Whole Mitochondrial Genome Sequencing and Multigene Panels for Mitochondrial Disorders Form

. Mitochondria are organelles found in eukaryotic cells (cell or organism that has a clearly defined nucleus) and are responsible for breaking down carbohydrates and fatty acids to power biochemical reactions and metabolism within the cell. Mitochondrial disorders are chronic, genetic conditions that are often inherited and occur when the mitochondria fail to produce sufficient energy for the body to function.
Mitochondrial disorders can affect almost any part of the body, including but not limited to, cells of the brain, ears, eyes, heart, kidneys, liver, muscles, nerves or

Whole Mitochondrial Genome Sequencing and Multigene Panels for Mitochondrial Disorders Effective Date: 10/01/2023 Revision Date: 10/01/2023 Review Date: 03/01/2023 Policy Number: HUM-0545-010 Page: 2 of 10 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. pancreas. Some individuals display features that fall into distinct syndromes while others present with overlapping features making a definitive diagnosis difficult.
Mitochondrial disorders include, but are not limited to:
• Barth syndrome
• Chronic progressive external ophthalmoplegia (CPEO) • Encephalopathy of infancy and childhood • Growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis and early death (GRACILE) • Kearns-Sayre syndrome (KSS) • Leber hereditary optic neuropathy (LHON) • Leigh syndrome (LS) • Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) • Mitochondrial recessive ataxia syndrome (MIRAS) • Multisystem disease with myopathy • Myoclonic epilepsy with ragged-red fibers (MERRF) • Neurogenic weakness with ataxia and retinitis pigmentosa (NARP) • Pearson syndrome • POLG-related disorders including, but may not be limited to: o Alpers syndrome o Autosomal dominant progressive external ophthalmoplegia See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Whole Mitochondrial Genome Sequencing and Multigene Panels for Mitochondrial Disorders Effective Date: 10/01/2023 Revision Date: 10/01/2023 Review Date: 03/01/2023 Policy Number: HUM-0545-010 Page: 3 of 10 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. o Autosomal recessive progressive external ophthalmoplegia o Childhood myocerebrohepatopathy syndrome o Myoclonic epilepsy myopathy sensory ataxia Mitochondrial disorders are caused by pathogenic variants in deoxyribonucleic acid (DNA) (nuclear DNA [nDNA]) or in DNA contained within the mitochondria (mitochondrial DNA [mtDNA]).
Multigene panels, whole genome/exome sequencing (of nDNA) and whole mitochondrial genome sequencing are laboratory techniques that use next- generation sequencing (NGS) to detect gene variations associated with mitochondrial disorders and have been suggested to aid in the diagnosis of these conditions.
Multigene (or expanded) panels analyze a broad set of genes simultaneously (as opposed to single gene testing that searches for variants in one specific gene) and have been proposed to evaluate the DNA of an individual with a personal and/or family history of more than one hereditary condition or syndrome. Panels often include medically actionable genes but may also include those with unclear medical management. Targeted (or focused) multigene panels analyze a limited number of genes targeted to a specific condition. Whole genome sequencing of mtDNA detects pathogenic point mutations and single large-scale deletions with heteroplasmy (the presence of more than one type of mtDNA in an individual) that contribute to mitochondrial dysfunction. However, nuclear gene variants that may cause mitochondrial dysfunction are not detected by this analysis. For information regarding nuclear-encoded mitochondrial gene testing for hearing loss, please refer to Genetic Testing for Diagnosis of Noncancer Indications Medical Coverage Policy.
For information regarding single gene testing for mitochondrial disorders, please refer to General Criteria for Genetic and Pharmacogenomics Tests in Genetic Testing Medical Coverage Policy. See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Whole Mitochondrial Genome Sequencing and Multigene Panels for Mitochondrial Disorders Effective Date: 10/01/2023 Revision Date: 10/01/2023 Review Date: 03/01/2023 Policy Number: HUM-0545-010 Page: 4 of 10 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. For information regarding whole genome sequencing (WGS) or whole exome sequencing (WES) for indications other than mitochondrial disorders and for WGS or WES performed with whole mitochondrial genome sequencing, please refer to Whole Genome/Exome Sequencing and Genome-Wide Association Studies Medical Coverage Policy.
For information regarding genetic testing for the following, please refer to Genetic Testing Medical Coverage Policy: • General population screening
• Individual 17 years of age or younger for adult-onset conditions • Interpretation and reporting for molecular pathology procedures • Negative or variant of unknown significance (VUS) testing result in a relative
• Retrieved archival tissue Humana recognizes that the field of genetic testing is rapidly changing and that other tests may become available. Coverage Determination Any state mandates for genetic testing take precedence over this medical coverage policy.
Genetic testing may be excluded by certificate. Please consult the member’s individual certificate regarding Plan coverage.
Humana members may NOT be eligible under the Plan for whole mitochondrial genome sequencing or multigene panels for mitochondrial disorders. Examples include, but may not be limited to:
• 58 mtDNA Point Mutations Plus Large Deletions Panel • Combined Mito Genome Plus Mito Nuclear Gene Panel • Comprehensive Mitochondrial Nuclear Gene Panel • Dual Genome Leigh Disease Panel by Massively Parallel Sequencing See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Whole Mitochondrial Genome Sequencing and Multigene Panels for Mitochondrial Disorders Effective Date: 10/01/2023 Revision Date: 10/01/2023 Review Date: 03/01/2023 Policy Number: HUM-0545-010 Page: 5 of 10 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. • Genomic Unity Comprehensive Mitochondrial Disorders Analysis (0417U) • Mitochondrial Disorders Panel
• Mitochondrial Encephalopathy/Leigh Syndrome Nuclear Gene Panel • Mitochondrial Genome: Sequencing • Mitochondrial Respiratory Chain Complex V Deficiency Panel by Massively Parallel Sequencing
• MitoMet Plus aCGH Analysis • MitoSwab • Nuclear encoded mitochondrial genomic sequencing panel of at least 100 genes for mitochondrial disorders including, but may not be limited to, neurologic or myopathic phenotypes (81440) • Whole mitochondrial genome large deletion analysis panel for mitochondrial disorders including, but may not be limited to, KSS or CPEO (81465) • Whole mitochondrial genome sequencing for mitochondrial disorders including, but may not be limited to, Leigh syndrome, MELAS, MERFF, NARP or LHON (81460) These are considered experimental/investigational as they are not identified as widely used and generally accepted for the proposed use as reported in nationally recognized peer-reviewed medical literature published in the English language. Background Additional information about mitochondrial disorders may be found from the following website: • National Library of Medicine See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Whole Mitochondrial Genome Sequencing and Multigene Panels for Mitochondrial Disorders Effective Date: 10/01/2023 Revision Date: 10/01/2023 Review Date: 03/01/2023 Policy Number: HUM-0545-010 Page: 6 of 10 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. Medical Alternatives Alternatives to whole mitochondrial genome sequencing or multigene panels for mitochondrial disorders include, but may not be limited to: • Mitochondrial disease diagnostic criteria • Muscle biopsy and biochemical analysis • Targeted single gene testing for specific mitochondrial disorders based on personal and family history (refer to General Criteria for Genetic and Pharmacogenomics Tests in Genetic Testing Medical Coverage Policy) Physician consultation is advised to make an informed decision based on an individual’s health needs. Provider Claims Codes Any CPT, HCPCS or ICD codes listed on this medical coverage policy are for informational purposes only. Do not rely on the accuracy and inclusion of specific codes. Inclusion of a code does not guarantee coverage and or reimbursement for a service or procedure. CPT® Code(s) 81228 Description Comments Cytogenomic constitutional (genome-wide) microarray analysis; interrogation of genomic regions for copy number variants (eg, bacterial artificial chromosome [BAC] or oligo-based comparative genomic hybridization [CGH] microarray analysis) Not Covered if used to report any test outlined in Coverage Limitations section 81401 MOLECULAR PATHOLOGY PROCEDURE LEVEL 2 81403 MOLECULAR PATHOLOGY PROCEDURE LEVEL 4 Not Covered if used to report any test outlined in Coverage Limitations section Not Covered if used to report any test outlined in Coverage Limitations section See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Whole Mitochondrial Genome Sequencing and Multigene Panels for Mitochondrial Disorders Effective Date: 10/01/2023 Revision Date: 10/01/2023 Review Date: 03/01/2023 Policy Number: HUM-0545-010 Page: 7 of 10 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. 81404 MOLECULAR PATHOLOGY PROCEDURE LEVEL 5 81405 MOLECULAR PATHOLOGY PROCEDURE LEVEL 6 81406 MOLECULAR PATHOLOGY PROCEDURE LEVEL 7 81440 81460 81465 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 Whole mitochondrial genome (eg, Leigh syndrome, mitochondrial encephalomyopathy, lactic acidosis, and stroke- like episodes [MELAS], myoclonic epilepsy with ragged-red fibers [MERFF], neuropathy, ataxia, and retinitis pigmentosa [NARP], Leber hereditary optic neuropathy [LHON]), genomic sequence, must include sequence analysis of entire mitochondrial genome with heteroplasmy detection Whole mitochondrial genome large deletion analysis panel (eg, Kearns-Sayre syndrome, chronic progressive external ophthalmoplegia), including heteroplasmy detection, if performed 81479 Unlisted molecular pathology procedure Not Covered if used to report any test outlined in Coverage Limitations section Not Covered if used to report any test outlined in Coverage Limitations section Not Covered if used to report any test outlined in Coverage Limitations section Not Covered Not Covered Not Covered Not Covered if used to report any test outlined in Coverage Limitations section See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

Whole Mitochondrial Genome Sequencing and Multigene Panels for Mitochondrial Disorders Effective Date: 10/01/2023 Revision Date: 10/01/2023 Review Date: 03/01/2023 Policy Number: HUM-0545-010 Page: 8 of 10 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing. 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 Not Covered New Code Effective 10/01/2023 CPT® Category III Code(s) No code(s) identified HCPCS Code(s) No code(s) identified References

4. Description Comments Description Comments American College of Medical Genetics and Genomics (ACMG). ACMG Technical Standard. Next-generation sequencing for constitutional variants in the clinical laboratory, 2021 revision. https://www.acmg.net. Published 2021. Accessed February 5, 2023.
   Hayes, Inc. Genetic Test Evaluation (GTE) Report (ARCHIVED). DNA polymerase gamma (POLG)-related disorders. https://evidence.hayesinc.com. Published April 4, 2013. Updated February 20, 2015. Accessed February 2, 2023. Hayes, Inc. Genetic Test Evaluation (GTE) Report (ARCHIVED). LHON (Leber hereditary optic neuropathy) for diagnosis and risk of transmission. https://evidence.hayesinc.com. Published March 30, 2008. Updated March 19,

   2012. Accessed February 2, 2023. Hayes, Inc. Genetic Test Evaluation (GTE) Report (ARCHIVED). Mitochondrial DNA (mtDNA) whole-genome scanning/sequencing. https://evidence.hayesinc.com. Published April 15, 2010. Updated May 28,
   2013. Accessed February 2, 2023. See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

   Whole Mitochondrial Genome Sequencing and Multigene Panels for Mitochondrial Disorders Effective Date: 10/01/2023 Revision Date: 10/01/2023 Review Date: 03/01/2023 Policy Number: HUM-0545-010 Page: 9 of 10 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

6. Hayes, Inc. Genetic Test Evaluation (GTE) Synopsis (ARCHIVED). MitoMetPlus Mitochondrial/Metabolic Microarray Analysis. https://evidence.hayesinc.com. Published August 14, 2014. Accessed February 2, 2023.
   Hayes, Inc. Precision Medicine Research Brief. MitoSwab (Religen Labs). https://evidence.hayesinc.com. Published April 3, 2020. Accessed February 2, 2023.
7. MCG Health. Whole genome/exome sequencing – metabolic, mitochondrial, and neurologic. 26th edition. https://www.mcg.com. Accessed February 2, 2023.
9. National Center for Biotechnology Information (NCBI). Genetic Testing Registry (GTR). Primary mitochondrial disorders overview. https://www.ncbi.nlm.nih.gov/gtr. Published June 8, 2000. Updated July 29, 2021. Accessed February 5, 2023. Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015;17(9):689-701. https://www.ncbi.nih.gov/pmc. Accessed February 2, 2023.
10. UpToDate, Inc. Approach to the metabolic myopathies. https://www.uptodate.com. Updated January 2023. Accessed February 2, 2023.
11. UpToDate, Inc. Inborn errors of metabolism: classification. https://www.uptodate.com. Updated January 2023. Accessed February 2, 2023.
12. UpToDate, Inc. Mitochondrial myopathies: clinical features and diagnosis. https://www.uptodate.com. Updated January 2023. Accessed February 2, 2023.

13. UpToDate, Inc. Mitochondrial structure, function, and genetics. https://www.uptodate.com. Updated January 2023. Accessed February 2,

    2023. See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.

    Whole Mitochondrial Genome Sequencing and Multigene Panels for Mitochondrial Disorders Effective Date: 10/01/2023 Revision Date: 10/01/2023 Review Date: 03/01/2023 Policy Number: HUM-0545-010 Page: 10 of 10 Humana's documents are updated regularly online. When printed, the version of this document becomes uncontrolled. Do not rely on printed copies for the most up-to-date version. Refer to Medical and Pharmacy Coverage Policies to verify that this is the current version before utilizing.

14. UpToDate, Inc. Myopathies affecting the extraocular muscles in children. https://www.uptodate.com. Updated January 2023. Accessed February 2, 2023.
15. UpToDate, Inc. Neuropathies associated with hereditary disorders. https://www.uptodate.com. Updated January 2023. Accessed February 2, 2023.
16. UpToDate, Inc. Next-generation DNA sequencing (NGS): principles and clinical applications. https://www.uptodate.com. Updated January 2023. Accessed February 2, 2023.
17. UpToDate, Inc. Overview of cerebellar ataxia in adults. https://www.uptodate.com. Updated January 2023. Accessed February 2, 2023.
18. UpToDate, Inc. Overview of ptosis. https://www.uptodate.com. Updated January 2023. Accessed February 2, 2023.
19. Witters P, Saada A, Honzik T, et al. Revisiting mitochondrial diagnostic criteria in the new era of genomics. Genetics in Medicine. 2018;20:444-451. https://www.nature.com. Accessed February 2, 2023. See the DISCLAIMER. All Humana member health plan contracts are NOT the same. All legislation/regulations on this subject may not be included. This document is for informational purposes only.