UnitedHealthcare WES/WGS Coverage Update

Coverage Criteria and Evidence

WES/WGS (Initial) — Covered when ALL of the following are met

Covered when ALL of the following are met:

Overall requirements: The affected individual displays signs or symptoms of an undiagnosed or unexplained disorder with a suspected genetic cause; test results are intended to directly impact the individual's medical management; the clinical presentation does not fit a Well-Delineated Genetic Syndrome or disorder for which a specific test or Targeted Panel is available (if a specific genetic syndrome is suspected, a single gene or Targeted Panel should be performed prior to determining if WES or WGS is necessary); and the test is ordered by a medical geneticist, neonatologist, neurologist, immunologist, or developmental pediatrician.

Clinical presentation option A: One or more of: Multiple Congenital Anomalies affecting at least two different organ systems; Intellectual Disability characterized as moderate, severe, or profound, diagnosed by 18 years of age; Global Developmental Delay; Epileptic Encephalopathy with onset before three years of age.

Clinical presentation option B: Two or more of: Congenital Anomaly; Significant hearing or visual impairment diagnosed by 18 years of age; laboratory abnormalities suggestive of an inborn error of metabolism; Autism Spectrum Disorder; Neuropsychiatric condition (e.g., bipolar disorder, schizophrenia, obsessive-compulsive disorder); Hypotonia or hypertonia in infancy; Dystonia, ataxia, hemiplegia, neuromuscular or movement disorder, or other serious neurologic abnormality; Unexplained developmental regression, unrelated to Autism Spectrum Disorder or epilepsy; Growth abnormality (e.g., failure to thrive, short stature, microcephaly, macrocephaly, or overgrowth); Persistent and severe immunologic or hematologic disorder; Dysmorphic features; Consanguinity; Other first- or second-degree family member(s) with similar clinical diagnosis.

Non-concurrent Comparator Analysis — Covered when BOTH are met

Covered when BOTH of the following are met:

Non-concurrent comparator: The affected individual meets the above criteria for WES or WGS; and WES or WGS has been previously performed on the affected individual.

Reanalysis of WES/WGS — Covered when ALL are met

Covered when ALL of the following are met:

Reanalysis: At least 18 months have passed since the initial WES or WGS was performed; the affected individual meets the above criteria for WES or WGS; and either (a) the affected individual experiences additional unexplained symptoms after initial testing that cannot be explained by the initial results, or (b) new data or new family history emerges which suggests a link between the individual's symptoms and specific genes.>=18 months

Prenatal WES — Covered when ALL are met

Prenatal WES is proven and medically necessary when ALL of the following are met:

Prenatal WES: Chromosome microarray analysis and/or karyotyping has been performed but was uninformative; WES is ordered by or in consultation with a medical geneticist or maternal-fetal medicine specialist (perinatologist); the specimen is obtained from amniotic fluid and/or chorionic villi, or DNA is extracted from fetal blood or tissue; and the fetus has one or more of the following: multiple Congenital Anomalies affecting at least two different organ systems, fetal hydrops of unknown etiology, or a Congenital Anomaly affecting a single organ system with family history that suggests a genetic etiology.

Not Medically Necessary / Unproven

Unproven indications: WES and WGS are unproven and not medically necessary for other indications not meeting the above criteria, including evaluation of fetal demise, prenatal testing via cell-free fetal DNA, and preimplantation genetic testing (PGT) in embryos; rapid/ultra-rapid WES/WGS (rWES, rWGS, urWGS) is unproven and not medically necessary for outpatient settings; whole transcriptome sequencing, epigenetic signature analysis, and optical genome mapping (OGM) are considered unproven and not medically necessary for any indication due to insufficient evidence of efficacy.

Evidence summaries and implications

Evidence-based findings and implications from systematic reviews, meta-analyses, and cohort studies

Comparative diagnostic yield: Systematic reviews and meta-analyses report that genome sequencing (GS) can identify additional diagnoses after negative exome sequencing (ES) (pooled GS-specific yield ~7.0% in some cohorts), and ES reanalysis can yield additional diagnoses with yields that may be comparable to GS in certain settings; evidence shows variability across studies and phenotypes.

Supports consideration of GS after negative ES and underscores value of ES reanalysis

Populations with higher demonstrated yield: Trio-based testing and combined approaches (e.g., trio-WES plus CNV-seq) demonstrate higher diagnostic yields, particularly in children with neurodevelopmental disorders, global developmental delay, and severe phenotypes (e.g., reports of 48.9% and 61% diagnostic yields in selected cohorts).

Trio testing and CNV analysis increase yield

Clinical utility evidence variability: Clinical utility (changes in management) is reported in subsets of studies with heterogenous quality; pooled analyses indicate higher diagnostic yields in pediatric populations versus adults and variable evidence for outcome impact across indications.

Study-derived indications and observed diagnostic yields

Study-based findings — reported diagnostic yields and contexts where ES/WGS showed incremental benefit

NDD/Developmental indications: Meta-analyses and cohort studies report high diagnostic yields for ES in neurodevelopmental disorders (e.g., overall ES yield ~36% and higher in NDD with associated conditions), supporting ES as a first-tier test in many unexplained pediatric NDD cases.

Prenatal skeletal abnormalities: Systematic reviews report very high additional detection rates of ES for fetal skeletal abnormalities after normal karyotype/CMA (e.g., pooled additional detection ~63%), with phenotype-specific subgroup yields up to ~85%.

Prenatal - apparently normal phenotype after standard testing: Studies of prenatal ES in fetuses with apparently normal phenotype after normal karyotype/CMA report very low incremental yields (pooled ~1.6%), and authors advise against routine use in this group pending more evidence.

Prenatal CNS anomalies:

Prenatal/genetic diagnostic criteria

Coverage-related conclusions and criteria reflected in the referenced evidence and guideline statements

Prenatal WES/WGS after normal CMA/karyotype: Consider fetal WES or WGS when (1) fetal structural anomalies are present and (2) standard prenatal testing including CMA and karyotype is nondiagnostic, and (3) multidisciplinary review suggests a likely monogenic etiology; diagnostic yield varies by phenotype (approximately 2%–53%) and is higher in multisystem anomalies.see diagnostic yield by phenotype

Supported by systematic reviews showing ~31% pooled incremental yield overall

Rapid sequencing for critically ill infants: Rapid WES/WGS and ultra-rapid WGS are supported in critically ill hospitalized infants where rapid diagnosis may change acute management (pooled diagnostic yields around 42%); outpatient rapid sequencing is not supported by current evidence.inpatient/critically ill setting

Reanalysis recommendations:

Rapid sequencing (rWES/rWGS/urWGS)

Rapid/ultra-rapid genomic sequencing

Use in critically ill infants: rWES, rWGS, and urWGS are supported for use in critically ill hospitalized infants where rapid diagnosis may affect acute management, with pooled diagnostic yields around 42% and evidence of higher yields and faster turnaround for urWGS in some trials; use in outpatient settings is not supported by current evidence.inpatient/critically ill setting

Reanalysis

Reanalysis of prior ES/WGS data

Periodic reanalysis of ES/WGS data is recommended/valuable because it increases diagnostic yield (studies report additional diagnoses ranging from ~2% to >20% in various cohorts); reanalysis is reasonable at intervals (e.g., at least 18 months) or sooner if new phenotype or family history emerges.intervals >=18 months suggested

Supports reanalysis policy criteria

Ancillary genomic technologies

Other sequencing and mapping technologies

Whole transcriptome sequencing (RNAseq/TS): Insufficient evidence to support routine clinical use of whole transcriptome sequencing for constitutional genetic disorders; it may be useful as a second-tier test to resolve select unexplained cases when tissue expression is informative.

Limited by tissue-specific expression and small studies

Optical genome mapping (OGM): Optical genome mapping currently has insufficient evidence to support clinical use for any indication despite promising concordance with standard assays in small studies; additional development and clinical utility studies are needed.

Epigenetic signature analysis (episignature): Epigenetic signature analysis is considered unproven and not medically necessary for general use due to insufficient evidence, though it may aid diagnosis in selected referrals where validated episignatures exist.

ACMG: Pediatric and congenital anomalies

ACMG recommendations for WES/WGS use

ACMG first- or second-tier: ACMG recommends WES and WGS as a first- or second-tier test for individuals with one or more congenital anomalies with onset prior to one year of age or for individuals with developmental delay/intellectual disability with onset prior to 18 years of age.age-based onset thresholds

Prenatal: ISPD and ACOG positions

Prenatal sequencing guidance

ISPD prenatal indications: ISPD supports prenatal genome-wide sequencing in cases of a current pregnancy with a major single anomaly or multiple organ system anomalies when CMA/karyotype is nondiagnostic or when multiple-anomaly patterns strongly suggest a single-gene disorder; CMA should be run before or in parallel with prenatal WES in these cases.post-CMA or parallel testing

ACOG stance: ACOG does not recommend routine use of WES/WGS for prenatal diagnosis outside clinical trials but acknowledges WES may be reasonable in certain prenatal cases (e.g., fetuses with multiple anomalies) when standard testing fails to provide a diagnosis.context of clinical validation

Epilepsy: ILAE, NICE, NSGC

Epilepsy genetic testing recommendations

ILAE recommends WES or WGS (including CNV analysis) as first-line testing in most cases of genetic epilepsy and advises periodic reanalysis for individuals without a molecular diagnosis; recommended indications include severe childhood-onset epilepsies, epilepsy with intellectual disability or autism, progressive myoclonus epilepsies, and related presentations.clinical suspicion of genetic epilepsy

NICE recommends considering WGS for individuals with epilepsy of unknown cause with early onset (<2 years) or in certain early-onset cases per multidisciplinary recommendation, and recommends discussing uncertainties with genetics specialists.age and clinical features

NSGC strongly recommends genetic testing with WES/WGS and/or multi-gene panels (>25 genes) as first-tier testing for unexplained epilepsy, followed by CMA; testing should be ordered and interpreted by qualified providers with comprehensive counseling.panel size or WES/WGS preference

Laboratory accreditation and validation

Laboratory and quality recommendations

ESHG and laboratory standards: Diagnostic WGS and other NGS approaches should be performed in accredited laboratories with acceptable validation; introduction of WGS is recommended when it improves quality, efficiency, or diagnostic yield; research results should be confirmed in diagnostic laboratories.laboratory accreditation and validation

Coverage criteria (summary of revisions)

Policy revisions clarify when WES/WGS and reanalysis are considered proven and medically necessary and adjust several specific criterion wordings.

Reanalysis of WES/WGS: Reanalysis is proven and medically necessary when at least 18 months have passed since the initial testing and the affected individual meets the listed criteria for WES/WGS or experiences additional unexplained symptoms following initial testing; timing threshold revised to 'at least 18 months'.>=18 months

Reanalysis criteria revised in policy history

Prenatal WES specimen and phenotype: Prenatal specimen requirements and phenotype criteria clarified: specimen must be obtained from amniotic fluid and/or chorionic villi or DNA extracted from fetal blood or tissue; fetus must have multiple congenital anomalies affecting at least two different organ systems or a single-organ congenital anomaly with family history suggesting genetic etiology.

Prenatal criteria language revised

This policy applies only to non-oncology whole exome sequencing (WES) and whole genome sequencing (WGS) performed in an outpatient setting or upon discharge from an inpatient stay. Services performed exclusively for cancer evaluation follow separate UnitedHealthcare oncology molecular testing policies. The policy’s medical necessity criteria must be met for coverage; documentation in the medical record should support that the member meets the listed clinical criteria and that results are intended to directly impact medical management. (See policy Coverage Rationale and Documentation sections.)

Hayes’ clinical utility review found insufficient or very low-quality evidence to support WES or WGS for certain adult diagnostic populations — for example, adults with suspected neuromuscular or movement disorders — and noted limited evidence for some other indications. Use of WES/WGS for these low-evidence indications may not demonstrate clinical utility and could be a basis for denial when documentation does not show likely benefit.

Prenatal exome sequencing (prenatal ES/WES) may be medically necessary when fetal structural anomalies are present and standard prenatal testing (karyotype and/or CMA) is nondiagnostic and the case is ordered by or in consultation with a medical geneticist or maternal–fetal medicine specialist. However, systematic reviews show very low incremental yield when prenatal ES is performed in fetuses with an apparently normal phenotype after normal CMA/karyotype (~1.6% pooled incremental yield), and authors advise against routine use in pregnancies without a medical indication pending further research.

Rapid and ultra‑rapid sequencing (rWES, rWGS, urWGS) have demonstrated value in critically ill, hospitalized neonates and infants but the available evidence does not support their routine use in outpatient settings. Accordingly, rapid/ultra‑rapid sequencing in outpatient (non‑critically ill) contexts is considered unproven and not medically necessary. Similarly, broader adoption of expedited sequencing for outpatient indications should be supported by clinical evidence that demonstrates improved management or outcomes.

Professional guidance from ACOG states that the routine use of prenatal WES/WGS is not recommended outside clinical trials until sufficient validation data are available; however, WES may be reasonable in selected prenatal cases (for example, fetuses with multiple anomalies) after nondiagnostic standard testing and multidisciplinary review. This policy aligns with those positions by reserving prenatal WES for prenatally anomalous fetuses after CMA/karyotype are uninformative and when ordered by appropriate specialists.

Epigenetic signature (episignature) testing is currently being studied but the evidence base is limited to selected conditions with validated episignatures. Per the revised policy language and current evidence assessments, epigenetic signature analysis is considered unproven and not medically necessary for any indication at this time.

The policy does not routinely support several emerging technologies or uses: rapid/ultra‑rapid WES/WGS for outpatient indications, whole transcriptome sequencing (RNAseq/TS) for routine constitutional genetic diagnosis, optical genome mapping (OGM), and broad epigenetic signature analysis are considered unproven and not medically necessary because current evidence of clinical utility is insufficient. These technologies may be investigational or appropriate only in research or highly selected cases where clinical validity and utility have been demonstrated.

Some clinical scenarios lack adequate evidence to support routine WES/WGS coverage. Hayes and other reviews identified insufficient or very low‑quality evidence for indications such as Autism Spectrum Disorder (ASD) in isolation, adult neuromuscular or movement disorders, and isolated intellectual disability in adults; therefore these indications are not routinely supported unless additional clinical factors or documentation indicate likely diagnostic benefit and direct impact on management.

Evidence synthesis shows that prenatal ES yields are strongly dependent on phenotype. For fetuses with an apparently normal phenotype who have already had a normal CMA and karyotype, pooled incremental diagnostic yield is very low (approximately 1.6% pooled incremental yield), and routine prenatal ES in this population is not supported. Prenatal ES is most informative when performed for fetuses with structural anomalies, particularly multisystem anomalies, after non‑diagnostic standard testing.

Rapid sequencing approaches (rWES/rWGS/urWGS) have established utility primarily in inpatient, critically ill neonates and infants where rapid turnaround may change acute management. Rapid sequencing is not supported in outpatient, non‑critically ill settings due to lack of evidence demonstrating benefit in that context. Requests for outpatient rapid sequencing should be expected to face coverage review and potential denial unless compelling clinical justification is provided.

Optical genome mapping (OGM) has shown promising analytic concordance with standard cytogenetic assays in small proof‑of‑principle studies but lacks sufficient clinical utility data. The policy therefore treats OGM as unproven and not medically necessary for routine clinical use until larger validation and outcome studies demonstrate clinical benefit.

Summary index: applicable sequencing and related procedure codes that may be used to bill for covered and noncovered genomic services are listed in the Coding section. Codes include current CPT/PLA entries for exome and genome sequencing, comparator exomes/genomes, reanalysis, rapid and ultra‑rapid sequencing, transcriptome assays, optical genome mapping, and related procedure codes. Refer to the Coding table for the full list of specific codes and descriptions.

Applicable Codes: No additional or alternate code groupings are listed in this section beyond those provided in the main coding table; see the coding index for the complete set of procedure codes referenced by this policy.

When Testing Is Covered

Undiagnosed or unexplained disorder with suspected genetic cause when results will directly impact medical management and presentation meets the policy's clinical criteria (see criteria_sets).

Undiagnosed disorder impacting management: Undiagnosed or unexplained disorder with suspected genetic cause when results will directly impact medical management and presentation meets the policy's clinical criteria (see criteria_sets).

Ordering provider types and detailed phenotype criteria are specified in the initial coverage criteria.

Prenatal WES for fetal anomalies when CMA/karyotype uninformative and ordered by/with medical geneticist or MFM specialist.

Prenatal WES requirement: Prenatal WES for fetal anomalies is covered when CMA and/or karyotype are uninformative and testing is ordered by or in consultation with a medical geneticist or maternal-fetal medicine specialist; specimen requirements and phenotype criteria must be met.

See prenatal criteria for specimen types and phenotype thresholds (e.g., >=2 organ systems or single-system anomaly with suggestive family history).

Ordering, Documentation, and Provider Responsibilities

Prior Authorization

Prior Authorization and Tools

Prior authorization may be required for WES/WGS per the member's benefit contract and UnitedHealthcare administrative tools. Providers should check applicable medical policy exceptions, plan-specific prior authorization requirements, and use any available utilization management tools (eg, online portals or third‑party criteria such as InterQual®) before ordering testing.

Prior authorization requirement is contract-dependent — verify member benefits and obtain authorization when required.
Use available prior authorization portals and third‑party tools (eg, InterQual®) to support requests.

Denial Risk

Potential Denial Risk for Low‑Evidence Indications

Requests for WES/WGS for indications lacking sufficient evidence (eg, outpatient rapid sequencing, routine screening, prenatal testing without prior CMA/karyotype when indicated, or other uses listed as unproven) may be denied. Lack of supporting clinical documentation or mismatch between the care setting and the test type (eg, outpatient use of rapid sequencing technologies intended for critically ill inpatients) increases denial risk.

Services Considered Not Medically Necessary or Unproven

Not covered (examples): WES/WGS for fetal demise evaluation; prenatal testing via cell‑free fetal DNA for purposes of WES/WGS; preimplantation genetic testing (PGT) in embryos; rapid/ultra‑rapid WES/WGS used in outpatient settings; whole transcriptome sequencing for routine constitutional testing; optical genome mapping (OGM); and broad epigenetic signature analysis. These uses are described in the policy as unproven or not medically necessary due to insufficient evidence of clinical utility.

Both optical genome mapping and epigenetic signature (episignature) analysis are discussed as technologies currently under study. While OGM has demonstrated analytic concordance in small series, and episignature testing has diagnostic yield in selected cohorts, the evidence is not yet sufficient to establish routine clinical use; the policy therefore classifies both as not established and not medically necessary for routine indications.

Prenatal exome sequencing for fetuses with an apparently normal phenotype after a normal CMA and karyotype demonstrates very low incremental yield in pooled studies (~1.6% incremental yield) and is not supported for routine clinical use. Prenatal sequencing is supported when fetal structural anomalies are present and prior standard testing is nondiagnostic, and when testing is ordered or reviewed by appropriate specialists.

Routine outpatient use of rapid sequencing and several emerging tests is not supported by current evidence. Rapid/ultra‑rapid sequencing is supported for inpatient critically ill infants but not for outpatient, non‑critically ill indications. Similarly, whole transcriptome sequencing, optical genome mapping, and broad epigenetic signature analysis lack sufficient evidence of clinical utility for routine outpatient coverage.

Professional society guidance from ACOG explicitly advises against routine prenatal WES/WGS outside of research or clinical trial contexts until adequate validation data exist; the policy reflects that stance by limiting routine prenatal sequencing to fetuses with anomalies and after nondiagnostic standard testing, and by requiring specialist involvement for prenatal orders.

Applicable Codes and Billing Notes

Applicable sequencing and related procedure codesmixed

0094U	Genome (e.g., unexplained constitutional or heritable disorder or syndrome), rapid sequence analysis.
0212U	Rare diseases (constitutional/heritable disorders), whole genome 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.
0213U	Rare diseases (constitutional/heritable disorders), whole genome 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 genome (e.g., parent, sibling).
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 (e.g., parent, sibling).
0260U	Rare diseases (constitutional/heritable disorders), identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping.
0264U	Rare diseases (constitutional/heritable disorders), identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping.
0265U	Rare constitutional and other heritable disorders, whole genome and mitochondrial DNA sequence analysis, blood, frozen and formalin-fixed paraffin-embedded (FFPE) tissue, saliva, buccal swabs or cell lines, identification of single nucleotide and copy number variants.
0266U	Unexplained constitutional or other heritable disorders or syndromes, tissue-specific gene expression by whole-transcriptome and next-generation sequencing, blood, formalin-fixed paraffin-embedded (FFPE) tissue or fresh frozen tissue, reported as presence or absence of splicing or expression change.
0267U	Rare constitutional and other heritable disorders, identification of copy number variations, inversions, insertions, translocations, and other structural variants by optical genome mapping and whole genome sequencing.

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Applicable Codesmixed

No codes listed

inv-30: Reanalysis interval — At least 18 months since initial WES or WGS

Reanalysis intervalAt least 18 months since initial WES or WGS

Condition for reanalysisAffected individual must meet the policy criteria for WES or WGS

Triggering eventsAdditional unexplained symptoms after initial testing or new data/family history suggesting gene link

inv-31: Reanalysis interval (policy wording) — at least 18 months since the initial WES or WGS was performed

Policy wording (timing)Reanalysis is appropriate when at least 18 months have passed since the initial WES or WGS was performed

Policy wording (eligibility)

Definitions

inv-57: Whole Exome Sequencing (WES) definition

DefinitionWhole Exome Sequencing (WES) is a DNA analysis technique that sequences the exome — the protein-coding regions (exons) of the genome — where most known disease-causing variants are found

ScopeSequences ~1–2% of the genome (all exons) to identify single-nucleotide variants and small indels

Clinical noteWES generates many variants and interpretation depends on laboratory analytic and interpretive quality

inv-58: Whole Genome Sequencing (WGS) definition

DefinitionWhole Genome Sequencing (WGS) determines the order of all nucleotides in an individual's DNA, detecting variations across coding and noncoding regions including CNVs and structural variants

Scope

Member Eligibility and Criteria Notes

Eligibility requirements for coverage align with the policy’s clinical criteria and documentation expectations. Providers should ensure medical records clearly document the member’s clinical presentation, prior testing, and the intended impact of results on medical management. Specific eligibility rules and prior authorization requirements may vary by benefit plan and should be confirmed with plan administrators or prior authorization tools.

Providers must supply detailed clinical documentation including history, physical examination findings, and results of prior diagnostic tests (for example, CMA/karyotype for prenatal cases) to demonstrate that policy clinical criteria are met. Documentation should be legible, maintained in the patient record, and made available upon request to support coverage determinations.

When a Well‑Delineated Genetic Syndrome is suspected, the policy requires that a single‑gene test or a targeted multi‑gene panel be performed prior to WES/WGS if a specific diagnostic test is available; documentation of this stepwise approach should be included in the medical record.

For prenatal WES requests, providers should confirm prior non‑diagnostic chromosome microarray analysis and/or karyotype results and provide evidence of multidisciplinary review (e.g., genetics and maternal‑fetal medicine) indicating a suspected monogenic etiology when appropriate. Failure to document prior testing and specialist involvement may lead to coverage denial.

Reanalysis eligibility requires that at least 18 months have passed since the initial WES or WGS and that the member either develops additional unexplained symptoms or new data (including family history) emerges that could alter interpretation; providers should document the time since initial testing and the rationale for reanalysis.

Ordering practitioners should be qualified clinicians experienced in genetic testing and interpretation (e.g., medical geneticist, neonatologist, neurologist, immunologist, developmental pediatrician); prenatal orders must involve a medical geneticist or maternal‑fetal medicine specialist. The ordering clinician should attest to the intended clinical impact of test results.

Background and Rationale

Background: Whole Exome Sequencing (WES) targets the protein‑coding regions (exons), which represent roughly 1%–2% of the genome but contain the majority of known disease‑causing variants. Whole Genome Sequencing (WGS) determines the sequence of the entire genome, enabling detection of variants in coding and noncoding regions as well as copy number and structural variants. Both approaches generate variants of uncertain significance and rely on laboratory analytic and interpretive quality; test selection should be driven by clinical presentation and the diagnostic question.

Policy Revision History

2026-04-01policy_revisionLatest

Multiple substantive coverage revisions: added recommendation for genetic counseling prior to WES/WGS; declared epigenetic signature analysis unproven and not medically necessary; clarified outpatient applicability language; explicitly included WES/WGS 'with or without concurrent Comparator Analysis' in proven/medically necessary statement; removed prior requirement that WGS coverage required prior CMA or WES be not performed or nondiagnostic; revised several coverage criterion wordings (including phrasing about intended impact on medical management, Well-Delineated Genetic Syndrome, and organ-system criteria).

2026-04-01policy_revision

Clarified reanalysis criteria and timing: reanalysis of WES/WGS is proven and medically necessary when listed criteria are met and at least 18 months have passed since the initial WES or WGS was performed; refined language about additional unexplained symptoms or new data prompting reanalysis.

OpenPayer

Whole Exome and Whole Genome Sequencing (Non-Oncology Conditions) (for Tennessee Only)