Genetic Testing for Mitochondrial Disorders

MEDICAL POLICY POLICY RELATED POLICIES POLICY GUIDELINES CODING DESCRIPTION SCOPE BENEFIT APPLICATION RATIONALE REFERENCES APPENDIX HISTORY Genetic ...
Author: Eleanore Holt
8 downloads 0 Views 678KB Size
MEDICAL POLICY

POLICY RELATED POLICIES POLICY GUIDELINES CODING DESCRIPTION SCOPE BENEFIT APPLICATION RATIONALE REFERENCES APPENDIX HISTORY

Genetic Testing for Mitochondrial Disorders Number Effective Date Revision Date(s) Replaces

12.04.117 September 1, 2016 01/01/17; 08/09/16; 07/14/15; 08/11/14 2.04.117

Policy [TOP]

Genetic testing to confirm the diagnosis of a mitochondrial disorder may be considered medically necessary when signs and symptoms of a specific mitochondrial disorder are present but a definitive diagnosis cannot be made without genetic testing (see Policy Guidelines section), and both of the following criteria are present:  Genetic testing avoids the need for a muscle biopsy; AND  Genetic testing is restricted to the specific mutations that have been documented to be pathogenic for the particular mitochondrial disorder being considered (see Policy Guidelines section). Genetic testing of at-risk female relatives may be considered medically necessary as part of a preconceputal carrier testing under the following conditions (see Benefit Application section):  There is a defined mitochondrial disorder in the family of sufficient severity to cause impairment of quality of life or functional status; AND  A mutation that is known to be pathogenic for that specific mitochondrial disorder has been identified in the index case. Genetic testing for mitochondrial disorders using expanded panel testing is considered investigational (see Policy Guidelines section). Genetic testing for mitochondrial disorders is considered investigational when the criteria for medical necessity are not met.

Related Policies [TOP]

None

Policy Guidelines [TOP]

To maximize the positive and the negative predictive value of testing, testing should be restricted to patients with a clinical picture consistent with a specific disorder and to a small number of mutations that are known to be pathogenic for that disorder. Table 1 is a guide to clinical symptoms and particular genetic mutations that are

associated with particular mitochondrial syndromes.

Table 1 - Mitochondrial disorder/syndromes, clinical symptoms/manifestations, and associated pathogenic genes Adapted from Chinnery et al. (1). Disorder/Syndrome MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) MERRF (Myoclonic epilepsy with ragged-red fibers) CPEO (Chronic progressive external ophthalmoplegia) Kearns-Sayre Syndrome (KSS)

Leigh Syndrome (LS)

Main clinical manifestations  Stroke-like episodes at age 80%) MT-TF, MT-TP (rare)



Various deletions of MT-DNA



Various deletions of MT-DNA



 

MT-ATP6, MT-TL1, MT-TK, MTTW, MT-TV, MT-ND1, MT-ND2, MT-ND3, MT-ND4, MT-ND5, MTND6, MT-CO3 MT-DNA deletions (rare) MT-ND1, MT-ND4, MT-ND6



MT-ATP6

Disease Specific Panels Panels of mutations that are disease-specific and only contain tests for mutations associated with a specific type of mitochondrial disorder may meet the criteria for medical necessity under certain circumstances (See Related Policies). When criteria for medical necessity are met, these panels may be used in place of testing individual genes in sequence. Disease-specific panels should include a list of mutations that approximates (but may not be identical to) those listed in Table 1 for each specific disorder.

Expanded Panels Expanded panels refer to panel tests for many genes that are associated with many different types of mitochondrial disorders, typically including both mitochondrial and nuclear genes. These expanded panels are contrasted with the smaller number of genes specifically associated with any particular disorder. Examples of commercially available expanded panel testing are provided in Table 2.

Table 2 – Commercially Available Expanded Genetic Panels for Mitochondrial Disorders Laboratory Gene Dx® (Gaithersburg, MD) Transgenomic® (New Haven, CT) Courtagen® (Woburn, MA) ARUP® (Salt Lake City, UT)

Number of genes included on panel 101 447 1192 108

Percent of total that are “Classic” mutations 94% 49% 18% 68%

Baylor® (Houston, TX) Medical Neurogenetics® (Atlanta, GA) MEDomics® (Azusa, CA)

162 393 >1200

63% 28% No information

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, 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.

Coding There are several mitochondrial tests listed in the CPT Tier 2 molecular pathology codes. 81401

81403

81440

81460

81465 81479

CPT Molecular pathology procedure, Level 2 (e.g., 2-10 SNPs, 1 methylated variant, or 1 somatic variant [typically using nonsequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) Molecular pathology procedure, Level 4 (e.g., analysis of single exon by DNA sequence analysis, analysis of >10 amplicons using multiplex PCR in 2 or more independent reactions, mutation scanning or duplication/deletion variants of 2-5 exons) Nuclear encoded mitochondrial genes (e.g., neurologic or myopathic phenotypes), genomic sequence panel, must include analysis of at least 100 genes, including BCS1L, C10orf2, COQ2, COX10, DGUOK, MPV17, OPA1, PDSS2, POLG, POLG2, RRM2B, SCO1, SCO2, SLC25A4, SUCLA2, SUCLG1, TAZ, TK2, and TYMP (new code effective 1/1/15) Whole mitochondrial genome (eg, Leigh syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes [MELAS], myoclonic epilepsy with ragged-red fibers [MERFF], neuropathy, ataxia, and retinitis pigmentosa [NARP], Leber hereditary optic neuropathy [LHON]), genomic sequence, must include sequence analysis of entire mitochondrial genome with heteroplasmy detection Whole mitochondrial genome large deletion analysis panel (eg, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia), including heteroplasmy detection, if performed Unlisted molecular pathology procedure

Code 81401 includes:  MT-ATP6 (mitochondrially encoded ATP synthase 6) (e.g., neuropathy with ataxia and retinitis pigmentosa [NARP], Leigh syndrome), common variants (e.g., m.8993T>G, m.8993T>C)  MT-ND4, MT-ND6 (mitochondrially encoded NADH dehydrogenase 4, mitochondrially encoded NADH dehydrogenase 6) (e.g., Leber hereditary optic neuropathy [LHON]), common variants (e.g., m.11778G>A, m.3460G>A, m.14484T>C)  MT-TK (mitochondrially encoded tRNA lysine) (e.g., myoclonic epilepsy with ragged-red fibers [MERRF]), common variants (e.g., m.8344A>G, m.8356T>C)  MT-ND5 (mitochondrially encoded tRNA leucine 1 [UUA/G], mitochondrially encoded NADH dehydrogenase 5) (e.g., mitochondrial encephalopathy with lactic acidosis and stroke-like episodes [MELAS]), common variants (e.g., m.3243A>G, m.3271T>C, m.3252A>G, m.13513G>A)  MT-TL1 (mitochondrially encoded tRNA leucine 1 [UUA/G]) (e.g., diabetes and hearing loss), common variants (e.g., m.3243A>G, m.14709 T>C)  MT-TS1, MT-RNR1 (mitochondrially encoded tRNA serine 1 [UCN], mitochondrially encoded 12S RNA) (e.g., nonsyndromic sensorineural deafness [including aminoglycoside-induced nonsyndromic deafness]), common variants (e.g., m.7445A>G, m.1555A>G) Code 81403 includes:  MT-RNR1 (mitochondrially encoded 12S RNA) (e.g., nonsyndromic hearing loss), full gene sequence  MT-TS1 (mitochondrially encoded tRNA serine 1) (e.g., nonsyndromic hearing loss), full gene sequence If there is no specific listing in the CPT molecular pathology code list for the mitochondrial DNA test that is performed, the unlisted molecular pathology code 81479 may be reported. If multiple unlisted mitochondrial DNA tests are performed, the unlisted code is only reported once for all of the unlisted tests.

Description [TOP]

Mitochondrial disorders are multisystem diseases that arise from dysfunction in the mitochondrial protein complexes involved in oxidative metabolism. There are many related but distinct syndromes, and some patients have overlapping syndromes. As a result these disorders can be difficult to diagnose. Genetic testing has the potential to improve the accuracy of diagnosis for mitochondrial disorders. Genetic testing also has the potential to determine future risk of disease in individuals who have a close relative with a pathogenic mutation. For individuals who have signs and/or symptoms of a mitochondrial disorder who receive genetic testing for diagnosis of disease, the evidence includes case series and cohort studies. Relevant outcomes are test accuracy and validity, other test performance measures, symptoms, functional outcomes, health status measures, and quality of life. There is a lack of published data on analytic validity. Commercial testing sites claim analytic validity approaches 100% and describe testing methods expected to have high analytic validity. There is some evidence on clinical validity that varies by the specific disorder. For example, for the most well understood disorders such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, small series of patients with a clinically diagnosed disorder have reported that a high proportion of patients have a pathogenic mutation. Clinical specificity is unknown, but population-based studies have reported that the prevalence of certain mutations exceeds the prevalence of clinical disease, suggesting that the mutation will be found in some people without clinical disease (false positives). Clinical utility is relatively high for confirming the diagnosis of mitochondrial disorders in people who have signs and symptoms indicating a moderate-to-high pretest likelihood of disease. In these patients, a positive result on genetic testing can avoid a muscle biopsy and eliminate the need for further clinical workup. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. For individuals who are symptomatic with a close relative with a mitochondrial disorder and a known pathogenic mutation and who receive genetic testing to determine future risk of disease, the evidence includes case series and cohort studies. Relevant outcomes are test accuracy and validity, other test performance measures, changes in reproductive decision making, symptoms, functional outcomes, health status measures, and quality of life. There is a lack of published data on analytic validity. Commercial testing sites claim analytic validity approaching 100% and describe testing methods expected to have high analytic validity. There is some evidence on clinical validity that varies by the specific disorder. For example, for the most well understood disorders such as MELAS syndrome, small series of patients with a clinically diagnosed disorder have reported that a high proportion of patients have a pathogenic mutation. Clinical specificity is unknown, but population-based studies have reported that the prevalence of certain mutations exceeds the prevalence of clinical disease, suggesting that the mutation will be found in some people without clinical disease (false positives). Clinical utility can be demonstrated for testing of at-risk family members who have a close relative with a pathogenic mutation. When a specific mitochondrial disease is present in the family that is severe enough to cause impairment and/or disability, genetic testing may impact reproductive decision making. If genetic testing is used in this situation, there will be a decreased risk of a mitochondrial disorder in live offspring. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Background Mitochondrial DNA Mitochondria are organelles within each cell that contain their own set of DNA, distinct from the nuclear DNA that makes up most of the human genome. Human mitochondrial DNA (mtDNA) consists of 37 genes. Thirteen genes code for protein subunits of the mitochondrial oxidative phosphorylation complex, and the remaining 24 genes are responsible for proteins involved in the translation and/or assembly of the mitochondrial complex. (1) In addition, there are over 1000 nuclear genes that code for proteins that support mitochondrial function. (2) The protein products from these genes are produced in the nucleus and later migrate to the mitochondria. Mitochondrial DNA differs from nuclear DNA in several important ways. Inheritance of mtDNA does not follow traditional Mendelian patterns. Rather, mtDNA is inherited only from maternal DNA so that disorders that result from mutations in mtDNA can only be passed on by the mother. Also, there are thousands of copies of each mtDNA gene in each cell, as opposed to nuclear DNA, which contains only 1 copy per cell. Because there are many copies of each gene, mutations may be present in some copies of the gene but not others. This

phenomenon is called heteroplasmy. Heteroplasmy can be expressed as a percentage of genes that have the mutation, ranging from 0% to 100%. Clinical expression of the mutation will generally depend on a threshold effect (ie, clinical symptoms will begin to appear when the percentage of mutated genes exceeds a threshold amount).(3)

Mitochondrial disorders Primary mitochondrial disorders arise from dysfunction of the mitochondrial respiratory chain. The mitochondrial respiratory chain is responsible for aerobic metabolism, and dysfunction therefore affects a wide variety of physiologic pathways dependent on aerobic metabolism. Organs with a high energy requirement, such as the central nervous system, cardiovascular system, and skeletal muscle, are preferentially affected by mitochondrial dysfunction. The prevalence of these disorders has risen over the last 2 decades as the pathophysiology and clinical manifestations have been better characterized. It is currently estimated that the minimum prevalence of primary mitochondrial disorders is at least 1 in 5000.(1,4) Some of the specific mitochondrial disorders are listed next:  Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome;  Myoclonic epilepsy with ragged-red fibers (MERRF) syndrome;  Kearns-Sayre syndrome (KSS);  Leigh syndrome (LS);  Chronic progressive external ophthalmoplegia (CPEO);  Leber hereditary optic neuropathy (LHON);  Neurogenic weakness with ataxia and retinitis pigmentosa (NARP). Most of these disorders are characterized by multisystem dysfunction, which generally includes myopathies and neurologic dysfunction and may involve multiple other organs. Each of the defined mitochondrial disorders has a characteristic set of signs or symptoms. The severity of illness is heterogeneous and can vary markedly. Some patients will have only mild symptoms for which they never require medical care, while other patients have severe symptoms, a large burden of morbidity, and a shortened life expectancy. The diagnosis of mitochondrial disorders can be difficult. The individual symptoms are nonspecific and symptom patterns can overlap considerably. As a result, a patient often cannot be easily classified into 1 particular syndrome.(5) Biochemical testing is indicated for patients who do not have a clear clinical picture of 1 specific disorder. Measurement of serum lactic acid is often used as a screening test, but the test is neither sensitive nor specific for mitochondrial disorders.(2) A muscle biopsy can be performed if the diagnosis is uncertain after biochemical workup. However, this is an invasive test and is not definitive in all cases. The presence of “ragged red fibers” on histologic analysis is consistent with a mitochondrial disorder. Ragged red fibers represent a proliferation of defective mitochondrial.(1) This characteristic finding may not be present in all types of mitochondrial disorders, and also may be absent early in the course of disease.(2) Treatment of mitochondrial disease is largely supportive, because there are no specific therapies than impact the natural history of the disorder.(5) Identification of complications such as diabetes and cardiac dysfunction is important for early treatment of these conditions. A number of vitamins and cofactors (eg, coenzyme Q, riboflavin) have been used, but empirical evidence of benefit is lacking.(6) Exercise therapy for myopathy is often prescribed, but the effect on clinical outcomes is uncertain.(5) The possibility of gene transfer therapy is under consideration, but is at an early stage of development and has not yet been tested in clinical trials.

Genetic testing for mitochondrial disorders Genetic testing for mitochondrial disorders may involve testing for point mutations, deletion/duplication analysis, and/or whole mitochondrial exome sequencing. The type of testing done depends on the specific disorder being considered. For some primary mitochondrial disorders such as MELAS and MERFF, most mutations are point mutations, and there are a finite number of mutations associated with the disorder. When testing for one of these disorders, known pathogenic mutations can be tested for with polymerase chain reaction, or sequence analysis can be performed on the particular gene. For other mitochondrial disorders such as CPEO and KSS, the most common mutations are deletions, and therefore duplication/deletion analysis would be the first test when these

disorders are suspected. Testing for the individual mutations associated with mitochondrial disorders is offered by numerous labs. Genetic panel testing is also available, with numerous different panels available. Some of these are disease-specific panels that include only a small number of genes associated with a particular mitochondrial disorder. For example, Transgenomic™ offers a MELAS panel consisting of 10 mutations that have specific associations with MELAS syndrome.(7) There are at least 7 labs that currently offer “expanded” panel testing for mitochondrial disorders by nextgeneration sequencing.(8) The number of genes included in these panels varies widely, ranging from 37 to 1,192. These types of panels include a larger number of genes that are associated with numerous different mitochondrial disorders. These expanded panels are often intended to be comprehensive panels that test for all known mitochondrial and nuclear genes associated with any mitochondrial disorder. All of the expanded panels, with the exception of MEDomics® include analysis of both mitochondrial genes and nuclear genes that are thought to be involved with mitochondrial function. The specific labs and number of genes tested, taken from websites and/or published literature,(8) are listed in Table 2. The composition of these expanded panels vary widely in terms of the number of genes, the percent of genes that are “classic” mutations for mitochondrial disorders, and the inclusion of genes that are not associated with any disease phenotype.(8)

Regulatory Status Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratorydeveloped tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Genetic testing for mitochondrial disorders is under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test. (See Table 2 for commercially available Genetic Panels).

Scope [TOP]

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.

Benefit Application [TOP]

Some Plans may have contract or benefit exclusions for genetic testing. Specific contract language must be reviewed and considered when determining coverage for genetic testing. In some cases, coverage for testing the index case may be available through the contract that covers the unaffected, at-risk individual who will benefit from knowing the results of the genetic test.

Rationale [TOP] Populations Individuals:  With signs and/or symptoms of a mitochondrial disorder

Interventions Interventions of interest are:  Genetic testing for the diagnosis of disease

Comparators Comparators of interest are:  Standard clinical workup without genetic testing

Outcomes Relevant outcomes include:  Test accuracy  Test validity  Other test performance measures  Symptoms

Individuals:  Who are asymptomatic with a close relative with a mitochondrial disorder and a known pathogenic mutation

Interventions of interest are:  Genetic testing to determine future risk of disease

Comparators of interest are:  Standard risk assessment without genetic testing

 Functional outcomes  Health status measures  Quality of life Relevant outcomes include:  Test accuracy  Test validity  Other test performance measures  Changes in reproductive decision making  Symptoms  Functional outcomes  Health status measures  Quality of life

This policy was created in May 2014, and updated periodically with literature review. The most recent update with literature review covers the period from April 1, 2014, through April 29, 2016. Review of evidence will focus on three categories of genetic testing: diagnostic testing of an individual’s germline to benefit the individual; testing an asymptomatic individual to determine future risk of disease; and preconceptual carrier testing. The evaluation of a genetic test focuses on 3 main principles: 1. Analytic validity (technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent); 2. Clinical validity (diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease); and 3. Clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes).

Analytic Validity The analytic validity of testing for mitochondrial DNA (mtDNA) may vary by the type of testing performed, the type of mutation present, and the particular gene being evaluated. The 2 main types of genetic testing are polymerase chain reaction analysis and next-generation sequencing (NGS). Both are, in general, associated with high analytic validity of greater than 95%. The Courtagen webpage cites a sensitivity and specificity both greater than 99%.(9) No further information is provided, but this presumably refers to the analytic validity of the Courtagen panel to detect mutations present and exclude mutations not present. In addition to determining the presence of the mutation, another important component of analytic validity is whether the degree of heteroplasmy has been accurately measured. The proportion of DNA that is mutated is an important component of whether clinical symptoms will develop and is generally reported along with the presence or absence of the mutation. No information was available to judge the accuracy of heteroplasmy determination for mutations in mtDNA.

Section Summary There is a lack of published information on the analytic validity of genetic testing for mitochondrial disorders. There are manufacturer claims that the analytic validity approaches 100%, but no empirical data is available. The analytic validity of testing mtDNA has the added complexity of heteroplasmy, and no evidence was identified that evaluated the accuracy of methods for determining heteroplasmy.

Clinical Validity The evidence on the clinical sensitivity and specificity of genetic testing for mitochondrial disorders is limited. There are some small case series of patients with well-defined syndrome such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, and some studies include larger numbers of patients with less specific clinical diagnose. There are wide variations reported in testing yield, probably reflecting the selection process used to select patients for testing. Some representative information is pertinent to clinical

validity is reviewed here.

Clinical Sensitivity Several series of patients with mixed diagnoses, or suspected mitochondrial disorders, have been published. In these studies, the mutation detection rate may or may not be an accurate estimate of clinical sensitivity, because the proportion of patients with a mitochondrial disorder is uncertain. Kohda et al evaluated a cohort of 142 children with early-onset respiratory chain disease using NGS of the entire mtDNA together with whole exome sequencing of the nuclear DNA.(10) There were 37 (26.1%) patients who had a likely pathogenic mutation identified. Most (37/42 [88.1%]) were novel mutations discovered in the mtDNA. Two 2 (1.4%) patients were found to have a known pathogenic mutation in a mitochondrial gene. Qi et al studied 552 patients with mitochondrial encephalopathies and tested them for the presence of 4 of the most common mitochondrial mutations.(11) Patients had a diagnosis of MELAS, myoclonic epilepsy with raggedred fibers (MERRF) syndrome, Leigh syndrome (LS), Leber hereditary optic neuropathy, or an overlap syndrome. A total of 64 (11.6%) patients had a pathogenic mutation, most of which (57/64) were the n3243 variant. Lieber et al studied 102 patients with heterogeneous clinical symptoms suspected to be due to mitochondrial disorders.(12) Using NGS, the authors sequenced the entire mitochondrial genome and the exons of 1598 nuclear genes. Twenty-two (22.4%) patients had mutations thought to be pathogenic. An additional 26 variants identified were of uncertain clinical significance. A similar population of patients with heterogeneous symptoms and suspected mitochondrial disease was evaluated by Remenyi et al.(13) In this study, 1328 patients from China were tested for the 5 most common mitochondrial mutations. A pathogenic mutation was found in 22.5% of patients. The most common mutations were those associated with Leber hereditary optic neuropathy, occurring in 17.9% of patients. For patients with a well-defined syndrome, smaller case series have been published. For MELAS syndrome, a high proportion of patients were diagnosed clinically with the disorder test positive for a pathogenic mutation. The most common mutation is an AG base pair substitution at nucleotide pair 3,243. Goto et al tested 31 nonrelated patients with MELAS for the presence of this point mutation and reported that 83.9% (26/31) were positive.(14) For MERRF, it is commonly cited that more than 80% of patients with the clinically defined syndrome will have a mutation in the MT-TK gene, with an AG substitution at location (nt)8344, and that an additional 10% of patients with MERRF will have 1 of 3 other mutations in the MT-TK gene.(15) However, there is a lack of published evidence that supports this claim. Leigh syndrome has criteria for diagnosis that include:  Neurodegenerative disease with symptoms of mitochondrial dysfunction,  Hereditary pattern of disease,  Bilateral central nervous system lesions on imaging.(16) There are at least 12 genes associated with Leigh syndrome, with each gene accounting for only a small minority of cases. The most common gene involved is the MT-ATP6 gene, which is implicated in approximately 10% of cases.(16)

Clinical Specificity The clinical specificity of genetic testing for mitochondrial disorders is largely unknown, but false-positive results have been reported.(17) Some epidemiologic evidence is available on the population prevalence of pathogenic mutations, which provides some indirect evidence on the potential for false-positive results. A study of population-based testing reported that the prevalence of pathogenic mutations is higher than the prevalence of clinical disease. In this study, 3168 consecutive newborns were tested for the presence of 1 or more of the 10 most common mtDNA mutations thought to be associated with clinical disease.(18) At least 1 pathogenic mutation was identified in 15 (0.54%) of 3168 people (95% confidence interval, 0.30% to 0.89%). This finding implies that there are many more people with a mutation who are asymptomatic than there are people with clinical disease, and it raises the possibility of false-positive results on genetic testing. An earlier population-based study evaluated the prevalence of the n3243 variant associated with MELAS

syndrome.(19) This study included 245,201 subjects from Finland. Participants were screened for common symptoms associated with MELAS, and screen-positive patients were tested for the mutation. The population prevalence was estimated at 16.3 (0.16%) in 100,000. This study may have underestimated the prevalence because patients who screened negative were not tested for the mutation. In addition to false-positive results, there are variants of uncertain significance (VOUS) detected in substantial numbers of patients. The number of variants increases when NGS methods are used to examine a larger portion of the genome. In 1 study using targeted exome sequencing, VOUS were far more common than definite pathogenic mutations.(20) In that study, 148 patients with suspected or confirmed mitochondrial disorders were tested by a genetic panel including 447 genes. A total of 13 patients were found to have pathogenic mutations. In contrast, VOUS were very common, occurring at a rate of 6.5 per patient. A further consideration is the clinical heterogeneity of mutations known to be pathogenic. Some mutations associated with mitochondrial disorders can result in heterogeneous clinical phenotypes, and this may cause uncertainty about the pathogenicity of the mutation detected. For example, the (nt)3243 mutation in the MT-TL1 gene is found in most patients with clinically defined MELAS syndrome.(21) This same mutation has also been associated with chronic progressive external ophthalmoplegia and Leigh syndrome.(22) Therefore, the more closely the clinical syndrome matches MELAS, the more likely a positive genetic test will represent a pathogenic mutation.

Section Summary Case series and cohort studies provide information on the clinical sensitivity of testing. For patients with signs and symptoms of mitochondrial disorders, but without a well-defined clinical syndrome, the mutations detection rate is low, ranging from 11.6% to 26.1%. This rate is an underestimation of clinical sensitivity because at least some patients do not have a mitochondrial disorder, but the degree to which it approximates clinical sensitivity is uncertain. For patients with a defined clinical syndrome, the clinical sensitivity is higher (range, >80%). However, clinical sensitivity has not been reported for all mitochondrial disorders. There is very little evidence on clinical specificity, but there have been false-positive tests reported.

Clinical Utility No direct evidence on clinical utility was identified. There are 2 ways that clinical utility might be demonstrated from an indirect chain of evidence. First, confirmation of the diagnosis may have benefits in ending the need for further clinical workup and eliminating the need for a muscle biopsy. Second, knowledge of mutation status may have benefits for family members in determining their risk of developing disease.

Confirmation of Diagnosis For patients with signs and symptoms that are consistent with a defined mitochondrial syndrome, testing can be targeted to those mutations associated with that particular syndrome. In the presence of a clinical picture consistent with the syndrome, the presence of a known pathogenic mutation will confirm the diagnosis with a high degree of certainty. Confirmation of the diagnosis by genetic testing can result in reduced need for further testing, especially a muscle biopsy. The clinical utility of testing will be maximized if patients are selected who have at least a moderate to high pretest probability of disease. If confirmation of the diagnosis depends on both on the presence of signs of and symptoms of a specific disorder in conjunction with the presence of a known pathogenic mutation, then the problem of potential false-positive results will be minimized. There is no specific therapy for mitochondrial disorders. Treatment is largely supportive management for complications of the disease. It is possible that confirmation of the diagnosis by genetic testing leads to management changes, such as increased surveillance for complications of disease and/or the prescription of exercise therapy or antioxidants. However, the impact of these management changes on health outcomes is not known.

Testing of at-risk Relatives Confirmation of a genetic mutation has implications for family members of the affected person. Knowledge of mutation status will clarify the inheritance pattern of the mutation, thus clarifying risk to family members. For example, for a male patient with MELAS syndrome, confirmation of a pathogenic mutation in the mitochondrial DNA would indicate that his offspring are not at risk for inheriting the mutation, because inheritance of the

mitochondrial mutation could only occur through the mother. In contrast, identification of a pathogenic mutation in nuclear DNA would indicate that his offspring are at risk for inheriting the mutation.

Reproductive Testing When there is disease of moderate severity or higher, it is reasonable to assume that many patients will consider results of testing in reproductive decision making. Prevention of disease through genetic testing is 1 way to reduce the burden of illness. Preconceptual carrier testing can lead to informed reproductive decision making, which may alter decisions on pursuing pregnancy or lead to preimplantation genetic testing. There is some empirical evidence that mitochondrial disorders can be prevented though carrier testing. Nesbitt et al published a retrospective review of 62 patients who underwent prenatal genetic testing for mitochondrial disorders at a European center.(23) Based on test results and their review of records, the authors estimated that at least 11 cases of mitochondrial disorder had been prevented.

Expanded Panel Testing and Whole Exome Sequencing Expanded panels are defined as panels that include many more genes than are associated with any specific disorder. They are sometimes promoted for individuals with signs and/or symptoms that are not consistent with any specific disorder. When these panels are used in individuals with nonspecific signs and symptoms not consistent with a “classic” presentation of a mitochondrial disorder, the probability of finding a pathogenic mutation is considerably less. Conversely, the likelihood of a false-positive result and the number of VOUS may be substantially increased.(24) Whole exome sequencing has also been examined to detect mutations associated with mitochondrial disorders. (10,25,26) This technique is likely to increase the detection rate but will also increase the rate of VOUS. In 1 study from the U.K. of 53 patients who had biochemical evidence of a mitochondrial disorder but were negative on genetic testing of the primary mitochondrial disorder, mutations underwent whole exome sequencing.(25) Probable pathogenic mutations causative of a mitochondrial disorder were identified in 28 (53%) patients, and there were an additional 4 patients who had variants that were possibly pathogenic. Further research is needed into the benefits and harms of expanded panel testing and whole exome sequencing for the diagnosis of mitochondrial disorders. At present, due the uncertainty about the balance of benefits and harms, it is not possible to determine whether there is a net health outcome benefit.

Section Summary For diagnostic testing, clinical utility is relatively high when a definite diagnosis cannot be made without genetic testing. In this situation a positive test for a pathogenic mutation will confirm the diagnosis and may avoid further testing, including invasive tests (eg, muscle biopsy). It is likely that confirmation of the diagnosis will lead to management changes, including referral to a specialist in mitochondrial disease. However, it is not known whether these management changes improve outcomes, because of the lack of research on treatment interventions for mitochondrial disorders. For testing at-risk relatives, clinical utility can also be demonstrated. When a disease phenotype displays moderate-to-severe disease, it is likely that knowledge of mutation status will affect reproductive decision making. Genetic testing prior to pregnancy, with or without preimplantation genetic testing, is likely to reduce the likelihood of live offspring with mitochondrial disorders.

Ongoing and Unpublished Clinical Trials A search of ClinicalTrials.gov in June 2016 did not identify any ongoing or unpublished trials that would likely influence this review.

Summary of Evidence For individuals who have signs and/or symptoms of a mitochondrial disorder who receive genetic testing for diagnosis of disease, the evidence includes case series and cohort studies. Relevant outcomes are test accuracy and validity, other test performance measures, symptoms, functional outcomes, health status measures, and quality of life. There is a lack of published data on analytic validity. Commercial testing sites claim analytic validity approaches 100% and describe testing methods expected to have high analytic validity. There is some evidence on clinical validity that varies by the specific disorder. For example, for the most well understood disorders such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome, small series of

patients with a clinically diagnosed disorder have reported that a high proportion of patients have a pathogenic mutation. Clinical specificity is unknown, but population-based studies have reported that the prevalence of certain mutations exceeds the prevalence of clinical disease, suggesting that the mutation will be found in some people without clinical disease (false positives). Clinical utility is relatively high for confirming the diagnosis of mitochondrial disorders in people who have signs and symptoms indicating a moderate-to-high pretest likelihood of disease. In these patients, a positive result on genetic testing can avoid a muscle biopsy and eliminate the need for further clinical workup. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. For individuals who are symptomatic with a close relative with a mitochondrial disorder and a known pathogenic mutation and who receive genetic testing to determine future risk of disease, the evidence includes case series and cohort studies. Relevant outcomes are test accuracy and validity, other test performance measures, changes in reproductive decision making, symptoms, functional outcomes, health status measures, and quality of life. There is a lack of published data on analytic validity. Commercial testing sites claim analytic validity approaching 100% and describe testing methods expected to have high analytic validity. There is some evidence on clinical validity that varies by the specific disorder. For example, for the most well understood disorders such as MELAS syndrome, small series of patients with a clinically diagnosed disorder have reported that a high proportion of patients have a pathogenic mutation. Clinical specificity is unknown, but population-based studies have reported that the prevalence of certain mutations exceeds the prevalence of clinical disease, suggesting that the mutation will be found in some people without clinical disease (false positives). Clinical utility can be demonstrated for testing of at-risk family members who have a close relative with a pathogenic mutation. When a specific mitochondrial disease is present in the family that is severe enough to cause impairment and/or disability, genetic testing may impact reproductive decision making. If genetic testing is used in this situation, there will be a decreased risk of a mitochondrial disorder in live offspring. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Practice Guidelines and Position Statements The Foundation for Mitochondrial Medicine published an overview of mitochondrial disease in 2013; genetic testing was specifically addressed. (27) The overview includes the following statements: Mitochondrial disease can look like a number of different diseases such as autism, Parkinson disease, Alzheimer disease, Lou Gehrig disease, muscular dystrophy, and chronic fatigue. No one approach is sufficient for an accurate diagnosis. There are 3 categories of diagnostic criteria: 1. Clinical 2. Biochemical 3. Genetic A diagnosis of mitochondrial disease requires an integrated approach; there is “no single test to diagnose mitochondrial disease in most patients.” Genetic testing, alone, is “rarely … sufficient to diagnose mitochondrial disease.”

U.S. Preventive Services Task Force Recommendations Not applicable.

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

References [TOP]

1. Schon EA, DiMauro S, Hirano M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nat Rev Genet. Dec 2012;13(12):878-890. PMID 23154810 2. Wong LJ. Diagnostic challenges of mitochondrial DNA disorders. Mitochondrion. Feb-Apr 2007;7(12):45-52. PMID 17276740

3. DiMauro S, Schon EA. Mitochondrial DNA mutations in human disease. Am J Med Genet. Spring 2001;106(1):18-26. PMID 11579421 4. Falk MJ, Sondheimer N. Mitochondrial genetic diseases. Curr Opin Pediatr. Dec 2010;22(6):711-716. PMID 21045694 5. Chinnery PF. Mitochondrial Disorders Overview. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA) 2014. 6. Chinnery P, Majamaa K, Turnbull D, et al. Treatment for mitochondrial disorders. Cochrane Database Syst Rev. 2006(1):CD004426. PMID 16437486 7. Transgenomic Web Site. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). 2014; http://www.transgenomic.com/labs/neurology/melas. Accessed July 2016. (Note: test not found on Lab website at time of review July, 2016) 8. Platt J, Cox R, Enns GM. Points to consider in the clinical use of NGS panels for mitochondrial disease: an analysis of gene inclusion and consent forms. J Genet Couns. Aug 2014;23(4):594-603. PMID 24399097 9. Courtagen Web site. Physician Overview. 2014; http://www.courtagen.com/professionals-overview.htm. Accessed July 2016. 10. Kohda M, Tokuzawa Y, Kishita Y, et al. A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet. Jan 2016;12(1):e1005679. PMID 26741492 11. Qi Y, Zhang Y, Wang Z, et al. Screening of common mitochondrial mutations in Chinese patients with mitochondrial encephalomyopathies. Mitochondrion. Feb-Apr 2007;7(1-2):147-150. PMID 17276742 12. Lieber DS, Calvo SE, Shanahan K, et al. Targeted exome sequencing of suspected mitochondrial disorders. Neurology. May 7 2013;80(19):1762-1770. PMID 23596069 13. Remenyi V, Inczedy-Farkas G, Komlosi K, et al. Retrospective assessment of the most common mitochondrial DNA mutations in a large Hungarian cohort of suspect mitochondrial cases. Mitochondrial DNA. Aug 2015;26(4):572-578. PMID 24438288 14. Goto Y, Nonaka I, Horai S. A mutation in the tRNA(Leu)(UUR) gene associated with the MELAS subgroup of mitochondrial encephalomyopathies. Nature. Dec 13 1990;348(6302):651-653. PMID 2102678 15. DiMauro S, Hirano M, Pagon RA, Adam MP, Ardinger HH, et al., eds. Myoclonic epilepsy with raggedred fibers (MERRF). In: GeneReviews®. Seattle (WA) 2009. 16. Thorburn DR, Rahman S. Pagon RA, Adam MP, Ardinger HH, et al., eds. Mitochondrial DNA-Associated Leigh Syndrome and NARP. In: GeneReviews®. Seattle (WA)1993. 17. Deschauer M, Krasnianski A, Zierz S, et al. False-positive diagnosis of a single, large-scale mitochondrial DNA deletion by Southern blot analysis: the role of neutral polymorphisms. Genet Test. Winter 2004;8(4):395-399. PMID 15684869 18. Elliott HR, Samuels DC, Eden JA, et al. Pathogenic mitochondrial DNA mutations are common in the general population. Am J Hum Genet. Aug 2008;83(2):254-260. PMID 18674747 19. Majamaa K, Moilanen JS, Uimonen S, et al. Epidemiology of A3243G, the mutation for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes: prevalence of the mutation in an adult population. Am J Hum Genet. Aug 1998;63(2):447-454. PMID 9683591 20. DaRe JT, Vasta V, Penn J, et al. Targeted exome sequencing for mitochondrial disorders reveals high genetic heterogeneity. BMC Med Genet. 2013;14:118. PMID 24215330 21. DiMauro S, Hirano M, Pagon RA, Adam MP, Ardinger HH, et al., eds. MELAS. In: GeneReviews(R). Seattle (WA) 2013. 22. Jean-Francois MJ, Lertrit P, Berkovic SF, et al. Heterogeneity in the phenotypic expression of the mutation in the mitochondrial tRNA(Leu) (UUR) gene generally associated with the MELAS subset of mitochondrial encephalomyopathies. Aust N Z J Med. Apr 1994;24(2):188-193. PMID 8042948 23. Nesbitt V, Alston CL, Blakely EL, et al. A national perspective on prenatal testing for mitochondrial disease. Eur J Hum Genet. Nov 2014;22(11):1255-1259. PMID 24642831 24. O'Brien M, Cryan J, Brett F, et al. Ten years on: genetic screening for mitochondrial disease in Ireland. Clin Neuropathol. Jul-Aug 2014;33(4):279-283. PMID 24986207 25. Taylor RW, Pyle A, Griffin H, et al. Use of whole-exome sequencing to determine the genetic basis of multiple mitochondrial respiratory chain complex deficiencies. JAMA. Jul 2 2014;312(1):68-77. PMID 25058219 26. Ohtake A, Murayama K, Mori M, et al. Diagnosis and molecular basis of mitochondrial respiratory chain disorders: exome sequencing for disease gene identification. Biochim Biophys Acta. Apr 2014;1840(4):1355-1359. PMID 24462578 27. Foundation for Mitochondrial Medicine. Mitochondrial Disease: Overview of Mitochondrial Disease. 2013; http://mitochondrialdiseases.org/mitochondrial-disease/. Accessed July 2016. 28. Gene DX-DNA Diagnostic Experts Web Site. Mitochondrial encephalomyopathy, lactic acidosis, and

stroke-like episodes (MELAS) 2016. URL source: https://www.genedx.com/testcatalog/disorders/mitochondrial-encephalomyopathy-with-lactic-acidosis-and-stroke-like-episodesmelas/. Accessed July 2016.

Appendix [TOP]

N/A

History [TOP]

Date 08/11/14

01/14/15 07/14/15

08/09/16

01/01/17

Reason New Policy. Policy developed with literature review through April 20, 2014. Genetic testing for specific mitochondrial mutations may be considered medically necessary for patients with signs and symptoms of mitochondrial disorders, and for at-risk family members if there is disease of at least moderate severity and a pathogenic mutation has been identified. The use of expanded genetic panels for mitochondrial disorders is considered investigational. Coding update. New CPT code 81440, effective 1/1/15, added to the policy. Annual Review. Policy updated with literature review through 05/01/15, references 8 and 22-24 added. Wording of policy statements revised to be consistent with standardized genetic language. ICD-9 and ICD-10 diagnosis codes removed; these were listed for informational purposes only. Annual Review. Policy updated with literature review through April 2016; references added. Related Policy 12.04.92 added. CPT codes 81460 and 18465 added to coding section. Policy statements unchanged. Update Related Policies. Removed 12.04.520 as it was archived.

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). ©2017 Premera All Rights Reserved.

Discrimination is Against the Law Premera Blue Cross complies with applicable Federal civil rights laws and does not discriminate on the basis of race, color, national origin, age, disability, or sex. Premera does not exclude people or treat them differently because of race, color, national origin, age, disability or sex. Premera: • Provides free aids and services to people with disabilities to communicate effectively with us, such as: • Qualified sign language interpreters • Written information in other formats (large print, audio, accessible electronic formats, other formats) • Provides free language services to people whose primary language is not English, such as: • Qualified interpreters • Information written in other languages If you need these services, contact the Civil Rights Coordinator. 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).