Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders Form

500 EXCHANGE STREET, PROVIDENCE, RI 02903-2699 MEDICAL COVERAGE POLICY | 1 (401) 274-4848 WWW.BCBSRI.COM EFFECTIVE DATE: 01|01|2026 POLICY LAST REVIEWED: 09|03|2025 OVERVIEW Whole exome sequencing (WES) sequences the portion of the genome that contains protein-coding DNA, while whole genome sequencing (WGS) sequences both coding and noncoding regions of the genome. Whole exome sequencing and WGS have been proposed for use in patients presenting with disorders and anomalies not explained by a standard clinical workup. Potential candidates for WES and WGS include patients who present with a broad spectrum of suspected genetic conditions. The following test(s) are addressed in this policy: • Genomic Unity® Exome Plus Analysis – Proband (Variantyx, Inc.) CPT code 0214U • Genomic Unity® Exome Plus Analysis – Comparator (Variantyx, Inc.) CPT code 0215U For CPT codes 81415, 81416, 81417, 81425, 81426 and 81427, please refer to the Genetic Testing Services policy listed in the Related Policies section below.
MEDICAL CRITERIA Medicare Advantage Plans and Commercial Products Effective 1/1/2026, the following test(s) are considered medically necessary when the medical criteria in the online authorization tool for participating providers is met: • RCIGM Rapid Whole Genome Sequencing Comparator Genome (CPT code 0425U) • RCIGM Ultra-Rapid Whole Genome Sequencing (CPT code 0426U) Medicare Advantage Plans and Commercial Products The following tests may be considered medically necessary when all of the following medical necessity criteria below are met: • Genomic Unity® Exome Plus Analysis – Proband (CPT code 0214U) • Genomic Unity® Exome Plus Analysis – Comparator (CPT code 0215U) Standard whole exome sequencing, with trio testing when possible (see guidelines below), may be considered medically necessary for the evaluation of unexplained congenital or neurodevelopmental disorders in children when ALL of the following criteria are met: 1. Documentation that the individual has been evaluated by a clinician with expertise in clinical genetics, including at minimum a family history and phenotype description, and counseled about the potential risks of genetic testing. 2. There is potential for a change in management and clinical outcome for the individual being tested. 3. A genetic etiology is considered the most likely explanation for the phenotype despite previous genetic testing (eg, chromosomal microarray analysis and/or targeted single-gene testing), OR when previous genetic testing has failed to yield a diagnosis, and the affected individual is faced with invasive procedures or testing as the next diagnostic step (eg, muscle biopsy). Rapid whole exome sequencing or rapid whole genome sequencing, with trio testing when possible (see guidelines below), may be considered medically necessary for the evaluation of critically ill infants in Medical Coverage Policy | Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders

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neonatal or pediatric intensive care with a suspected genetic disorder of unknown etiology when BOTH of the following criteria are met:

1. At least one of the following criteria is met: a. Multiple congenital anomalies; b. An abnormal laboratory test or clinical features suggests a genetic disease or complex metabolic phenotype; c. An abnormal response to standard therapy for a major underlying condition.

2. None of the following criteria apply regarding the reason for admission to intensive care: a. An infection with normal response to therapy; b. Isolated prematurity; c. Isolated unconjugated hyperbilirubinemia; d. Hypoxic Ischemic Encephalopathy; e. Confirmed genetic diagnosis explains illness; f. Isolated Transient Neonatal Tachypnea; or g. Nonviable neonates. *Trio Testing The recommended option for testing when possible is testing of the child and both parents (trio testing). Trio testing increases the chance of finding a definitive diagnosis and reduces false-positive findings.

   Trio testing is preferred whenever possible but should not delay testing of a critically ill individual when rapid testing is indicated. Testing of one available parent should be done if both are not immediately available and one or both parents can be done later if needed. PRIOR AUTHORIZATION
   Medicare Advantage Plans and Commercial Products Prior authorization is required for Medicare Advantage Plans and recommended for Commercial Products via the online tool for participating providers for the following tests: • RCIGM Rapid Whole Genome Sequencing Comparator Genome (CPT code 0425U)
   • RCIGM Ultra-Rapid Whole Genome Sequencing (CPT code 0426U)

   Medicare Advantage Plans and Commercial Products Prior authorization is required for Medicare Advantage Plans and recommended for Commercial Products for the following tests:
   • Genomic Unity® Exome Plus Analysis – Proband CPT code 0214U • Genomic Unity® Exome Plus Analysis – Comparator CPT code 0215U

   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 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

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

Medicare Advantage Plans and Commercial Products Effective 1/1/2026, the following test(s) may be considered medically necessary when the medical criteria in the online authorization tool for participating providers is met: • RCIGM Rapid Whole Genome Sequencing Comparator Genome (CPT code 0425U)
• RCIGM Ultra-Rapid Whole Genome Sequencing (CPT code 0426U)

Medicare Advantage Plans and Commercial Products The following tests may be considered medically necessary when the medical criteria above have been met: • Genomic Unity® Exome Plus Analysis – Proband CPT code 0214U • Genomic Unity® Exome Plus Analysis – Comparator CPT code 0215U

The following are not covered for Medicare Advantage Plans and not medically necessary for Commercial Products as the evidence is insufficient to determine that the technology results in an improvement in the net health outcomes: • Whole exome sequencing for the diagnosis of genetic disorders in all other situations. • Repeat whole exome sequencing for the diagnosis of genetic disorders, including re-analysis of previous test results • Whole exome sequencing for screening for genetic disorders.

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 Whole Exome Sequencing and Whole Genome Sequencing Whole exome sequencing (WES) is targeted next-generation sequencing (NGS) of the subset of the human genome that contains functionally important sequences of protein-coding DNA, while whole genome sequencing (WGS) uses NGS techniques to sequence both coding and noncoding regions of the genome. Whole exome sequencing and WGS have been proposed for use in patients presenting with disorders and anomalies not explained by a standard clinical workup. Potential candidates for WES and WGS include patients who present with a broad spectrum of suspected genetic conditions.

Given the variety of disorders and management approaches, there are a variety of potential health outcomes from a definitive diagnosis. In general, the outcomes of a molecular genetic diagnosis include (1) impacting the search for a diagnosis, (2) informing follow-up that can benefit a child by reducing morbidity, and (3) affecting reproductive planning for parents and potentially the affected patient.

The standard diagnostic workup for patients with suspected Mendelian disorders may include combinations of radiographic, electrophysiologic, biochemical, biopsy, and targeted genetic evaluations.1, The search for a diagnosis may thus become a time-consuming and expensive process.

Whole Exome Sequencing and Whole Genome Sequencing Technology Whole exome sequencing or WGS using NGS technology can facilitate obtaining a genetic diagnosis in patients efficiently. Whole exome sequencing is limited to most of the protein-coding sequence of an individual (»85%),

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

is composed of about 20,000 genes and 180,000 exons (protein-coding segments of a gene), and constitutes approximately 1% of the genome. It is believed that the exome contains about 85% of heritable disease-causing variants. Whole exome sequencing has the advantage of speed and efficiency relative to Sanger sequencing of multiple genes. Whole exome sequencing shares some limitations with Sanger sequencing. For example, it will not identify the following: intronic sequences or gene regulatory regions; chromosomal changes; large deletions; duplications; or rearrangements within genes, nucleotide repeats, or epigenetic changes. Whole genome sequencing uses techniques similar to WES but includes noncoding regions. Whole genome sequencing has a greater ability to detect large deletions or duplications in protein-coding regions compared with WES but requires greater data analytics.

Technical aspects of WES and WGS are evolving, including the development of databases such as the National Institutes of Health’s ClinVar database (http://www.ncbi.nlm.nih.gov/clinvar/) to catalog variants, uneven sequencing coverage, gaps in exon capture before sequencing, and difficulties with narrowing the large initial number of variants to manageable numbers without losing likely candidate disease-associated variants. The variability contributed by the different platforms and procedures used by different clinical laboratories offering exome sequencing as a clinical service is unknown.

In 2013, the American College of Medical Genetics and Genomics, Association for Molecular Pathology, and College of American Pathologists convened a workgroup to standardize terminology for describing sequence variants. In 2015, guidelines developed by this workgroup describe criteria for classifying pathogenic and benign sequence variants based on 5 categories of data: pathogenic, likely pathogenic, uncertain significance, likely benign, and benign.

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). Whole exome sequencing or WGS tests as a clinical service are available under the auspices of the 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 (FDA) has chosen not to require any regulatory review of this test. For individuals who are children who are not critically ill with multiple unexplained congenital anomalies or a neurodevelopmental disorder of unknown etiology following a standard workup who receive whole exome sequencing (WES) with trio testing when possible, the evidence includes large case series and within-subject comparisons. Relevant outcomes are test validity, functional outcomes, changes in reproductive decision making, and resource utilization. Patients who have multiple congenital anomalies or a developmental disorder with a suspected genetic etiology, but whose specific genetic alteration is unclear or unidentified by a standard clinical workup, may be left without a clinical diagnosis of their disorder, despite a lengthy diagnostic workup. For a substantial proportion of these patients, WES may return a likely pathogenic variant. Several large and smaller series have reported diagnostic yields of WES ranging from 25% to 60%, depending on the individual’s age, phenotype, and previous workup. One comparative study found a 44% increase in yield compared with standard testing strategies. Many of the studies have also reported changes in patient management, including medication changes, discontinuation of or additional testing, ending the diagnostic odyssey, and family planning. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome. For individuals who are children with a suspected genetic disorder other than multiple congenital anomalies or a neurodevelopmental disorder of unknown etiology following a standard workup who receive WES with trio testing when possible, the evidence includes small case series and prospective research studies. Relevant outcomes are test validity, functional outcomes, changes in reproductive decision making, and resource utilization. There is an increasing number of reports evaluating the use of WES to identify a molecular basis for disorders other than multiple congenital anomalies or neurodevelopmental disorders. The diagnostic yields in these studies range from as low as 3% to 60%. Some studies have reported on the use of a virtual gene panel with restricted analysis of disease-associated genes, and WES data allow reanalysis as new genes are linked to the patient phenotype. Overall, a limited number of patients have been studied for any specific disorder, and

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clinical use of WES for these disorders is at an early stage with uncertainty about changes in patient management. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who have previously received WES who receive repeat WES, including re-analysis of previous test results, the evidence includes nonrandomized studies and a systematic review. Relevant outcomes are test validity, functional outcomes, changes in reproductive decision making, and resource utilization. There is no direct evidence of clinical utility. In a meta-analysis of nonrandomized studies, re-analysis of WES data resulted in an 11% increase in diagnostic yield (95% confidence interval (CI), 8% to 14%) in individuals who were previously undiagnosed via WES. Three nonrandomized studies published after the meta-analysis had findings consistent with the meta-analysis. Conclusions were limited by heterogeneity across individual studies and a lack of detailed reporting on reasons for new diagnoses, changes in management based on new diagnoses, and the frequency of the identification of variants of uncertain significance (VUS). Therefore, a chain of evidence for clinical utility cannot be established. Additionally, the optimal timing of re-analysis has not been established, and there are no clear guidelines on what factors should prompt the decision to repeat testing. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome. For individuals who are critically ill infants with a suspected genetic disorder of unknown etiology following a standard workup who receive rapid WGS (rWGS) or rapid WES (rWES) with trio testing when possible, the evidence includes randomized controlled trials (RCTs) and case series. Relevant outcomes are test validity, functional outcomes, changes in reproductive decision making, and resource utilization. One RCT comparing rWGS with standard genetic tests to diagnose suspected genetic disorders in critically ill infants was terminated early due to loss of equipoise. The rate of genetic diagnosis within 28 days of enrollment was higher for rWGS versus standard tests (31% vs. 3%; p=.003). Changes in management due to test results were reported in 41% (p=.11) of rWGS versus 21% of control patients; however, 73% of control subjects received broad genetic tests (eg, next-generation sequencing panel testing, WES, or WGS) as part of standard testing. A second RCT compared rWGS to rWES in seriously ill infants with diseases of unknown etiology from the neonatal intensive care unit, pediatric intensive care unit, and cardiovascular intensive care unit. The diagnostic yield of rWGS and rWES was similar (19% vs. 20%, respectively), as was time to result (median, 11 vs. 11 days). The NICUSeq RCT compared rWGS (test results returned in 15 days) to a delayed reporting group (WGS with test results returned in 60 days) in 354 infants admitted to an intensive care unit with a suspected genetic disease. Diagnostic yield was higher in the rWGS group (31.0%; 95% CI, 25.5% to 38.7% vs. 15.0%; 95% CI, 10.2% to 21.3%). Additionally, significantly more infants in the rWGS group had a change in management compared with the delayed arm (21.1% vs. 10.3%; p=.009; odds ratio, 2.3; 95% CI, 1.22 to 4.32). Several retrospective and prospective studies including more than 800 critically ill infants and children in total have reported on diagnostic yield for rWGS or rWES. These studies included phenotypically diverse but critically ill infants and had yields of between 30% and 60% for pathogenic or likely pathogenic variants. Studies have also reported associated changes in patient management for patients receiving a diagnosis from rWGS or rWES, including avoidance of invasive procedures, medication changes to reduce morbidity, discontinuation of or additional testing, and initiation of palliative care or reproductive planning. A chain of evidence linking meaningful improvements in diagnostic yield and changes in management expected to improve health outcomes supports the clinical value of rWGS or rWES. 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 Effective 1/1/2026, the following CPT codes may be considered medically necessary for Medicare Advantage Plans and Commercial Products when the medical criteria in the online authorization tool for participating providers is met: • RCIGM Rapid Whole Genome Sequencing Comparator Genome – CPT code 0425U
• RCIGM Ultra-Rapid Whole Genome Sequencing – CPT code 0426U

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Medicare Advantage Plans and Commercial Products The following CPT code(s) are considered medically necessary for Medicare Advantage Plans and Commercial Products when the above medical criteria are met: This code can be used for Genomic Unity® Exome Plus Analysis – Proband (Variantyx, Inc.) 0214U Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, proband

This code can be used for Genomic Unity® Exome Plus Analysis – Comparator (Variantyx, Inc.) 0215U Rare diseases (constitutional/heritable disorders), whole exome and mitochondrial DNA sequence analysis, including small sequence changes, deletions, duplications, short tandem repeat gene expansions, and variants in non-uniquely mappable regions, blood or saliva, identification and categorization of genetic variants, each comparator exome (eg, parent, sibling)

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

PUBLISHED Provider Update, November 2025 Provider Update, December 2024 Provider Update, November 2023

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This medical policy is made available to you for informational purposes only. It is not a guarantee of payment or a substitute for your medical judgment in the treatment of your patients. Benefits and eligibility are determined by the member's subscriber agreement or member certificate and/or the employer agreement, and those documents will supersede the provisions of this medical policy. For information on member-specific benefits, call the provider call center. If you provide services to a member which are determined to not be medically necessary (or in some cases medically necessary services which are non-covered benefits), you may not charge the member for the services unless you have informed the member and they have agreed in writing in advance to continue with the treatment at their own expense. Please refer to your participation agreement(s) for the applicable provisions. This policy is current at the time of publication; however, medical practices, technology, and knowledge are constantly changing. BCBSRI reserves the right to review and revise this policy for any reason and at any time, with or without notice. Blue Cross & Blue Shield of Rhode Island is an independent licensee of the Blue Cross and Blue Shield Association. CLICK THE ENVELOPE ICON BELOW TO SUBMIT COMMENTS