Genetic Testing for Muscular Dystrophies

MEDICAL POLICY – 12.04.86 Genetic Testing for Muscular Dystrophies Effective Date: Jan. 1, 2017 RELATED MEDICAL POLICIES: Last Revised: Dec. 13, 2...
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MEDICAL POLICY – 12.04.86

Genetic Testing for Muscular Dystrophies Effective Date: Jan. 1, 2017

RELATED MEDICAL POLICIES:

Last Revised:

Dec. 13, 2016

None

Replaces:

12.04.105 and 12.04.132

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 Muscular Dystrophies (MDs) are a group of inherited (genetic) diseases that affect muscle tissues throughout the body. The diseases cause the affected muscles to waste away (atrophy) and become weaker (myopathy) resulting in progressive disability that can range from mild to severe. This policy explains when genetic testing may be covered to help guide medical management and reproductive decision-making for four common muscular dystrophies, Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD, a variant of DMD), Facioscapulohumeral muscular dystrophy (FSHD) and Limb-girdle muscular dystrophy (LGMD). 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 them about when a service may be covered.

Policy Coverage Criteria

Test

Coverage Criteria

Duchenne (DMD) and Becker

Genetic testing for the DMD gene mutation may be

(BMD) muscular dystrophies

considered medically necessary when the following criteria

Test

Coverage Criteria

(variant of DMD)

are met: 

In a male patient with signs and symptoms of a muscle disease (dystrophinopathy) when results of testing will confirm the diagnosis and guide the treatment plan

Note:

Signs and symptoms may include late in learning to walk, as the disease gradually weakens the skeletal or voluntary muscles of the arms, legs, and trunk. Toddlers can easily fall over and have trouble getting up; enlarged calf muscle may be seen. Heart and respiratory muscles are affected as the disease progresses. Onset of symptoms for DMD is as early as 3 years of age; BMD is usually in the teens or early adulthood.



In at-risk female relatives of the affected male (index patient) when: o

Results of testing may lead to changes in medical management that improves outcomes ( such as, confirming or excluding the need to monitor heart function)

AND/OR o

Results of testing will provide information about the possibility of passing the gene mutation to a child, prior to conception

Note:

Females that are carriers of the trait with the mutation in 1-copy of the gene (heterozygous) are at an increased risk for heart muscle disease (cardiomyopathy) and need routine follow-up and treatment. At-risk females are first- and second-degree female relatives and include the index patient’s mother, female siblings of the index patient, female offspring of the index patient, the index patient’s maternal grandmother, maternal aunts, and their offspring

Genetic testing for the DMD gene mutation is considered investigational when the criteria above are not met. Facioscapulohumeral

Genetic testing for FSHD gene mutations may be considered

muscular dystrophy (FSHD)

medically necessary in a patient with signs and symptoms of the muscle disease when results of testing will confirm the diagnosis. Page | 2 of 21

Test

Coverage Criteria Note:

Signs and symptoms may include facial, shoulder blade, upper arm weakness, and often weakness in the muscles on top of the foot that helps with walking. Onset of symptoms is usually between 6-20 years of age.

Genetic testing for FSHD gene mutations is considered investigational when the criteria above are not met. Limb-girdle muscular

Genetic testing for LGMD gene mutations may be

dystrophy (LGMD)

considered medically necessary when the following criteria are met: 

The patient has signs and symptoms of LGMD when results of testing will confirm the diagnosis

AND 

At least one of the following criteria are met: o

Results of testing may lead to changes in medical management that improves outcomes (e.g., confirming or excluding the need to monitor heart function)

OR o

Genetic testing will allow the affected patient to avoid invasive testing, including muscle biopsy

Note:

Signs and symptoms may include walking with a broad-based stance due to weak hip/leg muscles, trouble getting up from a seated position or from the floor, trouble climbing stairs, difficulty reaching overheard, combing hair, or using a computer keyboard. Onset can begin between childhood and adulthood.

Genetic testing for LGMD gene mutations may be considered medically necessary for reproductive planning when: 

There is a diagnosis of LGMD in one or both of the parents

AND 

Results of testing will provide information about the possibility of passing the gene mutation to a child, prior to conception

Genetic testing for LGMD gene mutations may be Page | 3 of 21

Test

Coverage Criteria considered medically necessary in a patient without symptoms to determine future risk of disease when the following criteria are met: 

One first- or second-degree relative has a known mutation consistent with LGMD (see Definition of Terms).

OR 

One first- or second-degree relative has a diagnosis of LGMD and their genetic mutation status is unavailable (see Definition of Terms).

AND 

Results of testing will lead to changes in medical management that improves outcomes (e.g., confirming or excluding the need to monitor heart function).

Genetic testing for LGMD gene mutations is considered investigational when the criteria above are not met.

∞ Coding

CPT 81400

Molecular pathology procedure, Level 1(e.g., identification of single germline variant [e.g., SNP] by techniques such as restriction enzyme digestion or melt curve analysis)

81404

Molecular pathology procedure, Level 5 (e.g., analysis of 2-5 exons by DNA sequence analysis, scanning or duplication/deletion variant of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)

81405

Molecular pathology procedure, Level 6 (e.g., analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis

81406

Molecular pathology procedure, Level 7 (e.g., analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)

81408

Molecular pathology procedure, Level 9 (e.g., analysis of >50 exons in a single gene by DNA sequence analysis) - includes DMD (dystrophin) (e.g., Duchenne/Becker muscular dystrophy), full gene sequence Page | 4 of 21

CPT 81479 Note:

Unlisted molecular pathology procedure CPT codes, descriptions and materials are copyrighted by the American Medical Association (AMA). HCPCS codes, descriptions and materials are copyrighted by Centers for Medicare Services (CMS).

∞ Related Information

Definition of Terms Analytic Validity: This refers to the technical accuracy of the test in detecting the presence or absence of a gene mutation (such as a DNA sequence variant, chromosomal deletion, or biochemical indicator). Clinical Validity: This refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) to identify a particular clinical condition. Clinical Utility: This refers to how the results of the diagnostic test will be used to change medical management and whether these changes lead to clinically important improvements in health outcomes. Clinical utility refers to the risks and benefits resulting from genetic test use. At-risk females: This refers to a first and second-degree female relative of the index patient (proband) and includes the index patient’s mother, sisters, daughters, maternal grandmother, maternal aunts, and their female offspring. At-risk: This refers to having a greater chance (probability) of inheriting a specific gene mutation based on family relationship. (See degrees of relationship definition) Carrier testing: This test tells a patient if they “carry” a genetic change that can cause a disease. Carriers often do not show signs of the disorder but can pass the genetic variation to their children, who may develop the disorder or become carriers. Creatine kinase (CK) test: CK is a muscle enzyme found in the brain, skeleton and heart. An elevation in the CK level in the blood indicates muscle is being damaged by an abnormal development; such as in a heart attack or in disorders such as muscular dystrophies. Degrees of relationship: This refers to close blood relatives on the same side of the family (mother or father) Page | 5 of 21

First-degree relatives

Parents, children, brothers and sisters

Second-degree

Grandparents, aunts, uncles, nieces, nephews, grandchildren, and half brothers

relatives

and sisters

Third-degree

Great grandparents, great aunts, great uncles, great grandchildren, and first

relatives

cousins

Taken in part from: National Library of Medicine (NLM). Genetics Home Reference. Accessed December 2016.

Index case/patient: The first affected family member who seeks medical care for a genetic disorder. This person may also be called the proband. Dystrophinopathy: A muscle disease resulting in progressive muscle degeneration and weakness caused by changes in the DMD gene that tells the body to make the protein dystrophin. Duchenne muscular dystrophy (DMD) gene: This gene provides instructions for making a protein called dystrophin. (See dystrophin definition) Duchenne and Becker muscular dystrophies: These are two related genetic diseases. The disease is classified as Duchenne (DMD) when skeletal muscle is primarily affected, or Becker muscular dystrophy (BMD) when the heart is primarily affected. The diseases cause the affected muscles to waste away (atrophy) and become weaker (myopathy) These two diseases occur more often in males than in females. These forms of muscular dystrophy may also affect the heart and breathing functions. The symptoms usually appear in late childhood or adolescence. Dystrophin: A protein that helps muscle cells remain intact. Dystrophin is found in muscles used for movement of the body including the heart. Facioscapulohumeral muscular dystrophy: This refers to a group of genetic diseases that affect the muscles in the face, the shoulder blades, and upper arms. The disease causes the affected muscles to waste away (atrophy) and become weaker (myopathy). Unlike some other forms of muscular dystrophy, this one typically does not affect the heart and breathing functions. Limb-girdle muscular dystrophy (LGMD): A group of genetic diseases that affect the voluntary muscles closest to the body (proximal) that includes shoulders, upper arms, pelvic area and thighs. The disease causes muscles in the arms and legs to waste away (atrophy) and become weaker. There are at least 19 forms of LGMD. Proband: The first affected family member who seeks medical care for a genetic disorder. This person may also be called the index case.

Page | 6 of 21

Description

Muscular Dystrophies overview Muscular dystrophies (MD) are a group of inherited muscle disorders with physical characteristics of progressive weakness and degeneration of skeletal muscle, cardiac muscle, or both; there may be respiratory muscle involvement or problems swallowing (dysphagia) and problems speaking (dysarthria) when facial muscles are affected. MDs are associated with a wide range of observable traits (phenotypes) that go from rapidly progressive weakness leading to death in the second or third decade of life to no clinical symptoms of the disease (asymptomatic disease) with an elevated blood level of creatine kinase (CK) as the main indicator. MDs have been classified based on signs and symptoms of the disorder and the genetic cause (etiology). The most common MDs are the dystrophinopathies, Duchenne (DMD) and Becker (BMD) muscular dystrophies that are identified by mutations in the dystrophin (DMD) gene. Other MDs are differentiated by the location of muscle weakness in the body and include the limb-girdle muscular dystrophies (LGMD), facioscapulohumeral muscular dystrophies (FSHD), oculopharyngeal muscular dystrophies, distal muscular dystrophies, and humeroperoneal muscular dystrophies (also known as Emery-Dreifuss muscular dystrophy). The congenital muscular dystrophies are a genetically heterogeneous group of disorders, which historically included infants with weak muscle tone (hypotonia) at birth and findings of MD on biopsy. Finally, myotonic dystrophy is a multisystem disorder characterized by skeletal muscle weakness and muscle contraction/spasm (myotonia) in association with cardiac abnormalities, cognitive impairment, hormone gland disorder (endocrinopathies), and difficulty swallowing (dysphagia). This policy will focus on three common MDs.

Background

Duchenne (DMD) and Becker (BMD) muscular dystrophies Mutations in the DMD gene, which encodes the protein dystrophin, may result in a spectrum of X-linked muscle diseases, including the progressive diseases DMD and BMD. When the heart is primarily affected, the disease is classified as DMD-associated dilated cardiomyopathy (left ventricular dilation and heart failure). Genetic testing can confirm a diagnosis and distinguish the less and more severe forms, as well as identify female carriers at risk for heart muscle disease.

Page | 7 of 21

Virtually all males with DMD or BMD have detectable DMD mutations, indicating a high clinical sensitivity for genetic testing. Clinical utility of DMD gene testing can be established for the proband/index case to confirm the diagnosis without a muscle biopsy, to initiate effective treatment, and to distinguish between DMD and the less severe BMD. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. Direct evidence on the clinical utility of DMD gene testing in at-risk female relatives is lacking, but an indirect chain of evidence exists, as female carriers are at increased risk for dilated cardiomyopathy. Confirmation or exclusion of the mutation helps with decisions about the need for routine follow-up of cardiac health status and can indicate the likelihood of a woman considering pregnancy to have a baby with the gene mutation. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.

Facioscapulohumeral muscular dystrophy (FSHD) FSHD is an autosomal dominant disease that typically presents between the ages of 6 and 20 years. It is the third most common muscular dystrophy and involves progressive weakness and wasting of the facial muscles (facio), and shoulder and upper arm (scapulohumeral) muscles. The severity of the disease is highly variable, ranging from mildly affected, asymptomatic individuals to severely affected individuals, with approximately 20% of patients eventually requiring a wheelchair. FSHD affects males and females equally. There is no direct evidence for the clinical utility of genetic testing for patients with suspected FSHD, as no studies were identified that described how a molecular diagnosis of FSHD changed patient management. However, a chain of evidence supports the use of D4Z4 contraction mutation testing for suspected FSHD to establish a diagnosis, initiate therapies consistent with appropriate guidelines, and avoid a muscle biopsy in most cases.

Limb-girdle muscular dystrophy (LGMD) The term limb-girdle muscular dystrophy is a clinical descriptor for a group of muscular dystrophies characterized by predominantly proximal muscle weakness (pelvic and shoulder girdles) which may be included in the differential diagnosis of DMD and BMD.2 Onset can be in childhood or adulthood. LGMD is classified based on its inheritance pattern and genetic cause into more than 31 different types. The degree of disability depends on the location and degree of weakness. Some LGMD subtypes are characterized by only mild, slowly progressive weakness, Page | 8 of 21

while others are associated with early-onset, severe disease with loss of ambulation. LGMDs may be associated with cardiac dysfunction, cardiomyopathy (dilated or hypertrophic), respiratory depression, and dysphagia or dysarthria. Of particular note is the risk of cardiac complications, which is a feature of many but not all LGMDs. Most patients have an elevated creatine kinase (CK) level. The genes involved with known forms of LGMD43-46 are either autosomal dominant or autosomal recessive and include the following: Autosomal dominant genes: MYOT, LMNA, CAV3, DNAJB6, DES, TNPO3, HNRPDL Autosomal recessive genes: CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TCAP, TRIM32, FKRP, TTN, POMT1, ANO5,FKTN, POMT2, POMGnT1, DAG1, PLEC1, DES, TRAPPC11, GMPPB, ISPD, GAA, LIMS2 The clinical utility of testing for mutations associated with LGMD for a patient with clinically suspected LGMD (index case) includes: 

Confirming the diagnosis of LGMD and initiating/directing treatment of the disease, including evaluation by a cardiologist/cardiac testing, respiratory function testing/monitoring, and prevention of secondary complications (e.g., through immunizations, physical therapy/bracing, fracture risk reduction).



Avoidance of treatments that might be initiated for other neuromuscular disorders not known to be efficacious for LGMD, such as glucocorticoids for suspected dystrophinopathy or immunosuppressants for suspected myositis.



Potential discontinuation of routine cardiac and respiratory surveillance in patients who have an identified mutation not known to be associated with cardiac or respiratory dysfunction.



Potential avoidance of invasive testing (e.g., muscle biopsy).



Reproductive planning.

The clinical utility of testing for mutations associated with LGMD for an at-risk family member (i.e., first- or second-degree relative of the index case) includes: 

Confirming or excluding the need for cardiac surveillance.



Reproductive planning and decision-making prior to pregnancy, when results of testing will provide information about the possibility of passing the gene mutation to a child.

Page | 9 of 21

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.

Benefit Application Some plans may have contract or benefit exclusions for genetic testing.

∞ Evidence Review

This policy was created with a review of the literature using MEDLINE, most recently through September 2016. The following are evidence summaries from the literature search for each genetic disorder listed in the policy.

Duchenne (DMD) and Becker (BMD) muscular dystrophies The evidence for genetic testing for a DMD gene mutation to confirm a diagnosis in individuals who are male and have signs and symptoms of a dystrophinopathy includes case series and database entries describing screening and results of types of mutations found in patients with clinical signs of Duchenne (DMD) and Becker muscular dystrophy (BMD). Relevant outcomes are test accuracy and validity, symptoms, change in disease status, morbid events, quality of life, medication use, and resource utilization. Published studies of analytic validity are lacking, however, for deletion/duplication analysis by chromosomal microarray analysis and point mutations by full gene sequencing, analytic validity has been reported to be high (98%-99%), with false positives being rare. Virtually all males with DMD or BMD have identifiable DMD Page | 10 of 21

mutations, indicating a high clinical sensitivity for genetic testing. Clinical utility of DMD gene testing can be established for the index case to confirm the diagnosis without a muscle biopsy, to initiate effective treatment, and to distinguish between DMD and the less severe BMD. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome. The evidence for targeted DMD mutation testing for the known pathogenic mutation in a family in individuals who are female and are a relative of a patient with a DMD-associated dystrophinopathy is lacking. Relevant outcomes are test accuracy and validity, changes in reproductive decision making, symptoms, change in disease status, morbid events, quality of life, medication use, and resource utilization. Published data for the analytic and clinical validity for testing for a known familial mutation are lacking, but the validity is expected to be high. Direct evidence on the clinical utility of DMD gene testing in at-risk female relatives is lacking, but an indirect chain of evidence exists, in that confirmation or exclusion of a pathogenic mutation necessitates or eliminates the need for routine cardiac surveillance and can indicate the likelihood of an affected offspring in women considering children. The evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.1-20

Facioscapulohumeral Muscular Dystrophy The evidence for genetic testing in patients who have clinical signs of FSHD syndrome is generally lacking. Relevant outcomes are test accuracy, test validity, morbid events, functional outcomes, quality of life, and resource utilization. Test accuracy and validity have been reported to be high. A definitive diagnosis may end the need for additional testing in the etiologic workup, avoid the need for a muscle biopsy, and initiate and direct clinical management changes that can result in improved health outcomes. Therefore, the evidence is sufficient to determine qualitatively that the technology results in a meaningful improvement in the net health outcome.21-36

Limb-Girdle Muscular Dystrophies The analytic validity of genetic testing for mutations associated with limb-girdle muscular dystrophy (LGMD) is likely to be high. The true clinical sensitivity and specificity of genetic testing for LGMD in general cannot be determined. While the yield of genetic testing in patients with clinically suspected LGMD varies depending on the population characteristics (i.e., patients with only clinical symptoms versus patients with biopsy findings suggestive of LGMD), the Page | 11 of 21

available body of evidence suggests that the yield of testing is reasonably high. Genetic testing is generally considered the criterion standard for diagnosis of a specific LGMD subtype. For patients with clinically suspected LGMD, there is the potential for clinical utility in genetic testing to confirm a diagnosis of LGMD and guide medical management and monitoring on the basis of a specific genetic diagnosis (including discontinuation of routine cardiac and/or respiratory surveillance if a specific genetic diagnosis not associated with these complications can be made), avoid therapies not known to be effective for LGMD, potentially avoid invasive testing, and allow reproductive planning. For at risk relatives of a proband, there is potential for clinical utility in genetic testing to identify the need for routine cardiac surveillance and allow reproductive planning. There is no direct evidence about the impact of genetic testing on outcomes, however an indirect chain of evidence indicates that the use of genetic testing in general may help patients avoid invasive testing and/or initiation of appropriate therapies, and the establishment of a specific genetic diagnosis can allow increased surveillance for cardiac dysfunction, for which there are effective medical- and device-based therapies. The use of genetic testing for mutations associated with LGMD may be considered medically necessary to confirm a diagnosis of LGMD in a patient with symptoms suspicious for the disease. In addition, testing for mutations associated with LGMD may be considered medically necessary to identify a mutation in an at-risk family member of a proband/index case when the results of testing may confirm or exclude the need for cardiac surveillance or inform reproductive decision making.37-70

Ongoing and Unpublished Clinical Trials A search of ClinicalTrials.gov found some trials that may relate to this policy listed in Table 1.

Table 1. Clinical trials for muscular dystrophies Genetic

NCT No.

Trial Name

disorder

Planned

Completion

Enrollment

Date

80

Dec 2019

DMD/BMD NCT02780492

Developing Tools for Assessing the Natural History of Ambulant and Nonambulant DMD Individuals to Assist in Antisense-oligomer Clinical Trials Page | 12 of 21

Genetic

NCT No.

Trial Name

disorder

Planned

Completion

Enrollment

Date

50

Aug 2018

100

Oct 2016

154

Jul 2018

FSHD NCT01437345

A Multicenter Collaborative Study on the Clinical Features, Expression Profiling, and Quality of Life of Infantile Onset Facioscapulohumeral Muscular Dystrophy

NCT01970735

Clinical, Genetic and Epigenetic Characterization of Patients With FSHD Type 1/FSHD Type 2

LGMD NCT02810028

Acceptance and Commitment Therapy for Muscle Disease

Practice Guidelines and Position Statements

DMD/BMD Consensus Best Practice Guidelines for Diagnosis of DMD/BMD A meeting of 29 senior scientists from the United States, Europe, India, and Australia established consensus Best Practice Guidelines for the molecular diagnosis of DMD/BMD. Recommendations for testing are: 

If there is a clinical suspicion of a dystrophinopathy, first screen for deletions and duplications.



If no deletion or duplication is detected, but the clinical diagnosis is verified, screening for point mutations should be performed.8

Recommendations from consensus Best Practice Guidelines for molecular diagnosis of DMD/BMD indicate that testing of an affected male (the index case) be performed so that carrier testing in female relatives at risk can focus on the mutation found in the affected family member.

Page | 13 of 21

FSHD European Neuromuscular Centre International In a report from the 171st European Neuromuscular Centre International Workshop Standards of Care and Management of FSHD held in January 2010, it is stated that when a physician concludes facioscapulohumeral syndrome based on clinical findings, the odds are in favor of FSHD, and genetic testing is the preferred diagnostic choice.33

American Academy of Neurology In 2015, the American Academy of Neurology published an evidence-based guideline summary for evaluation, diagnosis and management of facioscapulohumeral muscular dystrophy.

34

They

made the statement that at present, commercial genetic testing in FSHD is limited to FSHD1 testing and available genetic testing for FSHD type 1 is highly sensitive and specific. Their recommendations include the following: 

When clinical presentation of FSHD is typical and the inheritance pattern is consistent with autosomal dominant inheritance, clinical diagnosis is usually straightforward. If, in such circumstances, the diagnosis is genetically confirmed in a first-degree relative, genetic testing is not necessary for each affected individual.



In the setting of atypical or sporadic cases, genetic confirmation is important for genetic counseling, especially with the recent discovery of two genetically distinct forms of FSHD. o

Clinicians should obtain genetic confirmation of FSHD1 in patients with atypical presentations and no first-degree relatives with genetic confirmation of the disease (Level B).

LGMD American Academy of Neurology In 2014, the American Academy of Neurology and the Practices Issues review Panel of the American Association of Neuromuscular and Electrodiagnostic Medicine issued evidencedbased guidelines for the diagnosis and treatment of limb-girdle and distal dystrophies, with the following recommendations37: For the diagnosis of LGMD: Page | 14 of 21



For patients with suspected muscular dystrophy, it is recommended that clinicians use a clinical approach to guide genetic diagnosis based on the clinical phenotype, including the pattern of muscle involvement, inheritance pattern, age at onset, and associated manifestations (e.g., early contractures, cardiac or respiratory involvement) (Level B recommendation).



For patients with suspected muscular dystrophy when the initial clinically directed genetic testing does not provide a diagnosis, the recommendation is that clinicians obtain genetic consultation or perform parallel sequencing of targeted exomes, whole-exome sequencing, whole genome screening, or next-generation sequencing to identify the genetic abnormality (Level C recommendation).

For the management of cardiac complications in LGMD: 

Clinicians should refer newly diagnosed patients with (1) LGMD1A, LGMD1B, LGMD1D, LGMD1E, LGMD2C–K, LGMD2M–P or (2) muscular dystrophy without a specific genetic diagnosis for cardiology evaluation, including ECG and structural evaluation (echocardiography or cardiac MRI), even if they are asymptomatic from a cardiac standpoint, to guide appropriate management (Level B recommendation).



If ECG or structural cardiac evaluation (e.g., echocardiography) has abnormal results, or if the patient has episodes of syncope, near-syncope, or palpitations, clinicians should order rhythm evaluation (e.g., Holter monitor or event monitor) to guide appropriate management (Level B recommendation).



Clinicians should refer muscular dystrophy patients with palpitations, symptomatic or asymptomatic tachycardia or arrhythmias, or signs and symptoms of cardiac failure for cardiology evaluation (Level B).



It is not obligatory for clinicians to refer patients with LGMD2A, LGMD2B, and LGMD2L for cardiac evaluation unless they develop overt cardiac signs or symptoms (Level B recommendation).

For the management of respiratory complications in LGMD: 

Clinicians should order pulmonary function testing (spirometry and maximal inspiratory/ expiratory force in the upright and, if normal, supine positions) or refer for pulmonary evaluation (to identify and treat respiratory insufficiency) in muscular dystrophy patients at the time of diagnosis, or if they develop pulmonary symptoms later in their course (Level B recommendation).



In patients with a known high risk of respiratory failure (e.g., those with LGMD2I), clinicians should obtain periodic pulmonary function testing (spirometry and maximal Page | 15 of 21

inspiratory/expiratory force in the upright position and, if normal, in the supine position) or evaluation by a pulmonologist to identify and treat respiratory insufficiency (Level B recommendation). 

It is not mandatory for clinicians to refer patients with LGMD2B and LGMD2L for pulmonary evaluation unless they are symptomatic (Level C recommendation).



Clinicians should refer muscular dystrophy patients with excessive daytime somnolence, nonrestorative sleep (e.g., frequent nocturnal arousals, morning headaches, excessive daytime fatigue), or respiratory insufficiency based on pulmonary function tests for pulmonary or sleep medicine consultation for consideration of noninvasive ventilation to improve quality of life (Level B recommendation).

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 Amendments (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.

∞ References

1.

Verma S, Anziska Y, Cracco J. Review of Duchenne muscular dystrophy (DMD) for the pediatricians in the community. Clin Pediatr (Phila). Nov 2010;49(11):1011-1017. PMID 20724320

2.

Kalman L, Leonard J, Gerry N, et al. Quality assurance for Duchenne and Becker muscular dystrophy genetic testing: development of a genomic DNA reference material panel. J Mol Diagn. Mar 2011;13(2):167-174. PMID 21354051

Page | 16 of 21

3.

Darras BT, Miller DT, Urion DK. Dystrophinopathies. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA) 2014. https://www.ncbi.nlm.nih.gov/books/NBK1119/ Accessed December 2016.

4.

Yoon J, Kim SH, Ki CS, et al. Carrier woman of Duchenne muscular dystrophy mimicking inflammatory myositis. J Korean Med Sci. Apr 2011;26(4):587-591. PMID 21468271

5.

Soltanzadeh P, Friez MJ, Dunn D, et al. Clinical and genetic characterization of manifesting carriers of DMD mutations. Neuromuscul Disord. Aug 2010;20(8):499-504. PMID 20630757

6.

Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. Jan 2010;9(1):77-93. PMID 19945913

7.

Mah JK, Selby K, Campbell C, et al. A population-based study of dystrophin mutations in Canada. Can J Neurol Sci. May 2011;38(3):465-474. PMID 21515508

8.

Abbs S, Tuffery-Giraud S, Bakker E, et al. Best practice guidelines on molecular diagnostics in Duchenne/Becker muscular dystrophies. Neuromuscul Disord. Jun 2010;20(6):422-427. PMID 20466545

9.

Laing NG. Genetics of neuromuscular disorders. Crit Rev Clin Lab Sci. Mar-Apr 2012;49(2):33-48. PMID 22468856

10. Koo T, Wood MJ. Clinical trials using antisense oligonucleotides in Duchene muscular dystrophy. Hum Gene Ther. May 2013;24(5):479-488. PMID 23521559 11. Bowles DE, McPhee SW, Li C, et al. Phase 1 gene therapy for Duchenne muscular dystrophy using a translational optimized AAV vector. Mol Ther. Feb 2012;20(2):443-455. PMID 22068425 12. Takeshima Y, Yagi M, Okizuka Y, et al. Mutation spectrum of the dystrophin gene in 442 Duchenne/Becker muscular dystrophy cases from one Japanese referral center. J Hum Genet. Jun 2010;55(6):379-388. PMID 20485447 13. Chen WJ, Lin QF, Zhang QJ, et al. Molecular analysis of the dystrophin gene in 407 Chinese patients with Duchenne/Becker muscular dystrophy by the combination of multiplex ligation-dependent probe amplification and Sanger sequencing. Clin Chim Acta. Aug 23 2013;423:35-38. PMID 23588064 14. Sansovic I, Barisic I, Dumic K. Improved detection of deletions and duplications in the DMD gene using the multiplex ligation-dependent probe amplification (MLPA) method. Biochem Genet. Apr 2013;51(3-4):189-201. PMID 23224783 15. Yang J, Li SY, Li YQ, et al. MLPA-based genotype-phenotype analysis in 1053 Chinese patients with DMD/BMD. BMC Med Genet. 2013;14:29. PMID 23453023 16. Wang Y, Yang Y, Liu J, et al. Whole dystrophin gene analysis by next-generation sequencing: a comprehensive genetic diagnosis of Duchenne and Becker muscular dystrophy. Mol Genet Genomics. Oct 2014;289(5):1013-1021. PMID 24770780 17. Ishizaki M, Fujimoto A, Ueyama H, et al. Life-threatening Arrhythmias in a Becker Muscular Dystrophy Family due to the Duplication of Exons 3-4 of the Dystrophin Gene. Intern Med. 2015;54(23):3075-3078. PMID 26631896 18. Palazzolo G, Quattrocelli M, Toelen J, et al. Cardiac Niche Influences the Direct Reprogramming of Canine Fibroblasts into Cardiomyocyte-Like Cells. Stem Cells Int. 2016;2016:4969430. PMID 26681949 19. Aartsma-Rus A, Van Deutekom JC, Fokkema IF, et al. Entries in the Leiden Duchenne muscular dystrophy mutation database: an overview of mutation types and paradoxical cases that confirm the reading-frame rule. Muscle Nerve. Aug 2006;34(2):135-144. PMID 16770791 20. Blue Cross-and Blue Shield Association. Genetic Testing for Duchenne and Becker Muscular Dystrophy. Medical Policy Reference Manual. Policy 2.04.86, 2016. 21. van der Maarel SM, Tawil R, Tapscott SJ. Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence. Trends Mol Med. May 2011; 17(5):252-258. PMID 21288772 22. Menezes MP, North KN. Inherited neuromuscular disorders: pathway to diagnosis. J Paediatr Child Health. Jun 2012; 48(6):458-465. PMID 22050238 23. Lemmers R, Miller DG, van der Maarel SM. Facioscapulohumeral Muscular Dystrophy. In: Pagon RA, Adam MP, Bird TD, et al., eds. GeneReviews. Seattle (WA) 2014.

Page | 17 of 21

https://www.ncbi.nlm.nih.gov/books/NBK1116/?term=Facioscapulohumeral+Muscular+Dystrophy Accessed December 2016. 24. Pastorello E, Cao M, Trevisan CP. Atypical onset in a series of 122 cases with FacioScapuloHumeral Muscular Dystrophy. Clin Neurol Neurosurg. Apr 2012; 114(3):230-234. PMID 22079131 25. Hassan A, Jones LK, Jr., Milone M, et al. Focal and other unusual presentations of facioscapulohumeral muscular dystrophy. Muscle Nerve. Sep 2012; 46(3):421-425. PMID 22907234 26. Lemmers RJ, Tawil R, Petek LM, et al. Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet. Dec 2012;44(12):1370-1374. PMID 23143600 27. Sacconi S, Lemmers RJ, Balog J, et al. The FSHD2 gene SMCHD1 is a modifier of disease severity in families affected by FSHD1. Am J Hum Genet. Oct 3 2013;93(4):744-751. PMID 24075187 28. National Center for Biotechnology Information (NCBI). GTR:Facioscapulohumeral Muscular Dystrophy. 2014; http://www.ncbi.nlm.nih.gov/gtr/tests/219919/#performance-characteristics Accessed December 2016. 29. University of Iowa Diagnostic Laboratories (UIDL). Facioscapulohumeral Information. 2008; http://www.healthcare.uiowa.edu/path_handbook/Appendix/Micro/fshd.html Accessed December 2016. 30. Ricci G, Scionti I, Sera F, et al. Large scale genotype-phenotype analyses indicate that novel prognostic tools are required for families with facioscapulohumeral muscular dystrophy. Brain. Nov 2013;136(Pt 11):3408-3417. PMID 24030947 31. Lutz KL, Holte L, Kliethermes SA, et al. Clinical and genetic features of hearing loss in facioscapulohumeral muscular dystrophy. Neurology. Oct 15 2013;81(16):1374-1377. PMID 24042093 32. Statland JM, Tawil R. Risk of functional impairment in Facioscapulohumeral muscular dystrophy. Muscle Nerve. Apr 2014;49(4):520-527. PMID 23873337 33. Tawil R, van der Maarel S, Padberg GW, et al. 171st ENMC international workshop: Standards of care and management of facioscapulohumeral muscular dystrophy. Neuromuscul Disord. Jul 2010; 20(7):471-475. PMID 20554202 34. Tawil R, Kissel JT, Heatwole C, et al. Evidence-based guideline summary: Evaluation, diagnosis, and management of facioscapulohumeral muscular dystrophy. Neurology. 2015 Jul 28;85(4):351-364. PMID 26215877 35. Lemmers RJ, O'Shea S, Padberg GW, et al. Best practice guidelines on genetic diagnostics of Facioscapulohumeral muscular dystrophy: workshop 9th June 2010, LUMC, Leiden, The Netherlands. Neuromuscul Disord. May 2012;22(5):463470. PMID 22177830 36. Blue Cross and Blue Shield Association. Genetic Testing for Facioscapulohumeral Muscular Dystrophy. Medical Policy Reference Manual. Policy 2.04.105, 2015. 37. Narayanaswami P, Weiss M, Selcen D, et al. Evidence-based guideline summary: diagnosis and treatment of limb-girdle and distal dystrophies: report of the guideline development subcommittee of the American Academy of Neurology and the practice issues review panel of the American Association of Neuromuscular & Electrodiagnostic Medicine. Neurology. Oct 14 2014;83(16):1453-1463. PMID 25313375 38. Nigro V, Savarese M. Genetic basis of limb-girdle muscular dystrophies: the 2014 update. Acta Myol. May 2014;33(1):1-12. PMID 24843229 39. Norwood F, de Visser M, Eymard B, et al. EFNS guideline on diagnosis and management of limb girdle muscular dystrophies. Eur J Neurol. Dec 2007;14(12):1305-1312. PMID 18028188 40. Mahmood OA, Jiang XM. Limb-girdle muscular dystrophies: where next after six decades from the first proposal (Review). Mol Med Rep. May 2014;9(5):1515-1532. PMID 24626787 41. Nigro V, Aurino S, Piluso G. Limb girdle muscular dystrophies: update on genetic diagnosis and therapeutic approaches. Curr Opin Neurol. Oct 2011;24(5):429-436. PMID 21825984 42. Pegoraro E, Hoffman EP. Limb-Girdle Muscular Dystrophy Overview. In: Pagon RA, Adam MP, H.H. A, eds. GeneReviews. Seattle, WA: National Library of Medicine, NCBI Bookshelf; 2012.

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43. Moore SA, Shilling CJ, Westra S, et al. Limb-girdle muscular dystrophy in the United States. J Neuropathol Exp Neurol. Oct 2006;65(10):995-1003. PMID 17021404 44. Menezes MP, Waddell LB, Evesson FJ, et al. Importance and challenge of making an early diagnosis in LMNA-related muscular dystrophy. Neurology. Apr 17 2012;78(16):1258-1263. PMID 22491857 45. Stramare R, Beltrame V, Dal Borgo R, et al. MRI in the assessment of muscular pathology: a comparison between limbgirdle muscular dystrophies, hyaline body myopathies and myotonic dystrophies. Radiol Med. Jun 2010;115(4):585-599. PMID 20177980 46. ten Dam L, van der Kooi AJ, van Wattingen M, et al. Reliability and accuracy of skeletal muscle imaging in limb-girdle muscular dystrophies. Neurology. Oct 16 2012;79(16):1716-1723. PMID 23035061 and updates under PMID 23751921 47. Rocha CT, Hoffman EP. Limb-girdle and congenital muscular dystrophies: current diagnostics, management, and emerging technologies. Curr Neurol Neurosci Rep. Jul 2010;10(4):267-276. PMID 20467841 48. Ankala A, Nallamilli BR, Rufibach LE, et al. Diagnostic overview of blood-based dysferlin protein assay for dysferlinopathies. Muscle Nerve. Sep 2014;50(3):333-339. PMID 24488599 49. Walter MC, Reilich P, Thiele S, et al. Treatment of dysferlinopathy with deflazacort: a double-blind, placebo-controlled clinical trial. Orphanet J Rare Dis. 2013;8:26. PMID 23406536 50. Sharma A, Sane H, Badhe P, et al. A clinical study shows safety and efficacy of autologous bone marrow mononuclear cell therapy to improve quality of life in muscular dystrophy patients. Cell Transplant. 2013;22 Suppl 1:S127-138. PMID 24070109 51. Herson S, Hentati F, Rigolet A, et al. A phase I trial of adeno-associated virus serotype 1-gamma-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C. Brain. Feb 2012;135(Pt 2):483-492. PMID 22240777 52. GeneDx. Information Sheet on Limb Girdle Muscular Dystrophy Panel 2014; http://www.genedx.com/wpcontent/uploads/2014/12/info_sheet_LGMD.pdf Accessed December 2016. 53. PreventionGenetics. Autosomal Dominant Limb Girdle Muscular Dystrophy (LGMD) Sanger Sequencing Panel. 2014; https://www.preventiongenetics.com/testInfo.php?sel=test&val=Autosomal+Dominant+Limb+Girdle+Muscular+ Dystrophy+%28LGMD%29+Sequencing+Panel Accessed December 2016. 54. PreventionGenetics. Autosomal Recessive Limb Girdle Muscular Dystrophy (LGMD) Sanger Sequencing Panel. 2014; https://www.preventiongenetics.com/testInfo.php?sel=test&val=Autosomal+Recessive+Limb+Girdle+Muscular+ Dystrophy+%28LGMD%29+Sequencing+Panel Accessed October 2016. 55. Centogene. Factsheet: LGMD Panel. 2015; http://www.centogene.com/centogene/index.php?LGMD Accessed December 2016. 56. Limb-Girdle Muscular Dystrophy Sequencing Panel; GTR test ID GTR000506322.3. GTR: Genetic Testing Registry http://www.ncbi.nlm.nih.gov/gtr/tests/506322/overview/ Accessed December 2016. 57. Piluso G, Dionisi M, Del Vecchio Blanco F, et al. Motor chip: a comparative genomic hybridization microarray for copynumber mutations in 245 neuromuscular disorders. Clin Chem. Nov 2011;57(11):1584-1596. PMID 21896784 58. Norwood FL, Harling C, Chinnery PF, et al. Prevalence of genetic muscle disease in Northern England: in-depth analysis of a muscle clinic population. Brain. Nov 2009;132(Pt 11):3175-3186. PMID 19767415 59. Maggi L, D'Amico A, Pini A, et al. LMNA-associated myopathies: the Italian experience in a large cohort of patients. Neurology. Oct 28 2014;83(18):1634-1644. PMID 25274841 60. Sarkozy A, Hicks D, Hudson J, et al. ANO5 gene analysis in a large cohort of patients with anoctaminopathy: confirmation of male prevalence and high occurrence of the common exon 5 gene mutation. Hum Mutat. Aug 2013;34(8):1111-1118. PMID 23606453 61. Ghosh PS, Zhou L. The diagnostic utility of a commercial limb-girdle muscular dystrophy gene test panel. J Clin Neuromuscul Dis. Dec 2012;14(2):86-87. PMID 23172390

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62. Fanin M, Nascimbeni AC, Aurino S, et al. Frequency of LGMD gene mutations in Italian patients with distinct clinical phenotypes. Neurology. Apr 21 2009;72(16):1432-1435. PMID 19380703 63. Guglieri M, Magri F, D'Angelo MG, et al. Clinical, molecular, and protein correlations in a large sample of genetically diagnosed Italian limb girdle muscular dystrophy patients. Hum Mutat. Feb 2008;29(2):258-266. PMID 17994539 64. Krahn M, Beroud C, Labelle V, et al. Analysis of the DYSF mutational spectrum in a large cohort of patients. Hum Mutat. Feb 2009;30(2):E345-375. PMID 18853459 65. Bartoli M, Desvignes JP, Nicolas L, et al. Exome sequencing as a second-tier diagnostic approach for clinically suspected dysferlinopathy patients. Muscle Nerve. Dec 2014;50(6):1007-1010. PMID 25046369 66. Finsterer J, Stollberger C, Keller H. Arrhythmia-related workup in hereditary myopathies. J Electrocardiol. Jul-Aug 2012;45(4):376-384. PMID 22424849 67. Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities. J Am Coll Cardiol. 2013 Jan 22;61(3); e6-75. PMID 23265327 68. Groh WJ. Arrhythmias in the muscular dystrophies. Heart Rhythm. Nov 2012;9(11):1890-1895. PMID 22760083 69. Murakami T, Hayashi YK, Noguchi S, et al. Fukutin gene mutations cause dilated cardiomyopathy with minimal muscle weakness. Ann Neurol. Nov 2006;60(5):597-602. PMID 17036286 70. Blue Cross and Blue Shield Association. Genetic Testing for Genetic Testing for Duchenne and Becker Muscular Dystrophy. Medical Policy Reference Manual. Policy 2.04.86, 2016. 71. Blue Cross and Blue Shield Association. Genetic Testing for Facioscapulohumeral Muscular Dystrophy. Medical Policy Reference Manual. Policy 2.04.105, 2015. 72. Blue Cross and Blue Shield Association. Mutation Testing for Limb-Girdle Muscular Dystrophies. Medical Policy Reference Manual. Policy 2.04.132, 2015.

∞ History

Date

Comments

05/28/13

New policy. Policy created with literature search through January 3, 2013. Medically necessary to establish a diagnosis in a male with clinical signs and symptoms suggestive of a dystrophinopathy and in at-risk female relatives.

06/13/14

Annual Review. Policy updated with literature review through January 29, 2014. No change to policy statement. References 11, 14, 17, and 18 added.

07/23/14

Update Related Policies. Remove 12.04.91.

05/27/15

Annual Review. Policy updated with literature review through February 23, 2015; references 19-21 added; reference 19 deleted. Policy statements unchanged. Language added to Benefit Application regarding testing index patient/case. Phrase “index patient” substituted for “proband.” ICD-9 diagnosis codes 783.9 and V26.31 removed; they are not specific to the policy. Page | 20 of 21

Date

Comments

09/01/15

Update Related Policies. Add 12.04.132.

05/10/16

Annual Review. Policy updated with literature review through January 28, 2016; no references added. Policy statements unchanged.

12/13/16

Interim Update. Combined content from policies 12.04.86, 12.04.105, 12.04.132 into this one policy document. Title changed. Genetic testing for the muscular dystrophies detailed in this policy may be considered medically necessary when criteria are met. No change to policy statements. References older than 2006 were removed. Removed CPT code 81161. Moved policy to new format.

∞ 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. 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.



Page | 21 of 21

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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).

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