮັ ກສາຄວາມຄຸ້ ມຄອງປະກັ ນສຸ ຂະພາບ ຫື ຼ ຄວາມຊ່ ວຍເຫື ຼ ອເລື່ອງ ຄ່ າໃຊ້ ຈ່ າຍຂອງທ່ ານໄວ້ . ທ່ ານມີສິດໄດ້ ຮັ ບຂ້ໍ ມູ ນນ້ີ ແລະ ຄວາມຊ່ ວຍເຫື ຼ ອເປັນພາສາ ຂອງທ່ ານໂດຍບໍ່ເສຍຄ່ າ. ໃຫ້ ໂທຫາ 800-722-1471 (TTY: 800-842-5357). ភាសាែខម រ (Khmer): េសចកត ីជូនដំណឹងេនះមានព័ត៌មានយា៉ងសំខាន់។ េសចកត ីជូនដំណឹងេនះរបែហល ជាមានព័ត៌មានយា៉ងសំខាន់អំពីទរមង់ែបបបទ ឬការរា៉ប់រងរបស់អនកតាមរយៈ Premera Blue Cross ។ របែហលជាមាន កាលបរ ិេចឆ ទសំខាន់េនៅកនុងេសចកត ីជូន ដំណឹងេនះ។ អន ករបែហលជារតូវការបេញច ញសមតថ ភាព ដល់កំណត់ៃថង ជាក់ចបាស់ នានា េដើមបីនឹងរកសាទុកការធានារា៉ប់រងសុខភាពរបស់អនក ឬរបាក់ជំនួយេចញៃថល ។ អន កមានសិទធិទទួ លព័ត៌មានេនះ និងជំនួយេនៅកនុងភាសារបស់អនកេដាយមិនអស លុយេឡើយ។ សូ មទូ រស័ពទ 800-722-1471 (TTY: 800-842-5357)។ ਪੰ ਜਾਬੀ (Punjabi): ਇਸ ਨੋਿਟਸ ਿਵਚ ਖਾਸ ਜਾਣਕਾਰੀ ਹੈ. ਇਸ ਨੋਿਟਸ ਿਵਚ Premera Blue Cross ਵਲ ਤੁਹਾਡੀ ਕਵਰੇਜ ਅਤੇ ਅਰਜੀ ਬਾਰੇ ਮਹੱ ਤਵਪੂਰਨ ਜਾਣਕਾਰੀ ਹੋ ਸਕਦੀ ਹੈ . ਇਸ ਨੋਿਜਸ ਜਵਚ ਖਾਸ ਤਾਰੀਖਾ ਹੋ ਸਕਦੀਆਂ ਹਨ. ਜੇਕਰ ਤੁਸੀ ਜਸਹਤ ਕਵਰੇਜ ਿਰੱ ਖਣੀ ਹੋਵੇ ਜਾ ਓਸ ਦੀ ਲਾਗਤ ਜਿਵੱ ਚ ਮਦਦ ਦੇ ਇਛੁੱ ਕ ਹੋ ਤਾਂ ਤੁਹਾਨੂੰ ਅੰ ਤਮ ਤਾਰੀਖ਼ ਤ ਪਿਹਲਾਂ ਕੁੱ ਝ ਖਾਸ ਕਦਮ ਚੁੱ ਕਣ ਦੀ ਲੋ ੜ ਹੋ ਸਕਦੀ ਹੈ ,ਤੁਹਾਨੂੰ ਮੁਫ਼ਤ ਿਵੱ ਚ ਤੇ ਆਪਣੀ ਭਾਸ਼ਾ ਿਵੱ ਚ ਜਾਣਕਾਰੀ ਅਤੇ ਮਦਦ ਪ੍ਰਾਪਤ ਕਰਨ ਦਾ ਅਿਧਕਾਰ ਹੈ ,ਕਾਲ 800-722-1471 (TTY: 800-842-5357). ( فارسیFarsi): اين اعالميه ممکن است حاوی اطالعات مھم درباره فرم. اين اعالميه حاوی اطالعات مھم ميباشد به تاريخ ھای مھم در. باشدPremera Blue Cross تقاضا و يا پوشش بيمه ای شما از طريق شما ممکن است برای حقظ پوشش بيمه تان يا کمک در پرداخت ھزينه. اين اعالميه توجه نماييد شما حق. به تاريخ ھای مشخصی برای انجام کارھای خاصی احتياج داشته باشيد،ھای درمانی تان برای کسب.اين را داريد که اين اطالعات و کمک را به زبان خود به طور رايگان دريافت نماييد ( تماس800-842-5357 تماس باشمارهTTY )کاربران800-722-1471 اطالعات با شماره .برقرار نماييد Polskie (Polish): To ogłoszenie może zawierać ważne informacje. To ogłoszenie może zawierać ważne informacje odnośnie Państwa wniosku lub zakresu świadczeń poprzez Premera Blue Cross. Prosimy zwrócic uwagę na kluczowe daty, które mogą być zawarte w tym ogłoszeniu aby nie przekroczyć terminów w przypadku utrzymania polisy ubezpieczeniowej lub pomocy związanej z kosztami. Macie Państwo prawo do bezpłatnej informacji we własnym języku. Zadzwońcie pod 800-722-1471 (TTY: 800-842-5357). Português (Portuguese): Este aviso contém informações importantes. Este aviso poderá conter informações importantes a respeito de sua aplicação ou cobertura por meio do Premera Blue Cross. Poderão existir datas importantes neste aviso. Talvez seja necessário que você tome providências dentro de determinados prazos para manter sua cobertura de saúde ou ajuda de custos. Você tem o direito de obter esta informação e ajuda em seu idioma e sem custos. Ligue para 800-722-1471 (TTY: 800-842-5357). Fa’asamoa (Samoan): Atonu ua iai i lenei fa’asilasilaga ni fa’amatalaga e sili ona taua e tatau ona e malamalama i ai. O lenei fa’asilasilaga o se fesoasoani e fa’amatala atili i ai i le tulaga o le polokalame, Premera Blue Cross, ua e tau fia maua atu i ai. Fa’amolemole, ia e iloilo fa’alelei i aso fa’apitoa olo’o iai i lenei fa’asilasilaga taua. Masalo o le’a iai ni feau e tatau ona e faia ao le’i aulia le aso ua ta’ua i lenei fa’asilasilaga ina ia e iai pea ma maua fesoasoani mai ai i le polokalame a le Malo olo’o e iai i ai. Olo’o iai iate oe le aia tatau e maua atu i lenei fa’asilasilaga ma lenei fa’matalaga i legagana e te malamalama i ai aunoa ma se togiga tupe. Vili atu i le telefoni 800-722-1471 (TTY: 800-842-5357). Español (Spanish): Este Aviso contiene información importante. Es posible que este aviso contenga información importante acerca de su solicitud o cobertura a través de Premera Blue Cross. Es posible que haya fechas clave en este aviso. Es posible que deba tomar alguna medida antes de determinadas fechas para mantener su cobertura médica o ayuda con los costos. Usted tiene derecho a recibir esta información y ayuda en su idioma sin costo alguno. Llame al 800-722-1471 (TTY: 800-842-5357). Tagalog (Tagalog): Ang Paunawa na ito ay naglalaman ng mahalagang impormasyon. Ang paunawa na ito ay maaaring naglalaman ng mahalagang impormasyon tungkol sa iyong aplikasyon o pagsakop sa pamamagitan ng Premera Blue Cross. Maaaring may mga mahalagang petsa dito sa paunawa. Maaring mangailangan ka na magsagawa ng hakbang sa ilang mga itinakdang panahon upang mapanatili ang iyong pagsakop sa kalusugan o tulong na walang gastos. May karapatan ka na makakuha ng ganitong impormasyon at tulong sa iyong wika ng walang gastos. Tumawag sa 800-722-1471 (TTY: 800-842-5357). ไทย (Thai): ประกาศนี ้มีข้อมูลสําคัญ ประกาศนี ้อาจมีข้อมูลที่สําคัญเกี่ยวกับการการสมัครหรื อขอบเขตประกัน สุขภาพของคุณผ่าน Premera Blue Cross และอาจมีกําหนดการในประกาศนี ้ คุณอาจจะต้ อง ดําเนินการภายในกําหนดระยะเวลาที่แน่นอนเพื่อจะรักษาการประกันสุขภาพของคุณหรื อการช่วยเหลือที่ มีค่าใช้ จ่าย คุณมีสิทธิที่จะได้ รับข้ อมูลและความช่วยเหลือนี ้ในภาษาของคุณโดยไม่มีค่าใช้ จ่าย โทร 800-722-1471 (TTY: 800-842-5357) Український (Ukrainian): Це повідомлення містить важливу інформацію. Це повідомлення може містити важливу інформацію про Ваше звернення щодо страхувального покриття через Premera Blue Cross. Зверніть увагу на ключові дати, які можуть бути вказані у цьому повідомленні. Існує імовірність того, що Вам треба буде здійснити певні кроки у конкретні кінцеві строки для того, щоб зберегти Ваше медичне страхування або отримати фінансову допомогу. У Вас є право на отримання цієї інформації та допомоги безкоштовно на Вашій рідній мові. Дзвоніть за номером телефону 800-722-1471 (TTY: 800-842-5357). Tiếng Việt (Vietnamese): Thông báo này cung cấp thông tin quan trọng. Thông báo này có thông tin quan trọng về đơn xin tham gia hoặc hợp đồng bảo hiểm của quý vị qua chương trình Premera Blue Cross. Xin xem ngày quan trọng trong thông báo này. Quý vị có thể phải thực hiện theo thông báo đúng trong thời hạn để duy trì bảo hiểm sức khỏe hoặc được trợ giúp thêm về chi phí. Quý vị có quyền được biết thông tin này và được trợ giúp bằng ngôn ngữ của mình miễn phí. Xin gọi số 800-722-1471 (TTY: 800-842-5357).