Medical policy: Genetic Testing for Mitochondrial Disorders

Policy number: MP 2.273

Effective date: 4/1/2026

Policy

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 targeted testing may eliminate the need for muscle biopsy.

Targeted genetic testing for a known familial variant of 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.

Genetic testing for mitochondrial disorders is considered investigational in all other situations when the criteria for medical necessity are not met. There is insufficient evidence to support a general conclusion concerning the health outcomes or benefits associated with this procedure.

Policy guidelines

Mitochondrial disorders can be caused by variants in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA). A three (3)-generation family history may suggest a mode of inheritance. A family history in which affected women transmit the disease to male and female children and affected men do not transmit the disease to their children suggests the familial variant(s) is in the mtDNA. A family history consistent with Mendelian autosomal dominant or autosomal recessive inheritance or with X-linked inheritance suggests the familial variant(s) is in the nDNA. De novo pathogenic variants are also possible.

Testing strategy

Individuals with a suspected mitochondrial disorder

If the phenotype is highly suggestive of a specific disorder that is supported by the inheritance pattern noted in the family history, it would be reasonable to begin genetic testing with single genes or targeted multigene panels that test for pathogenic variants specific for that disorder.

If a mitochondrial disorder is suspected, but the phenotype is nonspecific, broader genetic testing is appropriate under the guidance of a clinical geneticist and genetics counselor. For patients in whom the family history is suggestive of a disorder due to pathogenic variant(s) in mtDNA, multigene panels or sequencing of the mitochondrial genome may be appropriate. If multiple mtDNA deletions are noted, or the family history is suggestive of a disorder due to variants in nDNA, then multigene panels covering known nuclear genes associated with mitochondrial disease may be appropriate. Testing using whole exome sequencing is reviewed in MP 2.234 Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders.

Individuals with a family member with a mitochondrial disorder and known familial variant

Targeted testing for a known familial variant in at-risk relatives as part of preconceptional carrier testing is appropriate. At-risk relatives include only female relatives if the familial pathogenic variant is in the mtDNA but includes both male and female relatives if the familial pathogenic variant is in the nDNA.

Mitochondrial Medicine Society

The Mitochondrial Medicine Society (MMS, 2015) developed consensus recommendations using the Delphi method.

• Recommendations for DNA testing
  • “Massively parallel sequencing/NGS of the mtDNA genome is the preferred methodology when testing mtDNA and should be performed in cases of suspected mitochondrial disease instead of testing for a limited number of pathogenic point mutations.”
  • “Patients with a strong likelihood of mitochondrial disease because of an mtDNA mutation and negative testing in blood, should have mtDNA assessed in another tissue to avoid the possibility of missing tissue-specific mtDNA heteroplasmy in low levels or absent in blood; tissue-based testing also helps assess the risk of other organ involvement and heterogeneity in family members and guides genetic counseling.”
  • “When considering nuclear gene testing in patients with likely primary mitochondrial disease, NGS methodologies providing complete coverage of known mitochondrial disease genes is preferred. Single-gene testing should be avoided because mutations in different genes can produce the same phenotype. If no mutation is identified via known NGS panels, then whole exome sequencing should be considered.”
• Recommendations for pathology testing
  • “Muscle (and/or liver) biopsies should be performed in the routine analysis for mitochondrial disease when the diagnosis cannot be confirmed with DNA testing.”

Genetics nomenclature update

The Human Genome Variation Society nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table PG1). The Society’s nomenclature is recommended by the Human Variome Project, the Human Genome Organisation, and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) standards and guidelines for interpretation of sequence variants represent expert opinion from ACMG, AMP, and the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table PG2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table PG1. Nomenclature to report on variants found in DNA

Table PG2. ACMG-AMP standards and guidelines for variant classification

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.

Cross-references

• MP 2.326 General Approach to Genetic Testing
• MP 2.233 General Approach to Evaluating the Utility of Genetic Panels
• MP 2.234 Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders

Product variations

This policy is only applicable to certain programs and products administered by Capital Blue Cross and subject to benefit variations. Please see additional information below.

FEP PPO - Refer to FEP Medical Policy Manual.

Description/background

Mitochondrial DNA

Mitochondria are organelles within each cell that contain their own set of DNA, distinct from the nuclear DNA that makes up most of the human genome. Human mitochondrial DNA (mtDNA) consists of 37 genes. Thirteen genes code for proteins 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 disorders

Mitochondrial disorders are clinically diverse group of diseases that may present at any age and affect a single organ or present as a multi-system condition in which neurological and myopathic features predominate. Extensive clinical variability and phenotypic overlap exists among the many discrete mitochondrial disorders.

Some specific mitochondrial disorders are listed next:

• Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome;
• Myoclonic epilepsy with ragged red fibers syndrome;
• Kearns-Sayre syndrome;
• Leigh syndrome;
• Chronic progressive external ophthalmoplegia;
• Leber hereditary optic neuropathy;
• Neurogenic weakness with ataxia and retinitis pigmentosa.

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 disorder 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 one particular syndrome. Biochemical testing is indicated for patients who do not have a clear clinical picture of one 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 tissue biopsy, typically muscle, has often been thought of as the gold standard for mitochondrial diagnosis, although the test is affected by concerns of limited sensitivity and specificity. With newer molecular testing, there is less of a need to rely primarily on biochemical testing of tissue for diagnosis, although selecting the appropriate tissue remains a very informative procedure, especially for clinically heterogeneous conditions such as mitochondrial disease. New data and guidelines suggest that a muscle (and/or liver) biopsy should only be performed in routine analysis for mitochondrial disease when the diagnosis cannot be confirmed with DNA testing. Biopsy is an invasive test and is not definitive in all cases. The presence of “ragged red fibers” on histologic analysis is considered the mitochondrial disorder. Ragged red fibers represent a proliferation of defective mitochondria. This characteristic finding may not be present in all types of mitochondrial disorders and also may be absent early in the course of disease.

Overall, the advent of newer technologies that rely on massively parallel or next-generation sequencing (NGS) methodologies have emerged as the new gold standard methodology for mtDNA genome sequencing because they allow significantly improved reliability and sensitivity of mtDNA genome analyses for point mutations, low-level heteroplasmy, and deletions, thereby providing a single test to accurately diagnose mtDNA disorders. This new approach may be considered as first-line testing for comprehensive analysis of the mitochondrial genome in blood, urine, or tissue, depending on symptom presentation and sample availability.

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 (e.g., coenzyme Q, riboflavin) have been used, but empirical evidence of benefit is lacking. Exercise therapy for myopathy is often prescribed, but the effect on clinical outcomes is uncertain. 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 disorders can be caused by pathogenic variants in the maternally inherited mtDNA or one of many nDNA genes. Genetic testing for mitochondrial disorders may involve testing for point mutations, deletion/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 disorders such as mitochondrial encephalopathy with lactic acidosis and stroke-like episodes and myoclonic epilepsy with ragged red fibers, most variants are point mutations, and there are a finite number of variants associated with this 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 disorders, such as chronic progressive external ophthalmoplegia and Kearns-Sayre syndrome, the most common variants are deletions, and therefore deletion/duplication 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 disorders and their associated inheritance patterns are provided by the GeneTests website (funded by BioReference Laboratories) and Genetic Testing Registry of the National Center for Biotechnology Information website.

Table 1. Examples of mitochondrial diseases, clinical manifestations, and associated pathogenic genes

Adapted from Chinnery et al (2014), and Angelini et al (2009). CPEO: chronic progressive external ophthalmoplegia; GRACILE: growth retardation, aminoaciduria, cholestasis, iron overload, early death; IOSCA: infantile onset spinal cerebellar atrophy; LHON: Leber hereditary optic neuropathy; MELAS: mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MERFF: myoclonic epilepsy with ragged-red fibers; MNGIE: mitochondrial neurogastrointestinal encephalopathy; NARP: neuropathy, ataxia, and retinitis pigmentosa; SANDO: sensory ataxia, neuropathy, dysarthria and ophthalmoplegia.

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). Genetic testing for mitochondrial disorders is under the auspices of CLIA. Laboratories offering 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.

Rationale

Summary of evidence

For individuals who have signs and/or symptoms of a mitochondrial disorder 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 panels tend to report ranges from 15% to 25%. Clinical specificity is unknown, but population-based studies have reported that the prevalence of certain variants exceeds the prevalence of clinical disease, suggesting that the variant will be found in some people without clinical disease (false positives). Clinical utility is relatively high for confirming the diagnosis of mitochondrial disorders in people who have signs and symptoms of disease. In these patients, a positive result on genetic testing can avoid muscle biopsy and eliminate the need for further clinical workup. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who are symptomatic with a close relative with a mitochondrial disorder and a known pathogenic 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 of 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 a meaningful improvement in the net health outcome.

Definitions

N/A

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Coding information

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Covered when medically necessary

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