Genetic Testing for Duchenne and Becker Muscular Dystrophy Form

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 01|01|2024 POLICY LAST REVIEWED: 03|19|2025 OVERVIEW Variants in the Duchenne muscular dystrophy (DMD) gene, which encodes the protein dystrophin, may result in a spectrum of X-linked muscle diseases, including the progressive diseases Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) and dilated cardiomyopathy. Genetic testing can confirm a diagnosis of a dystrophinopathy and distinguish the less from more severe forms, as well as identify female carriers at risk. This policy addresses the following test(s): • Genomic Unity® DMD Analysis (Variantyx Inc) CPT code 0218U MEDICAL CRITERIA Medicare Advantage Plans and Commercial Products Genetic Testing for DMD gene variants may be considered medically necessary under the following conditions: • In a male with signs and symptoms of a dystrophinopathy in order to confirm the diagnosis and direct treatment. • For at-risk female relatives o To confirm or exclude the need for cardiac surveillance. o For preconception testing to determine the likelihood of an affected offspring in a woman considering pregnancy. At-risk females are defined as first- and second-degree female relatives and include the proband’s mother, female siblings of the proband, female offspring of the proband, the proband’s maternal grandmother, maternal aunts, and their offspring. • For at-risk male offspring o To confirm or exclude the need for medical cardiac surveillance. An at-risk male is defined as an asymptomatic male offspring of a female carrier or an asymptomatic male sibling of an individual with a DMD-associated dystrophinopathy PRIOR AUTHORIZATION Medicare Advantage Plans and Commercial Products Prior authorization is required for Medicare Advantage Plans and recommended for Commercial Products and is obtained via the online tool for participating providers. See Related Policies section.
Note: Laboratories are not allowed to obtain clinical authorization or participate in the authorization process on behalf of the ordering physician. Only the ordering physician shall be involved in the authorization, appeal or other administrative processes related to prior authorization/medical necessity.
In no circumstance shall a laboratory or a physician/provider use a representative of a laboratory or anyone with a relationship to a laboratory and/or a third party to obtain authorization on behalf of the ordering physician, to facilitate any portion of the authorization process or any subsequent appeal of a claim where the Medical Coverage Policy | Genetic Testing for Duchenne and Becker Muscular Dystrophy

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authorization process was not followed and/or a denial for clinical appropriateness was issued, including any element of the preparation of necessary documentation of clinical appropriateness. If a laboratory or a third party is found to be supporting any portion of the authorization process, BCBSRI will deem the action a violation of this policy and severe action will be taken up to and including termination from the BCBSRI provider network. If a laboratory provides a laboratory service that has not been authorized, the service will be denied as the financial liability of the participating laboratory and may not be billed to the member.

POLICY STATEMENT Medicare Advantage Plans and Commercial Products Genetic testing for DMD gene variants may be considered medically necessary for Medicare Advantage Plans and Commercial Products when the above criteria are met.

Genetic testing for DMD gene variants in all other situations is considered not covered for Medicare Advantage Plans and not medically necessary for Commercial Products.

Commercial Products
Some genetic testing services are not covered and a contract exclusion for any self-funded group that has excluded the expanded coverage of biomarker testing related to the state mandate, R.I.G.L. §27-19-81 described in the Biomarker Testing Mandate policy. For these groups, a list of which genetic testing services are covered with prior authorization, are not medically necessary or are not covered because they are a contract exclusion can be found in the Coding section of the Genetic Testing Services or Proprietary Laboratory Analyses policies. Please refer to the appropriate Benefit Booklet to determine whether the member’s plan has customized benefit coverage. Please refer to the list of Related Policies for more information.

COVERAGE Benefits may vary between groups and contracts. Please refer to the appropriate section of the Benefit Booklet, Evidence of Coverage, or Subscriber Agreement for applicable laboratory testing and not medically necessary/not covered benefits/coverage.

BACKGROUND Dystrophinopathies
The dystrophinopathies include a spectrum of muscle diseases. The mild end of the spectrum includes asymptomatic increases in serum concentration of creatine phosphokinase and clinical symptoms such as muscle cramps with myoglobinuria and/or isolated quadriceps myopathy. The severe end of the spectrum includes progressive muscle diseases that lead to substantial morbidity and mortality. When skeletal muscle is primarily affected, the disease is classified as Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD); when the heart is primarily affected, the disease is classified as DMD-associated dilated cardiomyopathy (left ventricular dilation and heart failure).

Duchenne Muscular Dystrophy
DMD, the most common muscular dystrophy, is a severe childhood X-linked recessive disorder that results in significant disability due to skeletal myopathy and cardiomyopathy. The disease is characterized by progressive, symmetric muscle weakness and gait disturbance resulting from a defective dystrophin gene. According to a 2022 systematic review and meta-analysis, the global prevalence of DMD is estimated at 4.8 cases (95% confidence interval [CI], 3.6 to 6.3) per 100,000 people. Approximately one-third of DMD cases arise from de novo variants and have no known family history. Infant males with DMD are often asymptomatic. Manifestations may be present as early as the first year of life in some individuals, but clinical manifestations most often appear during preschool, from years 2 to 5. Affected children present with gait problems, calf hypertrophy, positive Gower sign, and difficulty climbing stairs. The affected child’s motor status may plateau between 3 and 6 years of life with deterioration beginning at 6 to 8 years. Most individuals will be wheelchair-bound by ages 9 to 12 years but will retain preserved upper-limb function until a later period. Cardiomyopathy occurs after 18 years of age. Late complications are cardiorespiratory (eg, decreased pulmonary function as a result of respiratory muscle weakness and cardiomyopathy). These severe

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complications commonly appear in the second decade of life and eventually lead to death. Few individuals with DMD survive beyond the third decade.

Becker Muscular Dystrophy
BMD is characterized by later onset skeletal muscle weakness. Individuals remain ambulatory into their 20s. Despite the milder skeletal muscle involvement, heart failure from cardiomyopathy is a common cause of morbidity and the most common cause of death in these individuals, with a mean age of death in the mid-40s. According to a 2022 systematic review and meta-analysis, the global prevalence of BMD is estimated at 1.6 cases (95% CI, 1.1 to 2.4) per 100,000 people.

Female Carriers
Females heterozygous for a DMD disease-associated variant can manifest symptoms of the disease. An estimated 2.5% to 7.8% of female carriers are manifesting carriers who develop symptoms ranging from mild muscle weakness to a rapidly progressive DMD-like muscular dystrophy. Female carriers are at increased risk for dilated cardiomyopathy and need routine cardiac surveillance and treatment. Most heterozygous women do not show severe myopathic features of DMD, possibly due to compensation by a normal X chromosome with inactivation of the mutated DMD gene in the affected X chromosome. In some cases, this compensation can be reversed by a nonrandom or skewed inactivation of the X chromosome, resulting in greater expression of the affected X chromosome and some degree of myopathic features. Other mechanisms of manifesting female carriers include X chromosome rearrangement involving the DMD gene and complete or partial absence of the X chromosome (Turner syndrome).

Clinical Diagnosis Duchenne Muscular Dystrophy
Suspicion of DMD should be considered irrespective of family history; it is most commonly triggered by the observation of abnormal muscle function in a male child, the detection of an increase in serum creatine kinase tested for unrelated indications, or detection of increased serum transaminases (aspartate aminotransferase and alanine aminotransferases). Clinical examination by a neuromuscular specialist for DMD includes visual inspection of mechanical function such as running, jumping, climbing stairs, and getting up from the floor. Common presenting symptoms include abnormal gait with frequent falls, difficulties rising from the floor or tip-toe walking, and pseudohypertrophy of the calves. A clinical examination may reveal decreased or lost muscle reflexes and, commonly, a positive Gower sign. An elevation of serum creatine kinase, at least 10 to 20 times normal levels (between 5000 IU/L and 150000 IU/L), is nonspecific to DMD but is always present in affected individuals. Electromyography and nerve conduction studies were traditional parts of the assessment of neuromuscular disorders, but these tests may not be necessary for assessment of DMD. An open skeletal muscle biopsy is needed when a test for deletions or duplications of the DMD gene is negative. The biopsy will provide general signs of muscular dystrophy, including muscle fiber degeneration, muscle regeneration, and increased content of connective tissue and fat. Dystrophin analysis of a muscle biopsy will always be abnormal in affected individuals but is not specific to DMD.

Becker Muscular Dystrophy BMD is clinically similar to DMD but is milder and has a later onset. BMD presents with progressive symmetric muscle weakness, often with calf hypertrophy, although the weakness of quadriceps femoris may be the only sign. Activity-induced cramping may be present in some individuals, and flexion contractures of the elbows may be present late in the course. Neck flexor muscle strength is preserved, which differentiates BMD from DMD. Serum creatine kinase shows moderate-to-severe elevation (5 to 100 times the normal level).

Molecular Diagnosis DMD is the only gene of which variants are known to cause DMD, BMD, and DMD-associated cardiomyopathy. Molecular genetic testing of DMD can establish the diagnosis of a dystrophinopathy without muscle biopsy in most individuals with DMD and BMD.

The dystrophinopathies are X-linked recessive and penetrance is complete in males. The gene that codes for dystrophin is the largest known human gene. A molecular confirmation of DMD and BMD is achieved by

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confirming the presence of a pathogenic variant in this gene by a number of available assays. The large size of the dystrophin gene results in a complex variant spectrum with over 5000 reported disease-associated variants, as well as a high spontaneous de novo variant rate.

Treatment There is no cure for DMD or BMD. Treatment is aimed at controlling symptoms to improve quality of life. However, the natural history of the disease can be changed by strategies such as corticosteroid therapy, proper nutrition, or rehabilitative interventions. Glucocorticoids were shown in a 1991 randomized controlled trial (RCT) to prolong the period of independent ambulation by 3 years. The goal of this therapy is to preserve ambulation and minimize later respiratory, cardiac, and orthopedic complications. Glucocorticoids work by decreasing inflammation, preventing fibrosis, improving muscle regeneration, improving mitochondrial function, decreasing oxidative radicals, and stopping abnormal apoptosis pathways. Bone density measurement and immunization are prerequisites for corticosteroid therapy initiation, which typically begins at 2 to 5 years of age, although there has been no demonstrated benefit of therapy before 5 years of age.

New therapeutic trials require accurate diagnoses of these disorders, especially when the therapy is targeted at specific pathogenic variants. Exon-skipping is a molecular therapy aimed at skipping the transcription of a targeted exon to restore a correct reading frame using antisense oligonucleotides. Exon-skipping may result in a DMD protein without the mutated exon and a normal, nonshifted reading frame. Exon-skipping may also restore DMD protein function so that the treated individual’s phenotypic expression more closely resembles BMD. Several therapies are currently in clinical trials. Exon-skipping therapies using antisense oligonucleotides approved by the U.S. Food and Drug Administration include: eteplirsen (Exondys 51) for treatment for individuals who have a confirmed variant of the dystrophin gene amenable to exon 51 skipping, golodirsen (Vyondys 53), and viltolarsen (Viltepso) for individuals who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping. These approvals were based on improvements in the surrogate outcome of increased dystrophin production in skeletal muscle and benefits in clinical outcomes have not yet been established.

A gene therapy, delandistrogene moxeparvovec-rokl (Elevidys), was also approved in 2023 to treat ambulatory children 4 to 5years of age with DMD and a confirmed mutation in the DMD gene.

Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer laboratory-developed tests must be licensed by the 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.

For individuals who are male and have signs and symptoms of a dystrophinopathy who receive genetic testing for Duchenne muscular dystrophy (DMD) gene variants to confirm diagnosis without biopsy, the evidence includes case series and database entries describing screening and results of types of variants found in individuals with clinical signs of DMD or 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. Virtually all males with DMD or BMD have identifiable DMD disease-associated variants, indicating a high clinical sensitivity for genetic testing. The 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 that the technology results in an improvement in the net health outcome

For individuals who are female and are a relative of an individual with a DMD-associated dystrophinopathy who receive targeted DMD testing for a known familial variant to determine carrier status, the evidence includes case series and database entries describing screening and results of types of variants found in individuals with clinical signs of DMD or BMD. Relevant outcomes are test accuracy and validity, changes in

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reproductive decision making, symptoms, change in disease status, morbid events, quality of life, medication use, and resource utilization. Published data for the clinical validity for testing for a known familial variant are lacking but validity is expected to be high. Direct evidence on the clinical utility of DMD gene testing in at- risk female relatives is lacking. However, the chain of evidence is strong, because determination of carrier status in a female for a DMD familial variant 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 that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic male offspring of a female DMD familial variant carrier or an asymptomatic male sibling of an individual with a DMD-associated dystrophinopathy who receive targeted DMD testing for a known familial variant to determine DMD status, the evidence includes case series and database entries. Relevant outcomes are test accuracy and validity, symptoms, change in disease status, morbid events, quality of life, medication use, and resource utilization. Published data for clinical validity of testing for a known familial variant are lacking, but validity is expected to be high. Direct evidence on the clinical utility of DMD gene testing in asymptomatic male offspring of a female DMD familial variant carrier or male sibling of an individual with a DMD-associated dystrophinopathy is also lacking. However, the chain of evidence is strong, because detection of the DMD familial variant necessitates or eliminates the need for increased medical surveillance or cardiac surveillance in an asymptomatic male offspring of a female carrier or the asymptomatic male sibling of an individual with a DMD-associated dystrophinopathy. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

CODING Medicare Advantage Plans and Commercial Products The following CPT code is medically necessary for Medicare Advantage Plans and Commercial Products when the medical criteria above is met;

The following code(s) can be used for Genomic Unity® DMD Analysis; 0218U Neurology (muscular dystrophy), DMD gene sequence analysis, including small sequence changes, deletions, duplications, and variants in non-uniquely mappable regions, blood or saliva, identification and characterization of genetic variants.

RELATED POLICIES Biomarker Testing Mandate
Proprietary Laboratory Analysis (PLA)

PUBLISHED Provider Update, May 2025 Provider Update, September 2024 Provider Update, November 2023

REFERENCES

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2. Salari N, Fatahi B, Valipour E, et al. Global prevalence of Duchenne and Becker muscular dystrophy: a systematic review and meta-analysis. J Orthop Surg Res. Feb 15 2022; 17(1): 96. PMID 35168641
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500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 6 (401) 274-4848 WWW.BCBSRI.COM

8. 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-
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13. Griggs RC, Moxley RT, Mendell JR, et al. Prednisone in Duchenne dystrophy. A randomized, controlled trial defining the time course and dose response. Clinical Investigation of Duchenne Dystrophy Group. Arch Neurol. Apr 1991; 48(4): 383-8. PMID 2012511
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15. Food and Drug Administration (FDA). FDA News Release: FDA grants accelerated approval to first drug for Duchenne muscular dystrophy. 2016; https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm521263.htm. Accessed January 21, 2025.
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18. Food and Drug Administration. VILTEPSO (viltolarsen) Prescribing Information. 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212154Orig1s000lbl.pdf. Accessed January 20, 2025.
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25. Fratter C, Dalgleish R, Allen SK, et al. EMQN best practice guidelines for genetic testing in dystrophinopathies. Eur J Hum Genet. Sep 2020; 28(9): 1141-1159. PMID 32424326

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