Genetic Testing for Mitochondrial Disorders 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: 11|19|2025 OVERVIEW Mitochondrial diseases 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 diseases. Genetic testing also has the potential to determine future risk of disease in individuals who have a close relative with a pathogenic variant. The following test(s) are addressed in this policy: • Genomic Unity® Comprehensive Mitochondrial Disorders Analysis (Variantyx, Inc.) CPT code 0417U • Nuclear encoded mitochondrial genes (eg, 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 – CPT code 81440 • 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 – CPT code 81460 • Whole mitochondrial genome large deletion analysis panel (eg, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia), including heteroplasmy detection, if performed – CPT code 81465 MEDICAL CRITERIA Medicare Advantage Plans and Commercial Products Genetic testing to establish a genetic diagnosis of a mitochondrial disorder may be considered medically necessary when signs and symptoms of a mitochondrial disorder are present and genetic testing may eliminate the need for muscle biopsy. Targeted genetic testing for a known familial variant in at-risk relatives may be considered medically necessary as preconceptional carrier testing under the following conditions: • There is a defined mitochondrial disorder in the family of sufficient severity to cause impairment of quality of life or functional status; AND • A variant that is known to be pathogenic for that specific mitochondrial disorder has been identified in the index case. PRIOR AUTHORIZATION
Medicare Advantage Plans and Commercial Products Prior authorization is required for Medicare Advantage Plans and recommended for Commercial Products. 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.
Medical Coverage Policy | Genetic Testing for Mitochondrial Disorders

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 2 (401) 274-4848 WWW.BCBSRI.COM

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 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 The following tests may be considered medically necessary when the medical criteria above have been met: • Genomic Unity® Comprehensive Mitochondrial Disorders Analysis – CPT code 0417U • Nuclear encoded mitochondrial genes (eg, 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 – CPT code 81440 • 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 – CPT code 81460 • Whole mitochondrial genome large deletion analysis panel (eg, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia), including heteroplasmy detection, if performed – CPT code 81465

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 Benefit Booklet, Evidence of Coverage or Subscriber Agreement for applicable benefits/coverage.

BACKGROUND Mitochondrial DNA Mitochondria are organelles within each cell that contain their own set of DNA, distinct from the nuclear DNA (nDNA) 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. Additionally, there are over 1000 nuclear genes coding for proteins that support mitochondrial function. The protein products from these genes are produced in the nucleus and later migrate to the mitochondria.

Mitochondrial DNA differs from nDNA in several important ways. Inheritance of mtDNA does not follow traditional Mendelian patterns. Rather, mtDNA is inherited only from maternal DNA so disorders that result from variants in mtDNA can only be passed on by the mother. Also, there are thousands of copies of each

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 3 (401) 274-4848 WWW.BCBSRI.COM

mtDNA gene in each cell, as opposed to nDNA, which contains only 1 copy per cell. Because there are many copies of each gene, variants 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 variant ranging from 0% to 100%. Clinical expression of the variant will generally depend on a threshold effect (ie, clinical symptoms will begin to appear when the percentage of mutated genes exceeds a threshold amount).

Mitochondrial Diseases Primary mitochondrial diseases 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 diseases is at least 1 in 5000. Some specific mitochondrial diseases are listed next: • Mitochondrial encephalopathy with lactic acidosis and stroke-like symptoms (MELAS) syndrome; • Myoclon us epilepsy with ragged red fibers syndrome (MERFF); • Kearns-Sayre syndrome; • Leigh syndrome; • Chronic progressive external ophthalmoplegia (CPEO); • Leber hereditary optic neuropathy (LHON); • Neuropathy, 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 defined mitochondrial disease 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.

Diagnosis The diagnosis of mitochondrial diseases 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 a particular syndrome. Biochemical testing is indicated for patients who do not have a clear clinical picture of a specific disorder. Measurement of serum lactic acid is often used as a screening test but the test is neither sensitive nor specific for mitochondrial diseases. A muscle biopsy can be performed if the diagnosis is uncertain after biochemical workup. However, this invasive test is not definitive in all cases. The presence of "ragged red fibers" on histologic analysis is consistent with a mitochondrial disease. Ragged red fibers represent a proliferation of defective mitochondria. This characteristic finding may not be present in all types of mitochondrial diseases and also may be absent early in the course of disease.

Treatment Treatment of mitochondrial disease is largely supportive because there are no specific therapies that impact the natural history of the disorder. 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 untested in clinical trials.

Genetic Testing Mitochondrial diseases can be caused by pathogenic variants in the maternally inherited mtDNA or one of many nDNA genes. Genetic testing for mitochondrial diseases may involve testing for point mutations, deletion

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 4 (401) 274-4848 WWW.BCBSRI.COM

and duplication analysis, and/or whole exome sequencing of nuclear or mtDNA. The type of testing done depends on the specific disorder being considered. For some primary mitochondrial diseases such as MELAS and MERFF, most variants are point mutations, and there is a finite number of variants associated with the disorder. When testing for one of these disorders, known pathogenic variants can be tested for with polymerase chain reaction, or sequence analysis can be performed on the particular gene. For other mitochondrial diseases, such as CPEO and Kearns-Sayre syndrome, the most common variants are deletions, and therefore duplication and deletion analysis would be the first test when these disorders are suspected. Table 1 provides examples of clinical symptoms and particular genetic variants in mtDNA or nDNA associated with particular mitochondrial syndromes. A repository of published and unpublished data on variants in human mtDNA is available in the MITOMAP database. Lists of mtDNA and nDNA genes that may lead to mitochondrial diseases and testing laboratories in the U.S. are provided at Genetic Testing Registry of the National Center for Biotechnology Information website.

For individuals with signs and/or symptoms of a mitochondrial disease who receive genetic testing, the evidence includes case series and cohort studies. Relevant outcomes are test validity, other test performance measures, symptoms, functional outcomes, health status measures, and quality of life. There is some evidence on clinical validity that varies by the patient population and testing strategy. Studies reporting diagnostic yield for known pathogenic variants using next-generation sequencing (NGS) panels tend to report rates ranging from 15% to 25%. Clinical specificity is unknown, but population-based studies have indicated that the prevalence of certain variants exceeds the prevalence of clinical disease, suggesting that the variant will be found in some people without the clinical disease (false-positives). Clinical utility is relatively high for confirming the diagnosis of mitochondrial diseases in people who have signs and symptoms of the disease. In these patients, a positive result in genetic testing can avoid a muscle biopsy and eliminate the need for further clinical workup. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are asymptomatic with a close relative with a mitochondrial disease and a known pathogenic variant and who receive targeted familial variant testing, the evidence includes case series and cohort studies. Relevant outcomes are test validity, other test performance measures, changes in reproductive decision making, symptoms, functional outcomes, health status measures, and quality of life. Clinical validity is expected to be high for targeted testing of a known familial variant, assuming sufficient analytic validity. Clinical utility can be demonstrated by testing at-risk family members who have a close relative with a pathogenic variant. 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. 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(s) are medically necessary for Medicare Advantage Plans and Commercial Products when medical criteria above are met: 81440 Nuclear encoded mitochondrial genes (eg, 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

81460 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

81465 Whole mitochondrial genome large deletion analysis panel (eg, Kearns-Sayre syndrome,
chronic progressive external ophthalmoplegia), including heteroplasmy detection, if performed

This code can be used for Genomic Unity® Comprehensive Mitochondrial Disorders Analysis:

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 5 (401) 274-4848 WWW.BCBSRI.COM

0417U Rare diseases (constitutional/heritable disorders), whole mitochondrial genome sequence with heteroplasmy detection and deletion analysis, nuclear-encoded mitochondrial gene analysis of 335 nuclear genes, including sequence changes, deletions, insertions, and copy number variants analysis, blood or saliva, identification and categorization of mitochondrial disorder-associated genetic variants

RELATED POLICIES Biomarker Testing Mandate Proprietary Laboratory Analyses (PLA) and Multianalyte Assays with Algorithmic Analyses (MAAA)

PUBLISHED Provider Update, January 2026 Provider Update, January 2025 Provider Update, October/November 2023

REFERENCES

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500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 6 (401) 274-4848 WWW.BCBSRI.COM

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