Description

Whole genome sequencing (WGS) is a laboratory test utilized to determine the sequence (arrangement) of an individual’s entire genome at a single time. WGS allows the identification of mutations in the genome without having to target a gene or chromosome region based upon an individual’s personal or family history. WGS may also be referred to as full genome sequencing, complete genome sequencing or entire genome sequencing.

Exome sequencing, also referred to as whole exome sequencing (WES), is an alternative to WGS. It is a laboratory test used to determine the sequence of the protein coding regions of the genome. The exome is the part of the genome that encodes protein, where roughly 85% of variants are known to contribute to diseases in humans.

Exome sequencing has been proposed as a diagnostic method to identify these genetic variants in an individual not diagnosed by traditional diagnostic and genetic testing approaches.

Uses of Whole Exome Sequencing

• WES has been proposed as a methodology to analyze tumor mutational burden (TMB), an emerging biomarker that measures the number of mutations (changes) within the deoxyribonucleic acid (DNA) of cancer cells using tumor biopsy tissue. Determining TMB may be helpful for treatment decisions as well as assessing potential eligibility for clinical trials. An example of a WES test that measures TMB is Omics Core.
• Another suggested use for WES is for the detection of minimal residual disease (MRD) which is a term used for hematologic malignancies and is defined as the small number of cancer cells that remain in the body following treatment. Examples include, but may not be limited to, Invitae PCM Tissue Profiling and MRD Baseline Assay and Invitae PCM MRD Monitoring.

Exome Custom Panels

Exome custom panels (also known as exome backbone tests) are customizable, next-generation sequencing (NGS) assays that utilize the whole exome sequencing platform to sequence single genes or multigene panels. Healthcare providers select genes from a menu of genes to include in the request. These tests, depending on the results, may also reflex to (automatically trigger further testing) exome sequencing. Examples include Custom Slice, Custom Slice Xpanded and Slice.

Duo and Trio WES

Duo and trio WES involves testing family members in addition to the proband (first affected individual in a family) to facilitate a diagnosis. Duo WES is performed in the proband and one biologically related individual, typically a parent or sibling. Trio WES is performed using samples from the proband and two relatives, typically both parents. The evaluation of the relatives is referred to as comparator analysis.

Genome-Wide Association Study (GWAS)

A genome-wide association study (GWAS), also referred to as genome-wide analysis, is a method to identify genes involved in human disease by comparing the genome of an individual who have a disease or condition to the genome of an individual without the disease or condition. GWAS are performed using microarrays to search the genome for small variations, called single nucleotide polymorphisms (SNPs).

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.

(SNPs) that occur more often in an individual with a specific disorder than in those who do not have a disorder.

Mitochondrial genome sequencing can be performed in combination with WGS or WES. However, whole mitochondrial genome sequencing differs from WGS. For information regarding mitochondrial genome sequencing only (without WGS/WES), please refer to Whole Mitochondrial Genome Sequencing and Multigene Panels for Mitochondrial Disorders Medical Coverage Policy.

Optical genome mapping (OGM) is a technology used to enhance the detection and interpretation of WGS by analyzing ultra-high molecular weight DNA molecules that provides a high-resolution genome-wide analysis highlighting copy number and structural anomalies, including balanced translocations. Examples of OGM testing include, but may not be limited to:

• Augusta Hematology Optical Genome Mapping
• Augusta Optical Genome Mapping
• DH Optical Genome Mapping/Digital Karyotyping Assay
• Praxis Optical Genome Mapping
• Praxis Somatic Optical Genome Mapping

OGM may be offered in combination with WGS. Examples include, but may not be limited to:

• Praxis Combined Whole Genome Sequencing and Optical Genome Mapping
• Praxis Somatic Combined Whole Genome Sequencing and Optical Genome Mapping

WGS/WES reanalysis or reevaluation involves taking the raw data generated from a previous WGS/WES study and reprocessing it using updated software and new reference genome versions. Reanalysis or reevaluation differs from retesting.

Transcriptome sequencing is a method of analyzing the complete set of RNA molecules, or transcripts, produced by a cell or tissue at a specific time. Praxis Somatic Transcriptome and Praxis Transcriptome are examples of this type of testing.

Whole Genome/Exome Sequencing and Genome-Wide Association Studies Effective Date: 10/01/2023

Revision Date: 10/01/2023

Review Date: 03/23/2023

Policy Number: HUM-0496-027

Page: 4 of 27

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. Humana recognizes that the field of genetic testing is rapidly changing and that other tests may become available.

Coverage Determination

Any state mandates for WGS, WES or GWAS take precedence over this medical coverage policy.

Humana members may NOT be eligible under the Plan for WGS, WES or GWAS for any indication or test including, but may not be limited to:

• Carrier status or reproductive risk including, but may not be limited to:
  • Insight Genome
  • Repro Xpanded Test (individual or couple)
• Combined WES and mitochondrial genome testing including, but may not be limited to:
  • Comparator (parent, sibling) for rare disease (constitutional/heritable disorders) (eg, Genomic Unity Exome Plus Analysis – Comparator [0215U])
  • Proband (first affected individual in a family) for rare disease (constitutional/ heritable disorders) (eg, Genomic Unity Exome Plus Analysis – Proband [0214U])
  • XomeDx Plus Test
• Combined WGS and mitochrondrial genomic testing including, but may not be limited to:
  • Comparator (parent, sibling) for rare disease (constitutional/heritable disorders) (eg, Genomic Unity Whole Genome Analysis – Comparator [0213U])
  • Proband (first affected individual in a family) for rare disease (constitutional/ heritable disorders) (eg, Genomic Unity Whole Genome Analysis – Proband [0212U])
• Combined WGS and OGM including, but may not be limited to:
  • Praxis Combined Whole Genome Sequencing and Optical Genome Mapping (0267U)
  • Praxis Somatic Combined Whole Genome Sequencing and Optical Genome Mapping (0300U)
• Custom exome panels of single or targeted genes (eg, Custom Slice, Custom SliceXpanded, Slice)
• Duo and Trio WGS or WES including, but may not be limited to:
  • XomeDx – Duo
  • XomeDx – Trio
• Evaluation of any of the following:
  • Alzheimer disease/dementia
  • Ataxia
  • Autism spectrum disorder
  • Congenital anomalies
  • Developmental delay/intellectual disability
  • Dystonia
  • Epilepsy
  • Hearing loss
  • Primary immunodeficiency
  • Psychiatric conditions
  • Stillbirth/fetal demise
• Fetal evaluation including, but may not be limited to, XomeDx Fetal
• MRD assessment (baseline or monitoring) by WGS or WES including, but may not be limited to:
  • Invitae PCM Tissue Profiling & MRD Baseline Assay (0306U)
  • Invitae PCM MRD Monitoring (0307U)
  • Precise MRD

Whole Genome/Exome Sequencing and Genome-Wide Association Studies Effective Date: 10/01/2023

Revision Date: 10/01/2023

Review Date: 03/23/2023

Policy Number: HUM-0496-027

Page: 5 of 27

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.

• OGM including, but may not be limited to:
  • Augusta Hematology Optical Genome Mapping (0331U)
  • Augusta Optical Genome Mapping (0260U)
  • DH Optical Genome Mapping/Digital Karyotyping Assay (0413U)
  • Praxis Optical Genome Mapping (0264U)
  • Praxis Somatic Optical Genome Mapping (0299U)
• Preimplantation genetic testing
• Prenatal screening or diagnosis by WGS or WES including, but may not be limited to:
  • ExomeNext Prenatal
  • IriSight Prenatal Analysis (comparator [0336U] or proband [0335U])
  • XomeDx Prenatal Test (comprehensive or targeted)
• Rapid or ultrarapid WGS or WES including, but may not be limited to:
  • Custom SliceXpanded Priority
  • Custom SliceXanded Xpress Test
  • GenomeXpress Test
  • NICUXpress Panel
  • RCIGM Rapid Whole Genome Sequencing [0094U]
  • XomeDx Priority Test
  • XomeDxXpress Test
• Reanalysis or reevaluation by WGS or WES including, but may not be limited to:
  • Xome Reanalysis Test
  • Xome Subsequent Reanalysis Test
• Somatic WGS or WES including, but may not be limited to:
  • EXaCT-1 Whole Exome Testing [0036U]
  • Praxis Somatic Whole Genome Sequencing (0297U)
  • Tempus xE

Whole Genome/Exome Sequencing and Genome-Wide Association Studies Effective Date: 10/01/2023

Revision Date: 10/01/2023

Review Date: 03/23/2023

Policy Number: HUM-0496-027

Page: 7 of 27

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.

• Targeted gene rearrangement detection by WGS NGS for any of the following:
  • Germline congenital disorders (eg, MatePair Targeted Rearrangements, Congenital [0012U])
  • Hematology (acute myelogenous leukemia [AML]) (eg, MatePair Acute Myeloid Leukemia Panel [0056U])
  • Hematology (hematolymphoid neoplasia) (eg, MatePair Targeted Rearrangements, Hematologic [0014U])
  • Oncology (solid organ neoplasia) (eg, MatePair Targeted Rearrangements, Oncology [0013U])
• TMB assessment by WGS or WES including, but may not be limited to, Omics Core whole exome tumor-normal in vitro diagnostic
• Transcriptome including, but may not be limited to:
  • Praxis Somatic Transcriptome (0298U)
  • Praxis Transcriptome (0266U)
• WGS including, but may not be limited to, Praxis Whole Genome Sequencing (0265U)

These are considered experimental/investigational as they are not identified as widely used and generally accepted for the proposed uses as reported in nationally recognized peer-reviewed medical literature published in the English language.

Additional information about WGS, WES and GWAS may be found from the following websites:

Background

• National Library of Medicine

Whole Genome/Exome Sequencing and Genome-Wide Association Studies Effective Date: 10/01/2023

Revision Date: 10/01/2023

Review Date: 03/23/2023

Policy Number: HUM-0496-027

Page: 8 of 27

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 WGS, WES or GWAS include, but may not be limited to, the following:

• Chromosomal microarray analysis (please refer to Comparative Genomic Hybridization/Chromosomal Microarray Analysis Medical Coverage Policy)
• Fluorescence in situ hybridization (FISH)
• Fragile X syndrome genetic testing (please refer to Genetic Testing for Noncancer Indications Medical Coverage Policy)
• Standard cytogenetic testing (eg, karyotype)
• Targeted mutation analysis consistent with personal and family histories

Physician consultation is advised to make an informed decision based on an individual's health needs.

Humana may offer a disease management program for this condition. The member may call the number on his/her identification card to ask about our programs to help manage his/her care.

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.