ModifiedCentenePolicy N/A

Concert Genetic Testing: Exome and Genome Sequencing for the Diagnosis of Genetic Disorders

Defines medical necessity, investigational use, coding examples, and related requirements for exome (ES/WES), genome (GS/WGS), rapid sequencing, and reanalysis for diagnosing suspected genetic disorders in members of Centene-affiliated health plans.

Policy Summary

PayerCentene

PolicyExome and Genome Sequencing for the Diagnosis of Genetic Disorders (coverage criteria)

Policy CodePolicy N/A

Change TypeCriteria revised to expand reanalysis, align terminology, and encourage trio testing

Effective DateN/A

Next Review DateN/A

Key ActionObtain prior authorization using the listed sequencing CPT/PLA examples and ensure evaluation by a Medical Geneticist, Genetic Counselor, or APGN with required clinical documentation.

SourceLink

POLICY UPDATE CHANGES

Added phrase 'with trio testing when possible' to criteria to guide providers and provide clarity.

Expanded reanalysis criteria to allow approval prior to 18 months if there are new qualifying findings.

Changed developmental delay definition to 'global developmental delay' to align with guidelines.

Standard and rapid sequencing criteria updated to better align with PLUGS and NSGC guidance (e.g., inclusion of epileptic encephalopathy; bilateral sensorineural hearing loss plus another finding now covered).

Added CPT/PLA codes 0425U and 0426U to the policy reference table for rapid genome sequencing.

Trio preferredtesting approach preferred

~18 moreanalysis interval

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<=12 morapid sequencing age

2new CPT/PLA codes added

Coverage Criteria for Exome and Genome Sequencing

inv-01: Standard Exome Sequencing - Medically Necessary

Standard exome sequencing (81415, 81416, 0214U, 0215U), with trio testing when possible, is considered medically necessary when:

Standard ES eligibility

A-D prerequisites: A. The member/enrollee has not previously had genome sequencing; B. Alternate etiologies have been considered and ruled out when possible (e.g., environmental exposure, injury, infection, isolated prematurity); C. Clinical presentation does not fit a well-described syndrome for which single-gene or targeted multi-gene panel testing is available; D. The member/enrollee's personal and family histories have been evaluated by a Medical Geneticist, Genetic Counselor or an Advanced Practice Nurse in Genetics (APGN).
Trio testing is encouraged when possible to increase diagnostic yield.
E: clinical findings: Member meets at least one of the following: 1) unexplained epilepsy diagnosed at any age; OR 2) global developmental delay or intellectual disability with onset prior to age 18 years; OR 3) diagnosed with at least one congenital anomaly (functional and/or structural); OR 4) at least TWO of the following: a) bilateral sensorineural hearing loss of unknown etiology; b) symptoms of a complex neurological disorder (e.g., dystonia, hemiplegia, spasticity, epilepsy, myopathy, muscular dystrophy); c) family history suggestive of a genetic etiology, including consanguinity; d) clinical or laboratory findings suggestive of an inborn error of metabolism; e) autism; f) severe neuropsychiatric condition (e.g., schizophrenia, bipolar disorder, Tourette syndrome, self-injurious behavior, reverse sleep–wake cycles); g) period of unexplained developmental regression (unrelated to epilepsy or autism).

inv-02: Reanalysis of ES/GS - Medically Necessary

Reanalysis of exome or genome sequencing data (81417, 81427) is considered medically necessary when:

Reanalysis eligibility: At least one of the following must be true: A) The member/enrollee had prior exome or genome sequencing at least 18 months ago; OR B) The member/enrollee's phenotype has expanded to include clinical findings that were not present at the time of initial analysis AND results of prior exome or genome sequencing do not explain these new clinical findings.

If reanalysis of exome data is not possible, genome sequencing criteria may apply. Policy allows expedited reanalysis prior to 18 months when new qualifying findings emerge.

inv-03: Rapid Exome Sequencing - Medically Necessary

Rapid exome sequencing (rES) (81415, 81416), with trio testing when possible, is considered medically necessary when:

Rapid ES eligibility

A-E prerequisites: A. The member/enrollee is an acutely-ill infant (12 months of age or younger); B. The member/enrollee has not previously had genome sequencing; C. Alternate etiologies have been considered and ruled out when possible (e.g., environmental exposure, injury, infection, isolated prematurity); D. Clinical presentation does not fit a well-described syndrome for which rapid single-gene or targeted multi-gene panel testing is available; E. The member/enrollee's personal and family histories have been evaluated by a Medical Geneticist, Genetic Counselor or an Advanced Practice Nurse in Genetics (APGN).<= 12 months for age
Trio testing is preferred when feasible to improve diagnostic yield and reduce false positives.
F: clinical findings: Member meets at least one: 1) unexplained epilepsy; OR 2) global developmental delay; OR 3) diagnosed with at least one congenital anomaly (functional and/or structural); OR 4) at least TWO of: a) bilateral sensorineural hearing loss of unknown etiology; b) symptoms of a complex neurological disorder (e.g., dystonia, hemiplegia, spasticity, myopathy, muscular dystrophy); c) family history suggestive of a genetic etiology, including consanguinity; d) clinical or laboratory findings suggestive of an inborn error of metabolism.

inv-04: Standard Genome Sequencing - Medically Necessary

Standard genome sequencing (81425, 81426, 0212U, 0213U, 0265U), with trio testing when possible, is considered medically necessary when:

Standard GS eligibility

A-C prerequisites: A. Alternate etiologies have been considered and ruled out when possible (e.g., environmental exposure, injury, infection, isolated prematurity); B. Clinical presentation does not fit a well-described syndrome for which single-gene or targeted multi-gene panel testing is available; C. The member/enrollee's personal and family histories have been evaluated by a Medical Geneticist, Genetic Counselor or an Advanced Practice Nurse in Genetics (APGN).
Trio testing is encouraged when possible.
D: qualifying findings: 1) Prior uninformative exome sequencing AND ES reanalysis is not possible; OR 2) Unexplained epilepsy diagnosed at any age; OR 3) Global developmental delay or intellectual disability with onset prior to age 18 years; OR 4) Diagnosed with at least one congenital anomaly (functional and/or structural); OR 5) At least TWO of: a) bilateral sensorineural hearing loss of unknown etiology; b) symptoms of a complex neurological disorder (e.g., dystonia, hemiplegia, spasticity, epilepsy, myopathy, muscular dystrophy); c) family history suggestive of a genetic etiology, including consanguinity; d) clinical or laboratory findings suggestive of an inborn error of metabolism; e) autism; f) severe neuropsychiatric condition; g) period of unexplained developmental regression (unrelated to epilepsy or autism).

inv-05: Standard Genome Sequencing (medically necessary)

Standard genome sequencing is considered medically necessary when ALL of the following are met:

Standard GS medical necessity

Allowed clinical findings (one required): 1) Prior uninformative exome sequencing AND ES reanalysis is not possible; OR 2) Unexplained epilepsy at any age; OR 3) Global developmental delay or intellectual disability with onset before 18 years; OR 4) At least one congenital anomaly (functional and/or structural); OR 5) At least TWO of: bilateral sensorineural hearing loss of unknown etiology; complex neurological symptoms; family history suggestive of genetic etiology including consanguinity; clinical/laboratory findings suggestive of an inborn error of metabolism; autism; severe neuropsychiatric condition; unexplained developmental regression.

inv-06: Rapid Genome Sequencing (medically necessary)

Rapid genome sequencing (rGS) is considered medically necessary when ALL of the following are met for acutely-ill infants:

Rapid GS medical necessity

Allowed clinical findings for rGS: 1) Unexplained epilepsy; OR 2) Multiple congenital abnormalities affecting unrelated organ systems; OR 3) Epileptic encephalopathy; OR 4) At least TWO of: a) abnormality affecting at least one organ system; b) symptoms of a complex neurological condition (dystonia, hemiplegia, spasticity, epilepsy, hypotonia, myopathy, muscular dystrophy, global developmental delay, intellectual disability); c) family history suggestive of a genetic etiology including consanguinity; d) laboratory findings suggestive of an inborn error of metabolism; e) abnormal response to standard therapy.
rGS is intended for acutely-ill infants where rapid results may affect acute management; trio testing is preferred when feasible.

inv-07: Investigational / Not covered indications

Investigational uses: Repeat standard genome sequencing and standard genome sequencing or rapid exome sequencing for indications other than those specified (including screening asymptomatic/healthy individuals) are considered investigational.

Repeat standard exome or repeat standard genome sequencing is considered investigational and not medically necessary.

inv-08: Standard Exome/Genome Sequencing

Standard exome/genome sequencing is considered medically necessary when ALL of the following are met:

Standard GS/ES general criteria: 1. The etiology of the patient's features is not known, and a genetic etiology is considered a likely explanation for the phenotype based on one of the listed findings (e.g., unexplained epilepsy at any age; confirmed bilateral sensorineural hearing loss of unknown etiology with unrevealing panel testing; intellectual disability by DSM-5 diagnosed by 18 years; global developmental delay in children under five as defined by Belanger et al.; multiple congenital anomalies affecting unrelated organ systems; OR at least TWO specific findings such as a single-organ abnormality, autism, severe neuropsychiatric condition, complex neurological symptoms, family history suggestive of genetic etiology including consanguinity, unexplained developmental regression, or lab findings suggestive of an inherited metabolic disorder).

Also requires: 2) Alternate etiologies considered and ruled out when possible; 3) Clinical presentation does not fit a well-described syndrome with targeted testing available; 4) Personal and family histories evaluated by a Medical Geneticist, Genetic Counselor, or APGN.

inv-09: Rapid Genome Sequencing

Rapid genome sequencing (rGS) is considered medically necessary for acutely-ill individuals when ALL of the following are met:

Rapid GS criteria: 1. The etiology of the patient's features is not known and a genetic etiology is considered likely based on: a) multiple congenital abnormalities affecting unrelated organ systems, OR b) epileptic encephalopathy, OR c) TWO of: single organ system abnormality; complex neurological symptoms (dystonia, hemiplegia, spasticity, epilepsy, hypotonia, myopathy, muscular dystrophy, global developmental delay, intellectual disability); family history suggestive of genetic etiology including consanguinity; laboratory findings suggestive of an inborn error of metabolism; abnormal response to standard therapy. 2. Alternate etiologies have been considered and ruled out when possible. 3. rGS is more efficient and economical than separate single-gene tests or panels based on the differential diagnosis.

Intended for acutely-ill infants (≤12 months) where rapid results may alter acute management; trio testing preferred when possible.

inv-10: Reanalysis of Exome/Genome Sequencing Data

Reanalysis of prior exome/genome data may be approved when specified conditions are met:

Reanalysis criteria: Reanalysis of prior WES/WGS data is permitted when: A) prior ES/GS was performed ≥18 months ago; OR B) the phenotype has expanded with new clinical findings not present at initial analysis AND prior ES/GS results do not explain the new findings. Policy expanded to allow approval prior to 18 months if there are new qualifying findings.>= 18 months or earlier if new qualifying findings

If reanalysis of exome data is not possible, consider genome sequencing criteria as an alternative pathway; expedited approvals may be considered when new findings emerge.

Use of standard exome sequencing or standard genome sequencing for population screening of asymptomatic or healthy individuals is explicitly excluded from coverage. The policy states that these tests are investigational for indications outside those listed, including screening of asymptomatic/healthy individuals for genetic disorders, and may be denied when requested for such purposes.

Requests for rapid exome (rES), rapid genome (rGS), or standard genome sequencing for clinical indications that are not specified in the policy’s medical necessity criteria are considered investigational. The policy identifies these testing modalities as investigational for indications other than those explicitly listed (for example, screening of asymptomatic individuals) and notes such requests may be denied.

When the member’s clinical presentation clearly fits a well-described genetic syndrome for which a validated single-gene test or a targeted multi-gene panel is available, broad exome or genome sequencing is not appropriate. The policy requires that the clinical presentation does not fit a well-described syndrome with available targeted testing as a prerequisite for ES/GS coverage, and states that presentations amenable to targeted testing should be evaluated with those tests instead.

Coverage determinations under this policy are subject to the member’s benefit contract and all plan terms, conditions, exclusions, and limitations. The policy serves as guidance for medical necessity determinations but does not guarantee payment; claims remain subject to applicable state/federal requirements and the member’s coverage documents.

Repeat standard exome sequencing (e.g., CPT 81415, 81416; U-codes 0214U, 0215U) is considered investigational and therefore not medically necessary. Repeat testing with the same standard exome modality will generally not be approved under this policy.

Repeat standard genome sequencing (e.g., CPT 81425, 81426; PLA/ U-codes 0212U, 0213U, 0265U) is considered investigational and is not medically necessary. The policy specifies repeat standard GS as investigational and subject to non-coverage.

Prior versions of the policy included detailed ‘‘not medically necessary’’ sections that have been removed; however, the policy maintains that if a request does not meet the stated medical necessity criteria (for example, alternate etiologies were not considered, the presentation fits a syndrome with available targeted testing, or required documentation is lacking), the service would be considered investigational or not covered. Providers should document how the criteria are met to support coverage.

Covered Clinical Indications

inv-60: Unexplained epilepsy at any age

Covered clinical indications — single-feature and combination criteria:

Unexplained epilepsy at any age is an accepted qualifying indication for standard ES/GS and is included as an eligible finding for rGS (epileptic encephalopathy) in acutely-ill infants.

NSGC recommends offering genetic testing for unexplained epilepsy without age limitation.

inv-61: Global developmental delay or intellectual disability with onset prior to age 18

GDD/ID before 18: Global developmental delay or intellectual disability with onset prior to age 18 years is a qualifying indication for ES/GS when criteria are otherwise met; GDD definition per Belanger et al. is referenced for children under five.

Intellectual disability per DSM-5 (moderate/severe/profound) diagnosed by 18 years is included per NSGC/ACMG guidance.

inv-62: At least one congenital anomaly (functional and/or structural)

Coding and Billing References

Standard Exome Sequencing (examples)CPTCovered

81415	Exome sequencing, proband (example common CPT for standard exome)
81416	Exome sequencing, duo/trio comparator (example common CPT for standard exome)
0214U	Example U-code associated with exome sequencing
0215U	Example U-code associated with exome sequencing

Reanalysis of ES/GSCPTCovered

81417	Reanalysis of exome or genome sequencing data (example CPT)
81427	Whole genome reanalysis (example CPT)

Standard and Rapid Genome Sequencing (examples)CPTCovered

81425	Genome sequencing, proband (example CPT)
81426	Genome sequencing, duo/trio comparator (example CPT)
0212U	Example U-code associated with genome sequencing
0213U	Example U-code associated with genome sequencing
0265U	Example U-code associated with genome sequencing
0094U	Rapid whole genome sequencing (example U-code)
0425U	Rapid genome comparator (example U-code)
0426U	Ultra-rapid whole genome sequencing (example U-code)

Standard Genome Sequencing CodesCPTCovered

81425	Genome sequencing, interpretation and report
81426	Genome sequence analysis and interpretation
0212U	Proprietary PLA code listed in policy
0213U	Proprietary PLA code listed in policy
0265U	Proprietary PLA code listed in policy

Rapid Genome Sequencing CodesCPTCovered

81425	Genome sequencing, interpretation and report
81426	Genome sequence analysis and interpretation
0094U	Proprietary PLA code listed for rapid GS
0425U	Proprietary PLA code listed for rapid GS
0426U	Proprietary PLA code listed for rapid GS

Rapid Exome Sequencing CodesCPTExperimental

81415	Exome sequencing, interpretation and report (rapid)
81416	Exome sequence analysis and interpretation (rapid)

Referenced CPT/PLA codes in policyCPT

0425U	CPT/PLA code added for rapid genome sequencing (policy reference table)
0426U	CPT/PLA code added for rapid genome sequencing (policy reference table)
0212U	PLA code added/used in Standard Genome Sequencing reference table

Rapid sequencing age cutoff — operational threshold for rES/rGS

Age cutoffAcutely-ill infants 12 months of age or younger (<=12 months)

Applies toRapid exome (rES) and rapid genome (rGS) criteria for expedited testing

RationaleDesigned for acutely-ill infants where rapid results may affect acute management

Reanalysis interval — recommended timing for reanalysis after prior ES/GS

Standard interval>= 18 months from prior ES/GS (typical reanalysis timing)

Provider Actions, Documentation, and Authorization

Prior Authorization

Code groups referenced for authorization

Prior authorization is required for requests that include the exome and genome sequencing code groups referenced in the policy. Use the listed CPT/PLA/U-code examples when submitting authorization requests and claims to ensure proper routing and review.

Standard Exome Sequencing examples: 81415, 81416, 0214U, 0215U
Reanalysis examples: 81417, 81427
Standard Genome Sequencing examples: 81425, 81426, 0212U, 0213U, 0265U
Rapid Genome Sequencing examples: 81425, 81426, 0094U, 0425U, 0426U

Denial Risk

Screening excluded

Standard exome and genome sequencing, as well as rapid sequencing variants, are investigational and not covered when ordered for screening of asymptomatic or healthy individuals.

Eligibility and Pre-test Requirements

Top-level eligibility for exome or genome sequencing requires that the clinical evaluation supports a likely genetic etiology and that key prerequisites are met: alternate (non-genetic) etiologies have been considered and ruled out when possible; the clinical presentation does not fit a well-described syndrome for which single-gene or targeted panel testing is available; and the member’s personal and family histories have been evaluated by a Medical Geneticist, Genetic Counselor, or Advanced Practice Nurse in Genetics (APGN). Additional specific qualifying clinical findings (e.g., unexplained epilepsy, global developmental delay/intellectual disability, congenital anomalies, or ≥2 listed features) are required per the detailed criteria sets.

A documented evaluation of personal and family history by a Genetics professional (Medical Geneticist, Genetic Counselor, or APGN) is required prior to approval. Family history findings that suggest a genetic etiology — including consanguinity — are relevant and may count toward qualifying criteria (for example, as one of the required ‘‘TWO of the following’’ features). The policy explicitly lists family history suggestive of a genetic etiology as an accepted qualifying feature.

Evaluation by a Medical Geneticist, Genetic Counselor, or Advanced Practice Nurse in Genetics (APGN) is a required element of the coverage criteria across multiple sections. The policy repeatedly consolidates this requirement: personal and family histories must be assessed by an appropriate genetics professional before ES/GS/rES/rGS will be considered medically necessary.

The policy consistently requires that a genetics professional evaluate the member prior to testing. This requirement appears in multiple criteria sets and has been consolidated in the policy language to ensure that ordering includes documentation of genetics specialist involvement (Medical Geneticist, Genetic Counselor, or APGN).

Definitions and Key Terms

Exome Sequencing (ES/WES) — definition and scope

DefinitionSequencing and copy-number variant (CNV) analysis of the protein-coding regions (exons) of the genome (the exome)

ScopeCovers ~1% of the genome and includes the majority of currently known heritable disease-causing variants

Use casesDiagnostic evaluation when phenotype suggests a genetic etiology not explained by targeted testing

Genome Sequencing (GS/WGS) — definition and scope

DefinitionComprehensive sequencing of both coding and noncoding regions — the complete DNA sequence (whole genome)

ScopeBetter detection of large deletions/duplications, mid-size indels (~10-500 bp), repeat expansions, deep intronic variants, structural variants, and some methylation/uniparental disomy events

Not Covered and Investigational Uses

Not covered items include: screening asymptomatic or healthy individuals with ES or GS, and repeat standard ES/GS which are considered investigational. The policy explicitly lists screening of asymptomatic individuals and repeat standard genome/exome sequencing as not covered or investigational under the policy.

The policy explicitly states that performing exome or genome sequencing for the purpose of screening asymptomatic or healthy individuals is investigational and is not covered. Such use is outside the listed clinical indications and may be denied.

Repeat standard genome sequencing is considered investigational and therefore not covered. The policy identifies repeat standard GS as a not medically necessary indication.

Clinical presentations that clearly fit a well-described genetic syndrome — where validated single-gene or targeted multi-gene panel testing is available — should be evaluated with those targeted tests rather than broad exome or genome sequencing. The policy excludes such presentations from coverage for ES/GS and directs clinicians to pursue targeted testing when appropriate.

Additional non-covered items are governed by plan benefit documents and applicable exclusions; the policy does not list every possible exclusion in this excerpt. Coverage is subject to all plan terms, conditions, exclusions, and limitations, and state or federal requirements where applicable.

Background and Evidence Summary

Exome sequencing targets the protein-coding regions of the genome (the exome), which represent roughly 1% of the genome but contain the majority of known heritable disease-causing variants; exome testing typically captures many clinically relevant variants. Genome sequencing provides broader coverage of coding and noncoding regions and has greater ability to detect copy-number variants, mid-size indels, structural variants, and other variant types, and therefore may have a higher diagnostic yield in some clinical contexts. Rapid sequencing modalities (rES/rGS) accelerate turnaround time to produce preliminary results often in 7 days with final reports typically within two weeks and are intended for acutely ill infants where expedited diagnosis could alter acute management.

Policy Summary

PayerCentene

PolicyExome and Genome Sequencing for the Diagnosis of Genetic Disorders (coverage criteria)

Policy CodePolicy N/A

Change TypeCriteria revised to expand reanalysis, align terminology, and encourage trio testing

Effective DateN/A

Next Review DateN/A

Key ActionObtain prior authorization using the listed sequencing CPT/PLA examples and ensure evaluation by a Medical Geneticist, Genetic Counselor, or APGN with required clinical documentation.

SourceLink

On This Page

Rapid testing primarily intended for infants ≤12 months where results may affect acute management.

When GS is performed, the mitochondrial genome is assumed to be included as part of the analysis.

Congenital anomaly: At least one congenital anomaly (functional and/or structural) is a qualifying finding for ES/GS when other criteria are met; for rGS multiple congenital anomalies affecting unrelated organ systems is an rGS-specific allowed finding.

ACMG guidance supports ES/GS for patients with one or more congenital anomalies prior to one year of age.

inv-63: Two or more features from designated list

Two-or-more qualifying features: Member has at least TWO of the following features: 1) Bilateral sensorineural hearing loss of unknown etiology (panel testing unrevealing may be required in some scenarios); 2) Symptoms of a complex neurological disorder (e.g., dystonia, hemiplegia, spasticity, epilepsy, hypotonia, myopathy, muscular dystrophy); 3) Family history strongly suggestive of a genetic etiology, including consanguinity; 4) Clinical or laboratory findings suggestive of an inborn error of metabolism; 5) Autism; 6) Severe neuropsychiatric condition (e.g., schizophrenia, bipolar disorder, Tourette syndrome, self-injurious behavior, reverse sleep–wake cycles); 7) Period of unexplained developmental regression (unrelated to epilepsy or autism).At least 2 features required

Policy expanded to allow bilateral sensorineural hearing loss plus one other eligible finding in some scenarios.

inv-64: Reanalysis when prior ES/GS >=18 months ago or phenotype expanded with unexplained new findings

Reanalysis eligibility specifics: Reanalysis is appropriate when prior ES/GS was performed ≥18 months ago, OR when the phenotype has expanded with new unexplained clinical findings that prior ES/GS do not explain.>= 18 months or sooner if new qualifying findings

Policy allows expedited reanalysis prior to 18 months when new qualifying findings emerge (supported by PLUGS).

inv-65: Acutely-ill infants (<=12 months) when rapid testing may affect acute management

rGS eligibility for acutely-ill infants: Acutely-ill infants (<=12 months) may qualify for rapid genome or rapid exome sequencing when rapid testing may affect acute management and when rGS/rES criteria are otherwise met (see rapid criteria sets).<= 12 months

Trio testing preferred when possible; rGS intended when results will inform acute care.

inv-66: Standard GS when prior ES uninformative and ES reanalysis is not possible

GS after uninformative ES: Standard genome sequencing may be covered when prior exome sequencing was uninformative and ES reanalysis is not possible; consider GS criteria in such cases.

This pathway is an accepted coverage fallback when reanalysis cannot be performed.

inv-67: Unexplained epilepsy at any age (GS-specific mention)

Unexplained epilepsy (GS-specific): Unexplained epilepsy is included as an allowed finding for standard GS and as an eligible rGS finding (epileptic encephalopathy) for acutely-ill infants; NSGC recommends offering genetic testing without age limitation.

Multi-gene comprehensive testing is recommended as a first-tier test for unexplained epilepsy.

inv-68: Global developmental delay or intellectual disability before age 18

GDD/ID (ACMG-aligned): Global developmental delay or intellectual disability with onset before age 18 years meets criteria per ACMG guidance and is an allowed indication for ES/GS when other criteria are met.

GDD definition per Belanger et al. referenced for young children.

inv-69: Multiple congenital anomalies or at least one congenital anomaly

Congenital anomalies (GS/rGS applicability): Multiple congenital anomalies (affecting unrelated organ systems) qualify for rGS in acutely-ill infants; at least one congenital anomaly qualifies for standard GS/ES when other criteria are met.

ACMG and PLUGS guidance support ES/GS for congenital anomalies, especially in infants.

inv-70: Confirmed bilateral sensorineural hearing loss when panel testing unrevealing

Bilateral sensorineural hearing loss: Confirmed bilateral sensorineural hearing loss of unknown etiology with unrevealing panel testing is a qualifying feature for ES/GS; policy expansion allows bilateral SNHL plus another eligible clinical finding to meet criteria in some scenarios.

ACMG/NSGC resources inform tiered testing approaches; panel testing may be recommended first unless clinical features suggest otherwise.

inv-71: At least two listed features (complex presentations)

Two-or-more complex features list: At least two of the following meet the qualifying combination requirement: complex neurological symptoms; family history suggestive of genetic etiology including consanguinity; autism; severe neuropsychiatric condition; unexplained developmental regression; laboratory findings suggestive of an inherited metabolic disorder; single-organ abnormality or other designated features per policy lists.At least 2 features required

Counts toward ES/GS or rGS eligibility as specified in criteria sets.

inv-72: Prior uninformative exome sequencing when ES reanalysis not possible

Prior uninformative ES fallback: Prior uninformative exome sequencing when ES reanalysis is not possible permits coverage of standard genome sequencing as an alternative diagnostic pathway.

See Standard GS criteria for prerequisites and qualifying findings.

inv-73: Unexplained epilepsy - NSGC recommendation

Unexplained epilepsy guidance (NSGC): NSGC guidance recommends offering genetic testing for unexplained epilepsy without age limitation; epileptic encephalopathy is now explicitly included as an eligible rGS clinical finding for acutely-ill infants/individuals.

Multi-gene comprehensive testing (ES/GS/panel) is recommended as first-tier per NSGC.

inv-74: Bilateral sensorineural hearing loss plus another eligible clinical finding

Bilateral SNHL plus another finding: Bilateral sensorineural hearing loss plus another eligible clinical finding is now covered in certain scenarios per recent policy expansion; prior unrevealing panel testing may be required depending on clinical context.

Policy aligns with ACMG/NSGC guidance and tiered testing considerations.

inv-75: Intellectual disability and global developmental delay per formal assessment

Intellectual disability / GDD definition: Intellectual disability and global developmental delay are qualifying indications when defined by formal assessment (GDD per Belanger et al.; ID per DSM-5) and onset criteria are met (ID by 18 years).

Policy updated terminology to 'global developmental delay' to align with guidelines.

inv-76: Multiple congenital anomalies and other complex presentations

Complex presentations and multiple congenital anomalies: Multiple congenital anomalies affecting unrelated organ systems and other complex presentations (including epileptic encephalopathy) qualify for rGS in acutely-ill infants; similar complex presentations qualify for standard ES/GS when other criteria are met.

PLUGS and ACMG guidance support these indications.

inv-77: Pediatric patients with congenital anomalies, intellectual disability, and rare diseases

Pediatric guideline-supported populations: Pediatric patients with congenital anomalies, intellectual disability, and rare diseases are referenced as populations supported by cited guidelines and systematic reviews for ES/GS testing when clinical criteria are met.

References include ACMG, PLUGS, NSGC, and systematic reviews documenting diagnostic yield and clinical utility.

ExceptionReanalysis may be approved sooner if the phenotype has expanded with new clinical findings not explained by prior testing

Alternate pathwayIf reanalysis of exome data is not possible, genome sequencing criteria may be consulted

VUS rate comparison — key metric comparing VUS rates between ES/GS and multigene panels

VUS rates (genomic vs panels)Exome/Genome VUS rate 22.5% vs multigene panels 32.6%

Source studyRehm et al. (2023) comparison of reported VUS rates

ImplicationLower VUS burden with ES/GS may reduce uncertain results compared to panels

Do not authorize ES/GS/rES/rGS for asymptomatic screening purposes.

Denial Risk

Rapid Genome Sequencing denial triggers

Rapid genome sequencing (rGS) requests are at high risk for denial when the request does not meet the acute illness criteria, when alternate (non-genetic) etiologies have not been considered or documented, or when the presentation fits a well-described syndrome for which targeted testing is available.

rGS is intended for acutely-ill infants (≤12 months) meeting specified clinical criteria.
Denial triggers: lack of acute presentation documentation, failure to rule out alternate etiologies, or availability of more specific targeted testing.

Note

Coverage conditional on policy and contract terms

Coverage and payment decisions are governed by the member's coverage documents and contract terms. This policy provides medical necessity guidance but does not guarantee payment; state Medicaid provisions, Medicare NCDs/LCDs, and the Health Plan contract take precedence where applicable.

Verify member eligibility and contract-specific coverage prior to authorization.
For Medicaid, state provisions supersede this clinical policy.
For Medicare, review applicable NCDs/LCDs before applying criteria.

Documentation Required

Consider/rule out alternate etiologies

Document that alternate etiologies were considered and ruled out when possible (e.g., environmental exposure, injury, infection, isolated prematurity, MRI abnormalities/brain malformations) prior to ordering exome or genome sequencing.

Explicitly record evaluation for environmental, infectious, traumatic, and perinatal causes.
If applicable, document relevant imaging, laboratory testing, and clinical assessments that support exclusion of non-genetic causes.

Documentation Required

Required clinical documentation

Authorization requests must include sufficient clinical documentation to demonstrate that the member meets the policy's medical necessity criteria. This includes specialty evaluation, detailed phenotype, prior testing, and rationale for choosing ES/GS over targeted testing.

Documentation of evaluation by a Medical Geneticist, Genetic Counselor, or APGN.
Detailed personal and family history and a clear description of the phenotype.
Results of prior genetic testing (e.g., panels) or explanation why panels/single-gene tests are not appropriate.
For reanalysis requests, include timing of prior ES/GS (≥18 months) or documentation of new qualifying findings.

Documentation Required

Required clinical documentation and counseling

Pre-test counseling is recommended and documentation of counseling should be provided when possible. Counseling should include discussion of secondary/incidental findings and a plan for return of results.

Document patient or guardian discussion of risks, benefits, and alternatives.
Document elicited preferences regarding secondary/incidental findings and plan for result disclosure.

Billing Rule

Documentation and claim caveats

This policy guides medical necessity determinations but does not guarantee payment. Providers must exercise professional judgment and ensure claims are supported by documentation; billing should follow submitted authorization and coverage determinations.

Ensure claims use the codes that match the authorized service and include supporting documentation.
Payment is subject to contract terms, exclusions, and administrative procedures.

Note

Tiered testing considerations

When evaluating hearing loss, follow guideline-preferred tiered testing approaches: start with comprehensive hearing-loss gene panels unless clinical findings indicate genome sequencing as first-line. Panels remain appropriate when a specific syndromic cause is suspected; ES/GS is preferred when panels are unrevealing or multiple criteria are met.

If bilateral sensorineural hearing loss is confirmed and panel testing is unrevealing, ES/GS may be appropriate.
Document why panel testing is insufficient when requesting ES/GS for hearing loss.

Additional eligibility nodes follow the same structure: prerequisites (consideration of alternate etiologies, genetics professional evaluation, and that the presentation does not fit a well-described syndrome with available targeted testing) plus one or more qualifying clinical findings. Providers should follow the specific criteria set applicable to the requested test type (standard ES/GS, rapid ES/GS, or reanalysis).

One prerequisite for coverage is that the member’s clinical presentation does not fit a well-described syndrome for which validated single-gene testing or a targeted multi-gene panel is available. If the presentation is consistent with such a syndrome, targeted testing is preferred and ES/GS is not indicated under the policy.

The requirement that the clinical presentation not fit a well-described syndrome is reiterated across multiple criteria sets. When a syndrome-consistent presentation exists and targeted testing is available, the policy indicates that targeted single-gene or panel testing should be pursued instead of broad ES/GS.

Multiple entries in the eligibility section emphasize that ES/GS coverage is contingent on the clinical picture being unsuited to targeted testing. The policy repeats this condition to guide appropriate test selection and to encourage tiered diagnostic approaches where applicable.

The policy repeatedly states that presentation fitting a well-described syndrome with available single-gene or targeted panel tests precludes approval of broad exome/genome sequencing; these repeated statements are consolidated to inform clinician decision-making and documentation expectations.

Comparative yieldGS often has higher diagnostic yield and may be preferable as a first-line test in some settings

Rapid Exome/Genome Sequencing (rES/rGS) — definition and turnaround expectations

DefinitionAccelerated sequencing of the exome or genome with preliminary results often <7 days and final report typically <2 weeks

Primary indicationUsed for acutely-ill infants where rapid diagnosis may change acute medical or surgical management

Trio testingTrio testing is preferred when possible to increase diagnostic yield

Exome Sequencing (ES) — concise definition

Concise definitionA genomic technique for sequencing all protein-coding regions of genes in the genome (the exome)

SynonymAlso known as whole exome sequencing (WES)

PurposeDetects variants in coding regions associated with many heritable disorders

Genome Sequencing (GS) — concise definition

Concise definitionSequencing of the complete DNA sequence including coding and non-coding elements (whole genome)

CapabilityEnables detection of variants outside exons and structural/CNV events less readily detected by ES

When usedConsidered when broader coverage or detection of structural variants is needed

Trio Testing — definition and rationale

DefinitionSimultaneous testing of the proband and both biological/genetic parents to improve diagnostic yield and reduce false positives

RationaleHelps interpret variant inheritance and distinguishes de novo from inherited variants

Preferred approachRecommended whenever possible and noted explicitly in rapid and standard criteria

Congenital anomalies — definition

DefinitionStructural or functional abnormalities usually evident at birth or shortly thereafter, not specific to a well-delineated genetic syndrome

Scope examplesMay affect life expectancy, health status, or require medical intervention; multiple congenital anomalies affecting unrelated organ systems are emphasized in GS/rGS criteria

Role in criteriaOne congenital anomaly (for GS) or multiple for rGS in infants can qualify for sequencing under policy

Global Developmental Delay / Intellectual Disability — definition and onset criteria

DefinitionDelayed attainment in at least two developmental domains (e.g., communication, gross/fine motor, cognition, social-emotional, adaptive skills)

Onset criteriaUsed for children where deficits occur in the developmental period; intellectual disability has onset during developmental period per DSM-V

Evidence referencePolicy aligns with Belanger et al. and ACMG guidance for GDD/ID definitions

global developmental delay — short form definition

Short formGlobal developmental delay: slow-to-meet or not reaching expected milestones in at least two developmental areas

UsageUsed in rapid and standard sequencing eligibility criteria for pediatric patients

DomainsExamples: communication, gross/fine motor, cognition, social-emotional, adaptive skills

GDD definition (Belanger et al.) — formal GDD criteria citation

Formal GDD criteriaSignificant delay (≥2 standard deviations below the mean) in at least two developmental domains (gross/fine motor, speech/language, cognition, social/personal, activities of daily living) — Belanger et al.

ReferenceBélanger SA, Caron J. Evaluation of the child with global developmental delay and intellectual disability (2018)

Clinical applicationUsed to define qualifying developmental delay in policy coverage criteria

Secondary/incidental findings — NSGC/ACMG position references

DefinitionFindings unrelated to the indication for testing that may have medical value or utility (secondary/incidental findings)

GuidanceNSGC and ACMG recommendations on reporting and pre-test counseling about secondary/incidental findings are referenced; counseling should include option to opt out

Counseling implicationPre-test counseling should elicit preferences about secondary findings and plan for returning such results

Reanalysis of genomic results — definition and ACMG recommendations

DefinitionReanalysis: periodic reevaluation of previously obtained genomic data/variants using updated knowledge, methods, or expanded phenotype

ACMG recommendationsACMG 'Points to consider' recommends variant- and case-level reevaluation; reanalysis often performed ~18 months to 2 years after initial ES

Policy applicationReanalysis is medically necessary per criteria when prior testing ≥18 months ago or phenotype has expanded; reanalysis may be unavailable if earlier data incompatible with current pipelines