ModifiedCommunity Health Plan WashingtonPolicy N/A

Exome and Genome Sequencing for the Diagnosis of Genetic Disorders

Coverage criteria for clinical use of exome (ES/WES) and genome (GS/WGS) sequencing, including rapid and reanalysis, for diagnosis of suspected genetic disorders; intended for providers ordering genetic testing for members of Community Health Plan Washington.

Policy Summary

PayerCommunity Health Plan Washington

PolicyExome and Genome Sequencing for the Diagnosis of Genetic Disorders

Policy CodePolicy N/A

Change TypeModified clinical criteria, coding updates, and reanalysis timing

Effective DateN/A

Next Review DateN/A

Key ActionObtain prior authorization with clinical justification and required documentation (including evaluation by a Medical Geneticist or Genetic Counselor) when ordering ES/GS or reanalysis.

SourceLink

POLICY UPDATE CHANGES

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

Modified standard and rapid sequencing criteria to better align with guidelines and remove burdensome criteria (e.g., bilateral sensorineural hearing loss plus one other finding now covered).

Added new CPT codes 0425U and 0426U to the policy reference table for Rapid Genome Sequencing.

Added phrase 'with trio testing when possible' to criteria for standard genome sequencing to guide providers.

Added/strengthened pre- and post-test genetic counseling recommendations referencing NSGC guidance regarding secondary/incidental findings.

81415/81416Standard/rapid exome CPTs

81425/81426

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Coverage Criteria for Exome and Genome Sequencing

Standard Exome Sequencing - Medically Necessary

Standard exome sequencing (81415, 81416, 0214U, 0215U), with trio testing when possible, is considered medically necessary when ALL of the following are met:

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)

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)

E. Clinical findings (at least one): The member/enrollee meets at least one of: 1) unexplained epilepsy diagnosed at any age; OR 2) global developmental delay or intellectual disability with onset prior to age 18 years; OR 3) at least one congenital anomaly (functional and/or structural); OR 4) at least TWO of the following specified findings: 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)

Rapid Exome Sequencing - Medically Necessary

Rapid exome sequencing (rES) (81415, 81416), with trio testing when possible, is considered medically necessary when ALL of the following are met:

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

Standard Genome Sequencing - Medically Necessary

Standard genome sequencing (81425, 81426, 0212U, 0213U, 0265U), with trio testing when possible, is considered medically necessary when ALL of the following are met:

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)

D. Clinical findings (at least one): The member/enrollee meets at least one of: 1) previously had 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) at least one congenital anomaly (functional and/or structural); OR 5) at least TWO of the following specified findings: 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)

Reanalysis of Exome or Genome Sequencing Data - Medically Necessary

Reanalysis of exome or genome sequencing data (81417, 81427) is considered medically necessary when ANY of the following are met:

A: Initial exome or genome sequencing was performed at least 18 months ago>=18 months

If reanalysis of exome data is not possible, see genome sequencing criteria for coverage.

B: The member/enrollee's phenotype has expanded to include clinical findings that were not present at the time of the initial sequencing, AND results of prior exome or genome sequencing do not explain these new clinical findings

Standard Genome/Exome Sequencing

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

Qualifying findings (examples): a) Epilepsy of unexplained etiology with onset at any age; b) Confirmed bilateral sensorineural hearing loss of unknown etiology with unrevealing panel testing; c) Intellectual disability per DSM-5 diagnosed by age 18; d) Global developmental delay in children under age 5 affecting at least two developmental domains; e) Multiple congenital anomalies affecting unrelated organ systems; f) At least TWO of the following: abnormality affecting at minimum a single organ system; autism; severe neuropsychiatric condition; symptoms of a complex neurological condition; family history strongly suggestive of a genetic etiology, including consanguinity; period of unexplained developmental regression (unrelated to epilepsy or autism); laboratory findings suggestive of an inherited metabolic disorder.

2: Alternate etiologies have been considered and ruled out when possible (e.g., MRI abnormalities/brain malformations, environmental exposure, injury, infection, isolated prematurity).

3: Clinical presentation does not fit a well-described syndrome for which more targeted testing is available.

Rapid Genome/Exome Sequencing

Rapid genome/exome sequencing is considered medically necessary for acutely ill individuals when ALL of the following are met:

1: Etiology of the patient's features is unknown and a genetic etiology is considered likely based on one of the following: a) multiple congenital anomalies affecting unrelated organ systems; OR b) epileptic encephalopathy; OR c) at least TWO of the following: abnormality affecting at least one organ system; symptoms of a complex neurological condition; family history strongly suggestive of a genetic etiology, including consanguinity; laboratory findings suggestive of an inborn error of metabolism; abnormal response to standard therapy.

Used for acutely ill individuals per PLUGS Rapid Genome Sequencing guidance.

2: Alternate etiologies have been considered and ruled out when possible (e.g., MRI abnormalities/brain malformations, environmental exposure, injury, infection, isolated prematurity).

3: Rapid sequencing is more efficient and economical than separate single-gene tests or panels that would otherwise be recommended based on the differential diagnosis.

These conditions ensure rapid testing is appropriate and likely to impact immediate management.

Reanalysis of Exome/Genome Sequencing Data

Reanalysis of prior exome/genome data:

Reanalysis path: Reanalysis is permitted and the policy allows an approval path prior to 18 months if there are new qualifying findings; the reanalysis criteria were streamlined and renamed to 'Reanalysis of Exome or Genome Sequencing Data'.

Policy updated to align with PLUGS and ACMG considerations.

Standard exome and genome sequencing are explicitly limited by this policy: standard exome or genome sequencing is considered investigational for all indications not meeting the listed clinical criteria. This includes use of ES/GS for population screening or for screening asymptomatic or healthy individuals, which is investigational and not covered under the policy.

The policy also states that repeat standard exome or genome sequencing (i.e., repeating a prior standard ES or GS) is considered investigational (not covered) and therefore may be denied when submitted without meeting reanalysis or new-criteria pathways.

When a patient’s clinical presentation fits a well-described syndrome for which targeted single-gene testing or a focused multi-gene panel is available, targeted testing is preferred and broad exome/genome sequencing is excluded. The policy requires that the clinical presentation not fit a well-described syndrome with available targeted testing as a condition for ES/GS coverage.

Practically, providers should perform appropriate syndrome-directed testing first where a specific gene or panel is indicated; ES/GS should be reserved for cases where the phenotype is not explained by targeted testing or when prior targeted testing is unrevealing.

Coverage determinations under this policy are subject to the member’s plan documents and applicable legal requirements. All coverage decisions and benefit administration remain subject to the terms, conditions, exclusions, and limitations of the member’s coverage documents, and state Medicaid provisions take precedence where applicable.

This policy provides medical necessity guidance but does not guarantee payment; providers must follow the Health Plan’s administrative rules and the member’s contract when submitting claims.

The policy explicitly states that repeat standard exome sequencing (81415, 81416, 0214U, 0215U) and repeat standard genome sequencing (81425, 81426, 0212U, 0213U, 0265U) are considered investigational and are not covered when proposed as simple repeats of prior standard testing.

Requests for repeat standard ES/GS should be evaluated against the reanalysis criteria (see reanalysis policy language) rather than being automatically approved as repeat diagnostic sequencing.

The current policy language removed and streamlined prior explicit not-medically-necessary (NMN) sections and previously burdensome repeat-testing language. The update replaced some older NMN conditions with clarified reanalysis pathways and renamed sections (e.g., 'Reanalysis of Whole Exome Sequencing Data').

As reflected in the revisions, the policy now emphasizes reanalysis and updated criteria rather than maintaining multiple prior NMN clauses; providers should consult the reanalysis criteria when prior testing is at issue.

Covered Indications and Clinical Presentations

Diagnosis of suspected genetic disorders in individuals meeting the policy clinical criteria

Diagnosis of suspected genetic disorders in individuals meeting the policy clinical criteria (see Standard ES, Rapid ES for acutely ill infants, and Standard GS criteria).

Covered indications (examples): Includes individuals with unexplained epilepsy, global developmental delay or intellectual disability with onset <18 years, multiple congenital anomalies affecting unrelated organ systems, or combinations of listed clinical findings (e.g., bilateral sensorineural hearing loss plus other qualifying features).

See individual test-specific criteria (Standard ES, Rapid ES, Standard GS) for full qualifying detail.

Unexplained epilepsy at any age

Unexplained epilepsy at any age — testing recommendation and approach:

Recommendation: Individuals with unexplained epilepsy should be offered genetic testing without limitation of age; multi-gene comprehensive testing (panel, exome, or genome) is strongly recommended as a first-tier test per NSGC guidance.

Coding and Billing

Standard/Rapid Exome CPT CodesCPTCovered

81415	Exome sequencing, proband
81416	Exome sequencing, with parental samples (duo/trio)
0214U	Standard exome sequencing - proprietary/other
0215U	Standard exome sequencing - comparator

Standard Genome CPT CodesCPTCovered

81425	Genome sequencing, proband or trio (standard)
81426	Genome sequencing, with comparator/duo/trio
0212U	Proprietary whole genome analysis - proband
0213U	Proprietary whole genome analysis - comparator
0265U	Whole genome sequencing (other U-code)

Reanalysis CPT CodesCPTCovered

81417	Reanalysis of exome/genome data (exome reanalysis)
81427	Reanalysis of genome data (genome reanalysis)

Common ICD Codes referencedICD-10

F70-F79	Intellectual disabilities
F80.0-F89	Developmental disorders
Q00.0-Q99.9	Congenital malformations, deformations and chromosomal abnormalities
R56.9	Unspecified convulsions
R62.0	Delayed milestone in childhood
R62.50	Unspecified lack of expected normal physiological development in childhood
R62.51	Failure to thrive
G40.909	Epilepsy, unspecified

Updated policy reference table codesCPT

0212U	PLA/other code added for standard genome sequencing (as referenced)
0425U	CPT/PLA code added to policy reference table for Rapid Genome Sequencing
0426U	CPT/PLA code added to policy reference table for Rapid Genome Sequencing

Reanalysis timing — allowance to reanalyze prior to 18 months if new qualifying findings are present

Reanalysis timing policy changePolicy expanded to allow reanalysis approval prior to 18 months from the original test date if new qualifying clinical findings are present (supported by PLUGS).

Standard timing expectationReanalysis of exome data is often performed approximately 18 months to 2 years after an initial uninformative ES when no new qualifying findings exist.

Trigger for earlier reanalysisAn expanded or new phenotype with clinical findings not present at initial sequencing that are unexplained by prior results can justify reanalysis before 18 months.

If reanalysis not possibleIf exome reanalysis cannot be performed, genome sequencing may be considered per the Standard Genome Sequencing criteria.

Provider Actions, Authorization, and Documentation

Prior Authorization

Prior authorization required for ES/GS and reanalysis

Prior authorization is required for exome sequencing (ES), genome sequencing (GS), rapid ES/GS, and for requests for reanalysis. Requests must include clinical justification demonstrating the member meets the policy medical‑necessity criteria (see sequencing criteria sections) and specify whether prior ES/GS has been performed and whether reanalysis of prior data is possible.

Affected codes include CPT 81415, 81416, 81425, 81426 and related PLA/U codes (see policy reference table).
Prior authorization processes and code lists are subject to updates — verify current required CPT/PLA codes when submitting requests.

Documentation Required

Documentation required with prior authorization

Prior authorization submissions must document prior testing and the feasibility of reanalysis. If a prior ES/GS was performed, include the date, laboratory, and whether variant‑ or case‑level reanalysis is technically possible. Reanalysis requests should meet the policy’s reanalysis criteria (e.g., new qualifying clinical findings) to be approvable.

Eligibility Requirements and Restrictions

Eligibility for ES/GS requires evaluation of the member’s personal and family histories by a genetics professional. The policy specifies that personal and family histories must be evaluated by a Medical Geneticist, Genetic Counselor, or an Advanced Practice Nurse in Genetics (APGN) as part of the coverage determination.

A family history that is strongly suggestive of a genetic etiology (including consanguinity or multiple affected relatives) is one of the qualifying features that supports a likelihood of genetic disease and helps meet the policy criteria for sequencing.

The policy requires that for standard exome sequencing the member has not previously had genome sequencing; prior GS excludes standard ES coverage. Conversely, the policy permits standard genome sequencing when prior exome sequencing was uninformative and reanalysis of ES is not possible (i.e., GS can be covered to evaluate previously uninformative ES results if ES reanalysis cannot be performed).

When ordering standard ES or GS, documentation must include prior testing status and whether reanalysis of prior data was attempted or is feasible, per the policy’s prior-testing requirements.

No top-level eligibility nodes are defined for this placeholder entry.

Not Covered / Investigational

The policy lists specific exclusions under which testing is not covered: repeat standard exome or genome sequencing is considered investigational and is not covered, and screening of asymptomatic or healthy individuals with ES/GS is investigational and not covered.

Providers should not submit claims for routine repeat ES/GS or for population/screening use of exome/genome sequencing, as these are outside the scope of medically necessary indications in the policy.

Clinical scenarios that clearly match a well-described syndrome for which targeted single-gene or focused multi-gene panel testing is available are not covered for ES/GS; the policy specifies that targeted testing is preferred in these cases.

Before ordering ES/GS, clinicians should confirm that syndrome-directed or panel testing is not the appropriate, available option; if a targeted test exists and explains the presentation, ES/GS should not be used as first-line testing.

Definitions

Exome sequencing (ES/WES) — sequencing and CNV analysis of protein-coding regions (~1% of genome)

DefinitionExome sequencing (ES/WES) sequences protein-coding regions (exons) and includes CNV analysis; the exome is ~1% of the genome and contains ~85% of heritable disease-causing variants.

Common CPT codes81415, 81416, 0214U, 0215U (standard/rapid exome codes referenced in policy).

Analytic scopeDetects single-nucleotide variants, small indels, and many CNVs within coding regions but may miss noncoding and some structural variants detectable by GS.

Clinical roleUsed to diagnose suspected genetic disorders when phenotype suggests a likely genetic etiology and targeted testing is not appropriate or has been unrevealing.

Genome sequencing (GS/WGS) — sequencing of coding and noncoding regions; improved detection of CNVs, indels, repeat expansions, structural variants

Background

Exome sequencing targets the protein-coding regions of the genome (the exome), which comprise approximately 1% of the human genome but account for a majority of known heritable disease-causing variants; ES evaluates coding exons and can include CNV analysis.

Genome sequencing sequences both coding and noncoding regions across the entire genome and has broader detection capabilities than ES, including improved detection of copy-number variants, mid-size insertions/deletions, repeat expansions, intronic and regulatory variants, and structural variants—making GS more comprehensive for detecting genetic causes that ES may miss.

References and Evidence

Policy Summary

PayerCommunity Health Plan Washington

PolicyExome and Genome Sequencing for the Diagnosis of Genetic Disorders

Policy CodePolicy N/A

Change TypeModified clinical criteria, coding updates, and reanalysis timing

Effective DateN/A

Next Review DateN/A

Key ActionObtain prior authorization with clinical justification and required documentation (including evaluation by a Medical Geneticist or Genetic Counselor) when ordering ES/GS or reanalysis.

SourceLink

On This Page

F. Rapid ES clinical findings (at least one): The member/enrollee meets at least one of: 1) unexplained epilepsy; OR 2) global developmental delay; OR 3) at least one congenital anomaly (functional and/or structural); OR 4) at least TWO of the following specified features: 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

Global developmental delay or intellectual disability

Global developmental delay or intellectual disability — definitions and age/diagnosis thresholds:

Global developmental delay (GDD): Defined for children under age five as significant delay (at least two standard deviations below the mean) in at least two developmental domains (gross/fine motor, speech/language, cognition, social/personal, activities of daily living).

Intellectual disability: Defined per DSM-5 and diagnosed by age 18; qualifies for testing if features consistent with policy criteria are present.

Multiple congenital anomalies affecting unrelated organ systems

Multiple congenital anomalies affecting unrelated organ systems — qualifying indication:

Qualifier: Presence of multiple congenital anomalies affecting unrelated organ systems qualifies as an indication for standard or rapid exome/genome sequencing when other criteria (alternate etiologies considered, presentation not fitting a well-described syndrome, and genetics professional evaluation) are met.

Acutely ill infants with suspected genetic etiology where rapid results may affect management

Acutely ill infants with suspected genetic etiology where rapid results may affect management (e.g., NICU/PICU):

Acutely ill infant criteria: Rapid sequencing is considered when the etiology is unknown and a genetic cause is likely based on PLUGS criteria (e.g., multiple congenital anomalies, epileptic encephalopathy, or two other qualifying features), alternate etiologies have been considered, and rapid sequencing is more efficient/economical than separate tests.

NSIGHT2 and PLUGS evidence support rapid sequencing in ICU infants; trials often included infants up to four months, but policy rapid ES criteria specify 12 months or younger.

Literature references supporting use of ES/GS for pediatric congenital anomalies, ID, hearing loss, unexplained epilepsies, rare disease evaluation

References supporting clinical use of exome/genome sequencing:

Literature support: Selected references supporting use of ES/GS for pediatric congenital anomalies, intellectual disability, hearing loss, unexplained epilepsies, and rare disease evaluation include ACMG guidance (Manickam et al.), NSIGHT2 trial (Kingsmore et al.), and analyses of VUS rates and reanalysis utility (Rehm et al., Tan et al., Manickam et al.).

See policy References section for full citations (References 5–13).

Documentation Required

Coverage subject to benefit documents and contractual requirements

Follow the member’s benefit documents and applicable state/federal rules when determining coverage. This policy guides medical‑necessity determinations but is not a guarantee of payment; approvals remain subject to contract terms, exclusions, and administrative policies.

Verify eligibility and any plan‑specific exclusions or limits before ordering or submitting prior authorization.
If coverage is denied, denial reasons may include contractual exclusions, benefit limits, or lack of documentation supporting medical necessity.

Step Therapy

Prefer targeted testing when appropriate; ES/GS when phenotype warrants

Use targeted single‑gene or focused multi‑gene panel testing first when the clinical presentation fits a well‑described syndrome for which such testing is available and likely to provide diagnosis. ES/GS is preferred when the phenotype is heterogeneous or prior targeted testing was non‑diagnostic.

If a recognizable syndrome has a validated single‑gene or small panel test, document why targeted testing is insufficient before requesting ES/GS.
When PLUGS/NSGC guidance supports first‑tier comprehensive testing (e.g., unexplained epilepsy), include rationale if requesting ES/GS as initial test.

Denial Risk

Investigational uses and repeat testing

Repeat standard ES or GS is considered investigational and will typically be denied unless the request meets investigational-to-covered transition criteria (e.g., prior test unavailable for reanalysis and new, qualifying findings are present and documented). Requests that do not meet the policy’s clinical criteria or that request repeat testing without justification are likely to be declined.

Repeat ES/GS (same test type): investigational unless documentation demonstrates reanalysis impossible and new qualifying clinical information supports benefit.
Requests lacking documentation that alternate (non‑genetic) etiologies were considered and ruled out may be denied.
Screening of asymptomatic/healthy individuals is investigational and will be denied.

Documentation Required

Genetics professional involvement and counseling recommended

Ensure orders for ES/GS and reanalysis are supported by evaluation from an appropriate genetics professional when required by the policy: Medical Geneticist, Genetic Counselor, or Advanced Practice Genetic Nurse (APGN). Pre‑ and post‑test genetic counseling is strongly recommended to address secondary findings and result return plans.

Document the genetics professional who evaluated the member (name, credentials, and date of evaluation) in the prior authorization submission.
Include counseling notes or plan for return of secondary/incidental findings when available.

Rapid exome/genome sequencing (rES/rGS) — accelerated sequencing with preliminary results typically <7 days and final report within two weeks

DefinitionRapid exome/genome sequencing (rES/rGS) is accelerated sequencing with preliminary results typically returned in <7 days and a final report within two weeks.

Primary useIntended for acutely-ill infants or other critically ill individuals where timeliness of diagnosis may alter acute medical or surgical management.

Trio preferenceTrio testing (proband plus parents) is preferred whenever possible; testing one available parent is a valid alternative.

Typical clinical impactAllows more rapid identification of genetic diagnoses to shorten the diagnostic odyssey and guide urgent care decisions.

Global developmental delay (GDD) — definition: delay >=2 SD below mean in at least two developmental domains

Operational definitionGlobal developmental delay (GDD) is defined as significant delay (≥2 standard deviations below the mean) in at least two developmental domains (gross/fine motor, speech/language, cognition, social/personal, or activities of daily living).

Age contextGDD is used to describe children under age 5; intellectual disability per DSM-5 is diagnosed by 18 years.

Relevance to coveragePresence of GDD affecting ≥2 domains is a qualifying clinical finding for exome or genome sequencing under the policy.

Rapid genome/exome sequencing (rGS/rES) — expedited genomic sequencing for acutely ill individuals when timeliness matters

DefinitionRapid genome/exome sequencing (rGS/rES) is expedited genomic sequencing for acutely ill individuals (often infants) when a genetic diagnosis is suspected and timeliness is expected to impact acute management.

Typical eligibilityPolicy rapid sequencing criteria apply to acutely-ill infants (e.g., ≤12 months for rES) or other critically ill patients meeting PLUGS/NSGC criteria.

Coverage considerationsRapid sequencing is covered when rapid testing is more efficient and economical than sequential single-gene or panel testing and when alternate etiologies have been considered.

Clinical triggersQualifying features include multiple congenital anomalies, epileptic encephalopathy, or two of a list including organ system abnormality, complex neurological symptoms, suggestive family history, lab findings for inborn errors of metabolism, or abnormal response to standard therapy.