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Whole Exome and Whole Genome Sequencing for Diagnosis of Genetic Disorders
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Defines medical necessity, prior authorization, and coverage criteria for whole exome sequencing (WES) and whole genome sequencing (WGS), including rapid testing and specific proprietary Genomic Unity® Exome Plus analyses, for Medicare Advantage and Commercial products of BCBSRI.
No material clinical or coverage changes in this revision.
Coverage Criteria
inv-01: Standard WES/WGS — Pediatric unexplained congenital or neurodevelopmental disorders
Covered when ALL of the following are met:
Trio testing (child + both parents) is preferred when possible but should not delay testing; testing of one available parent is acceptable if both are not immediately available.
inv-02: Rapid WES/WGS — Critically ill neonates/infants
Rapid WES/WGS may be considered medically necessary when BOTH of the following are met:
Trio testing preferred when possible but should not delay rapid testing; testing of one available parent may be done if both are not immediately available.
Whole exome sequencing for the diagnosis of genetic disorders in situations that do not meet the specified medical necessity criteria is not covered for Medicare Advantage Plans and is considered not medically necessary for Commercial Products. This exclusion applies to WES performed outside the covered indications (for example, when the required clinical genetics evaluation, potential to change management, or prior testing conditions are not satisfied).
Repeat whole exome sequencing for diagnostic purposes, including re-analysis of prior WES results, is not covered / not medically necessary. The evidence summarized in the policy finds limited direct clinical utility for routine repeat WES or scheduled re-analysis, and while re-analysis can increase diagnostic yield in some studies, the overall evidence is insufficient to establish improved net health outcomes.
Whole exome sequencing used for population or routine screening for genetic disorders is not covered and is considered not medically necessary for both Medicare Advantage and Commercial Products.
This policy is provided for informational purposes and is not a guarantee of payment. Coverage and payment are governed by the member's subscriber agreement or employer agreement, which supersede this policy. For member-specific coverage information, providers should contact the provider call center.
Use of WES for suspected genetic disorders outside the specified covered indications—specifically disorders other than multiple congenital anomalies or neurodevelopmental disorders after standard workup—is considered investigational/insufficient evidence. The policy notes limited and heterogeneous evidence for these other indications and concludes the evidence is insufficient to demonstrate improvement in net health outcomes.
Services determined to be not medically necessary may be denied, and providers may not charge the member for such services unless the member has been informed in advance and has agreed in writing to accept financial responsibility. Providers should follow applicable participation agreements and member-benefit rules.
Covered Indications
inv-24: Evaluation of unexplained congenital or neurodevelopmental disorders in children after standard workup
Standard WES (with trio when possible) may be considered medically necessary when the following are met; reported diagnostic yields 25–60% depending on age, phenotype, and prior workup:
Trio testing preferred when possible but should not delay testing; singleton testing acceptable if parents unavailable.
inv-25: Critically ill infants in neonatal or pediatric intensive care with suspected genetic disorder of unknown etiology
Rapid WES/WGS (with trio when possible) may be considered medically necessary in critically ill neonatal/pediatric intensive care patients when the criteria below are met; reported diagnostic yields 30–60% in cited studies and associated changes in management have been described:
Trio testing preferred when possible but should not delay rapid testing; rapid testing supported by prospective and observational studies reporting yields of ~30–60% and demonstrated impacts on management (eg, avoidance of invasive procedures, medication changes, initiation of palliative care).
inv-26: Diagnosis of suspected genetic disorders across a range of presentations including neurodevelopmental disorders, critically ill infants, unexplained developmental disabilities, retinal disease, epilepsy, and other Mendelian conditions as supported by cited literature.
Diagnosis of suspected genetic disorders across a range of presentations may be supported by the cited literature; clinical contexts with evidence include neurodevelopmental disorders, critically ill infants, unexplained developmental disabilities, retinal disease, epilepsy, and other Mendelian conditions:
See references cited for detailed study-level yields and outcomes; trio testing generally increases diagnostic yield.
Coding
| 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 |
| 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) |
Provider Actions & Authorization
Prior authorization required for CPT 0214U and 0215U
Prior authorization is required for Medicare Advantage Plans and is recommended for Commercial Products for Genomic Unity® Exome Plus Analysis — Proband (CPT 0214U) and Comparator (CPT 0215U). Only the ordering physician may be involved in authorization; laboratories are not allowed to obtain authorization on behalf of the ordering physician.
- CPT codes: 0214U (Proband) and 0215U (Comparator)
- Laboratories must not obtain clinical authorization or participate in the authorization process on behalf of the ordering physician
Prior authorization and coverage determined by member agreement
Coverage and prior authorization requirements depend on the member's subscriber/employer agreement; contact the provider call center for member-specific benefits and eligibility information.
- Benefits and eligibility are determined by the member's subscriber agreement or employer agreement
- For member-specific benefit information, call the provider call center
Expect standard diagnostic workup (prior targeted testing/CMA) before WES/WGS
Perform a standard diagnostic workup before ordering standard WES/WGS unless rapid testing for a critically ill infant is indicated; this includes prior targeted genetic testing (eg, single-gene tests) or chromosomal microarray when clinically appropriate.
- Standard WES/WGS is considered when prior testing (e.g., chromosomal microarray and/or targeted single-gene testing) has been performed and failed to yield a diagnosis, unless rapid testing is indicated for critically ill infants
Ordering physician must handle authorization; labs prohibited from obtaining authorization
Follow ordering and authorization process rules: the ordering physician must be involved in authorization, and laboratories are prohibited from obtaining authorization or participating in the process on behalf of the ordering physician.
- Ordering physician shall be involved in authorization, appeal, and related administrative processes
- No laboratory representative or third party may obtain authorization on behalf of the ordering physician
Document clinical genetics evaluation and pre-test counseling
Document that the individual was evaluated by a clinician with expertise in clinical genetics, including at minimum a family history and phenotype description, and that pre-test counseling about risks of genetic testing was provided.
- Clinical genetics evaluation with family history and phenotype description required
- Pre-test counseling about potential risks must be documented
Document prior relevant genetic testing and nondiagnostic results
Provide evidence that prior relevant genetic testing (e.g., chromosomal microarray analysis and/or targeted single-gene testing) has been performed and failed to yield a diagnosis when required by the criteria for standard WES/WGS.
- Document prior testing such as chromosomal microarray and/or targeted single-gene testing and results showing no diagnosis when applicable
Verify member benefits and document medical necessity
Verify member-specific benefits and eligibility with the provider call center prior to testing; maintain documentation that supports medical necessity consistent with the member's subscriber or employer agreement.
- Confirm benefits/eligibility via the provider call center
- Retain documentation supporting medical necessity per subscriber/employer agreement
Unauthorized lab services will be denied and billed to the laboratory
If a laboratory provides a laboratory service that has not been authorized, that service will be denied and the financial liability will fall to the participating laboratory; such services may not be billed to the member.
- Unauthorized laboratory services will be denied as the financial liability of the laboratory
- Laboratories may not bill the member for unauthorized services
Do not allow labs/third parties to support authorization — violation may lead to termination
If a laboratory or third party supports any portion of the authorization process (including obtaining authorization), BCBSRI will deem this a violation of policy and may take severe action up to termination from the BCBSRI provider network.
- Support of authorization by a laboratory or third party is a policy violation
- Violations may result in termination from the BCBSRI provider network
Benefit and eligibility determine payment and potential denial
Coverage and payment are determined by the member's subscriber agreement or employer agreement; services determined to be not medically necessary or non-covered under those agreements may be denied or not paid.
- Member contract (subscriber/employer agreement) governs coverage and payment
- Services deemed not medically necessary may be denied or excluded from payment
Pre-test counseling by clinical genetics expert required
Pre-test counseling by a clinician with expertise in clinical genetics about potential risks of genetic testing is required and should be documented as part of the clinical evaluation.
- Counseling must be performed by a clinician with expertise in clinical genetics
- Counseling about potential risks must be documented
Ordering physician must manage authorization and documentation; labs prohibited from obtaining authorization
The ordering physician must be involved in the authorization and documentation process; laboratories are expressly prohibited from obtaining authorization or participating in the authorization process on behalf of the ordering physician.
- Ordering physician shall handle authorization and appeals
- Laboratories must not obtain authorization on behalf of the ordering physician
Definitions
Eligibility Requirements
No top-level eligibility requirement nodes are specified in this policy.
No top-level eligibility requirement nodes are specified in this policy.
No top-level eligibility requirement nodes are specified in this policy.
Not Covered
Whole exome sequencing or whole genome sequencing performed outside the specific covered criteria is not covered (Medicare Advantage) or not medically necessary (Commercial Products). This includes repeat WES (including re-analysis) and WES used for screening purposes. The policy cites limited and heterogeneous evidence for routine use outside defined indications and for re-analysis, and therefore does not support coverage for those scenarios.
This medical policy does not guarantee payment. Coverage exclusions and payment determinations are governed by the member's subscriber or employer agreements. Providers should verify member-specific benefits and eligibility and follow prior authorization and documentation requirements as applicable.
Background
Whole exome sequencing (WES) targets protein-coding regions of the genome (the exome, approximately 1% of the genome) while whole genome sequencing (WGS) includes both coding and noncoding regions. WES/WGS are intended for patients whose disorder remains unexplained after a standard diagnostic workup; trio testing (child plus both parents) is preferred when possible because it increases diagnostic yield and reduces false positives, but testing should not be delayed if trios are not immediately available. Rapid WES/WGS may be appropriate for critically ill neonates or infants in intensive care when specific clinical criteria are met.
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